ABSTRACT
Countries’ national drug policies include all key stakeholders (pharmacists, physicians, pharmaceutical firms, and patients) in the public, the private sector, and the field of pharmacy. The aim of this study was to outline pharmaceutical patents and data protection, orphan drugs, drug pricing, and surplus goods regarding pharmacoeconomics, promotions, inspections in the pharmaceutical industry, and policies in pharmacies with respect to buying and selling drugs, and to discuss ethics in particular.
Written laws in force relating to drugs in Turkey constitute the materials of this study.
Essential medicines must always be accessible. Both governments and pharmaceutical companies must fulfill the obligations imposed on them in an ethical way. Research and development activities must also be carried out for orphan drugs. While pricing drugs, authorities must take pharmacoeconomic evaluations into account.
Drugs must be accessible and in the first grade at all times under all circumstances because a product cannot replace it. The concept of surplus goods should be revised to ensure the common needs of the pharmaceutical industry, warehouses, and pharmacies. Promotions in the field by the pharmaceutical industry should be made based on scientific evidence in an ethical way. Inspectors should perform meticulous pharmaceutical industry inspections.
Keywords: Drug pricing, ethics, health policies, patient rights, pharmaceutical industry, pharmacists
INTRODUCTION
EXPERIMENTAL
CONCLUSION
The drugs patent protection regime brought to drugs with the TRIPS Agreement is encouraging the pharmaceutical industry at the point of original drug discovery. However, obstacles related to the protection of the right to health and access to essential medicines should not be overlooked. The problems of developing countries regarding access to essential medicines must be remedied. Governments must find the necessary solutions related to these issues, and essential medicines must always be accessible by the public. Governments and the pharmaceutical companies must fulfill the ethical obligations imposed on them. Pharmaceutical companies should perform R&D for profitable diseases and orphan drugs, and they have to conduct studies for health problems in developing countries. In the clinical research processes of orphan drugs yet to receive regulatory approval, utmost importance should be given to ethical principles in the implementation supply to people with severe illnesses. At this point, moral principles such as informed consent, respect for autonomy, beneficence, and non-maleficence are becoming crucial.
Regarding our national interests and pharmacoeconomic terms, choosing the cheapest between drugs with the same efficacy as a reference for pricing drugs is a logical and consistent action for our economic interests. If the RPS is applied, currency differences with the countries concerned should be arranged taking available national resources and pharmacoeconomic considerations into account. There must be no problem regarding the supply of essential drugs of foreign origin. Essential medicines should always be accessible in our country.
The Turkish drug industry should be supported, and more resources should be transferred to R&D activities. R&D activities must be conducted regarding biologic medicines, biosimilar products, and biotechnology products, which are of increasing importance in the world. The supply of surplus drugs should be rearranged to provide a common ground for the pharmaceutical industry, pharmaceutical warehouses, and pharmacies. As a result of pharmacoeconomic evaluations, if there is a generic equivalent drug having a lower price, it must be chosen and provided to the patient.
In the Turkish pharmaceutical industry, promotions should not only be for profit purposes and should not be conducted by non-qualified people. Drug promotions should be made based on scientific evidence and in an ethical manner by qualified product promotion members who have received a qualification certificate.
Inspections of the pharmaceutical industry must be performed by inspectors who are extremely well informed regarding all aspects of drug manufacturing through to delivering products to patients. Thus, various problems may be fixed during the manufacturing processes. Also, inspectors must comply with ethical principles during inspections. It is crucial to carefully follow whether deficiencies have been fixed owing to the fundamental requirement that drugs must always be top-grade quality.
Patent types in the pharmaceutical industry
Human rights and intellectual property rights
Right to health and medical care as a human right
Situation in poor countries, global-scale problem
Drug-research and development orientation
Rare diseases-orphan drugs
Drug pricing and surplus drugs
Promotions and inspections in the pharmaceutical sector
Ethics
Drug patents
In Turkey, there is Industrial Property Law.18 The protection provided to medical and veterinary pharmaceutical manufacturing processes and product patent certificates began on January 1, 1999. The use of magistral drugs is beyond the scope of patent rights. Information and test results, whose creation and accumulation requires a significant effort, expense and whose owners did not disclose to the public, are requested by the related authorities for certification of manufacturing and sales licenses of a patent application. Information on veterinary and agricultural drugs shall be kept confidential by the requesting authority. The authority requesting information and test results shall take the necessary measures to prevent their unlawful use. The duration of the patent given by examination is twenty years starting from the application date and cannot be extended. The duration of patents given without examination is seven years. If the review request is performed within seven years and at the end of this period if it is decided to award a patent, the patent duration will be integrated to twenty years starting from the application date. The patent owner or the authorized person must use the invention protected by patent. The obligation for use is within three years from the announcement of the patent award in critical bulletins. In the evaluation of use, market conditions are taken into consideration. Patents can be converted into compulsory licenses if patent-related inventions are not used and are subject to public interest. A compulsory license is a legal right granted by the Government without the permission of the patent holder to benefit from the patent.19
In Turkish law, the original drug’s patent protection period should have ended for a generic drug to be licensed. Generic pharmaceutical companies that make drug applications do not have to present results of toxicologic and pharmacologic tests or clinical trials in the event that the generic drug is similar to the original drug and consent has been obtained from the original pharmaceutical company having a licence in Turkey.20
However, for topics related to public health, license applications for generic medicines can be accepted concerning the data of the original drug by making an exception to the original drug data exclusivity without making additional studies. The Council of Ministers of the Republic of Turkey may decide upon patent applications or the inventions subject to patents as compulsory license issues when they are useful to the public. Regarding the interest of public health or national defense of putting an invention into practice; if there would be an increase in the use of the invention or dissemination in general or reforming for a beneficial use is of great importance, it is accepted that there is the public interest.21,22
Drug pricing and surplus drugs
In Turkey, RPS is used for drug pricing. Moreover, drug pricing activities are carried out according to the Communique on the Pricing of Pharmaceuticals for Human Use. There are five reference countries for drug pricing in Turkey: Spain, France, Portugal, Greece, and Italy. Every year, a constant Euro / Turkish Lira (TL) exchange rate is determined; for instance, 1 Euro=2.3421 TL). By using RPS, the lowest prices of the drug found in reference countries are taken into account while calculating the price of the drug. When the mentioned condition is evaluated in a pharmacoeconomic analysis, it is understood that cost-minimization analyses are directly or indirectly carried out. While applying the RPS, the Euro value is determined by multiplying the average annual value of the Euro (annual average daily selling Euro exchange rates of the Central Bank of Turkey and as declared in the Official Gazette of the Republic of Turkey) with the adaptation factor, which is determined as 70%. When pricing medicinal products for the first time, if the ex-factory price is below 3.63 TL, reference price monitoring is not made.23
Pricing of Original Products: If the original product enters the market for the first time (regarding active substance), its price must not exceed 100% of the lowest price of the reference product’s price in reference countries.
Pricing of twenty-year products: The prices of twenty-year original products (regarding active substances), whose sale price to wholesalers is above 6.79 TL, may be a maximum 80% of the reference prices. At the first pricing of twenty-year products, if the selling price to wholesalers is less than 6.79 TL, the selling price to wholesalers may be 100% of the reference price.
Pricing of generic products: The price cannot exceed 60% of the original product’s reference price in Turkey. If the price of the original product is less than the reference price, for the pricing of the generic drug, 60% of the reference price is taken into account. Thus, if the price of the original product is less than the reference price due to commercial concerns (entering the reimbursement list, the emergence of small price differences at pharmacies), 60% of the reference product is considered for the pricing of the generic product. At the first pricing of the generic products, if the selling price to wholesalers is less than 3.56 TL, the selling price to wholesalers may be 100% of the reference price.
When the first generic of the original product enters the market, the reference price of the original product is reduced from 100% to 60%. The price of the original product may be exactly 60% of the reference price or less due to commercial concerns of the owner company.
Pricing of combined drugs: for example, the related drug consists of 20 tablets, each of which contains 100 mg paracetamol and 200 mg atorvastatin as active drug substances. The basic principle for combined drugs: if two or more drug substances unite and form quite another indication, different from their indications alone, in that case, this combined drug is evaluated as an original product. Namely, if the combined drug consisting of analgesic and antihyperlipidemic drug substances is antineoplastic or antiviral, and if this indication is proved scientifically, this combined drug is then assessed as an original drug. However, these kinds of drugs are very few, which is why almost all combined drugs are evaluated as generic medicines.
Primarily, it is checked as to whether there is an identical combined drug (namely, a combined drug consisting of 20 tablets, each of which containing 100 mg paracetamol and 200 mg atorvastatin) on the Turkish market. If there is such a combined drug available in Turkey, then the price of the ‘new’ combined drug cannot exceed the price of that already on the market. If there is no equivalent combined drug on the Turkish market, then the five reference countries are checked for the probability of finding a like-for-like equivalent original combined drug. If there is no equivalent combined drug in the reference countries, the Turkish market is verified for combined drugs that can be scaled from small-packaged in nature, or small doses (e.g., combined drug consisting of 10 tablets, each containing 50 mg paracetamol and 100 mg atorvastatin). If there is no combined drug that can be scaled in Turkey, the market is then checked for combined drugs that can be scaled from a large-packaged nature or large doses (e.g., 40 tablets, each containing 200 mg paracetamol and 400 mg atorvastatin). The process for pricing is always the same. In essence, a like-for-like equivalent is searched for, if there is no equivalent, then the nearest small equivalent is investigated. If there is no nearest small equivalent, then the nearest large equivalent drug is searched for, and finally, price rationing is made. Related to the pricing of combined drugs, if there is no reference combined drug in Turkey (if there are neither small- nor large-form like-for-like equivalent drugs), then original products sold separately in the same doses are sought. That is, the market is searched for original drugs containing 100 mg paracetamol and another drug containing 200 mg atorvastatin. If there are original medicinal products on the market, first, a like-for-like equivalent is searched for; if there are no equivalent drugs in the market, then the nearest low- and high-dose equivalents medicines and the nearest single equivalent drugs are sought, respectively. Finally, rationing is made for drug pricing by calculating 60% of the reference drug’s price because the combined drug is accepted as a generic drug. If there are no original drugs containing drug substances (paracetamol and atorvastatin) of the combined drug, then the highest-priced generic products in Turkey are taken into account.
Surplus goods from the perspectives of the pharmaceutical industry
The pharmaceutical industry uses surplus goods as tools to increase sales volume in a highly competitive environment, promoting the products on the market, thus transferring the stock cost and risk to the post-production pharmaceutical supply chain (pharmaceutical warehouses, distribution channels, and pharmacies).
Surplus goods from the perspectives of the drug distribution channels
Distribution channels are interfaces between the pharmaceutical industry and pharmacies. Distribution channels think that surplus goods are marketing policy tools of the pharmaceutical industry, tools for increasing sales volumes, and a way sharing stock costs and risks with pharmacies, which are last in pharmaceutical supply chains. The direct and indirect benefits of drug distribution channels from surplus goods are dependent on parallel actions compatible with pharmacies and a “win-win” policy because if the selling of surplus goods to pharmacies from distribution channels is not healthy and measurable, problems linked with post mature products, stock cost, and the inability of drug prescriptions returns as a load on distribution channels.
Surplus goods from the perspectives of pharmacists
Although surplus goods from the perspectives of pharmacists are quantity discount practices that reduce unit cost purchasing and increase the gains on sales, they are factors in pharmacies that increase stock holding costs and stock carrying risks, such as decreased prices, post-mature problems, wastage, and chames in public institution’s discount (the discount given by pharmaceutical companies to the Government for products within the scope of reimbursement, billed to the Social Security Institution); additionally, they affect cash flow. The frequent replacement of prescribed drugs by doctors as a result of unethical practices by the pharmaceutical industry reveals risks and costs related with surplus goods for pharmacists. In addition, unfortunately, the selling strategies and planning of industry and distribution channels are not available in pharmacies. For instance, while the reimbursement agency is paying the invoice amounts of drugs to pharmacists at an average of 60 days, if the pharmacists do not evaluate the conditions of purchasing goods with surplus goods correctly, then there is no profit for those goods; on the contrary, pharmacists will have to bear the stock costs of the goods as surplus goods.
The conditions of pharmaceutical warehouses regarding surplus property and regarding commercial discounts (discounts given by drug companies to pharmacies for making their products more attractive) are significant for pharmacists. This discount is reflected in pharmacies by bypassing warehouses. Nowadays, the number of drug companies providing trade discounts has decreased greatly. Additionally, warehouse deal discounts (additional discounts reflected by warehouses to pharmacies as a result of commercial treaties) tend to decrease.
Regarding tax legislations, because surplus goods increase profit margins by reducing costs, they attract extra attention from tax authorities. There are many problems between tax authorities and pharmacies because there are inadequate facilities for accounting; if surplus goods are not handled in accounting books, then surplus goods are considered as cash sales, and pharmacies are subject to criminal procedures regarding income taxes and value-added taxes.24
Surplus goods from the perspectives of patients
Pharmacists purchase goods according to the socio-economic, socio-cultural, and educational levels of the people living in their neighborhoods. For example, in a neighborhood where the social and economic level of people is high, people want the same drugs (mostly expensive original medicines) prescribed by the doctor. The reimbursement agency pays the price of the cheapest equivalent drug, and the patient pays the rest. In affluent areas, patients can pay the price difference easily because they have money. In addition, patients in these regions go to private doctors’ offices and purchase the prescribed drugs by paying the full fee of the prescribed drugs. Pharmacists whose pharmacies are in these kinds of regions do not purchase many generic drugs because patients generally request the expensive original medicines. Surplus goods are given mostly with cheap generic drugs, accordingly, such pharmacists mostly do not purchase drugs with surplus goods because the patients can buy the drugs with cash and the selling rate of expensive cosmetic products is high. Also, cash flow at these pharmacies is very high. Cash flow is a crucial factor for trade, as such these pharmacists earn enough to compensate for the positives of purchasing drugs with surplus goods. In contrast, in places where people’s socio-economic levels are low, people do not have enough money to buy original drugs. Thus, residents in these neighborhoods usually do not want to pay money at pharmacies, and they accept generic equivalent drugs, which are paid in full by the reimbursement agency. Also, people in these regions do not purchase expensive cosmetic products, and cash flow, which is critical for trade, is very low. Therefore, pharmacists whose pharmacies are in those regions usually purchase generic drugs with large amounts of surplus goods because they try to make up for the cash loss and try to gain through purchasing drugs.
Rare diseases and orphan drugs
There is a paucity of accessible data about the prevalence of rare diseases in Turkey, but researchers estimate that at least 5 million people have at least one rare disease. More importantly, millions of patients and their many relatives try to obtain a rapid diagnosis and effective treatment.21 Orphan drugs are medicinal products developed to treat rare diseases in humans. In Turkey, there is no regulation directly related to orphan drugs.22 On the Amendment of the Communique on the Pricing of Pharmaceuticals for Human Use23, orphan drugs are defined as drugs used for diseases with an incidence of less than 1/100.000 people, and which are not exactly defined. The same communique expresses that orphan products can be priced up to the reference price put forth with official documents obtained from the country of import and manufacture, and the price of these commodities will be revised every year making calculations on sales amounts. In Turkey, according to the Regulation on the Licensing of Human Medicinal Products, the Ministry of Health finalizes full drug registration applications, whose preliminary investigation is completed within 210 days following the acceptance of this application by examining the fulfillment of regulatory requirements. In Turkey’s drug regulations, the parts that can be associated with the orphan drugs are: registration of filed drugs being the first in the treatment or diagnosis of diseases; innovation or reduction of public spending on health; and requirement in terms of public health. Examination are completed after no more than 180 days to ensure rapid access to the whole community. Also in the same Regulation, it is stated that the authority can issue licenses depending on certain conditions such as rarely seen indications of the referring drug and accordingly, when the applicant cannot provide absolute evidence for efficacy and safety.20
The first diagram shows the percentage distribution of EU orphan drugs in Turkey. Twenty-eight percent of licensed EU orphan drugs are not available for use in Turkey. The second diagram is about the percentage distribution of licensed EU orphan medicinal products used with different access procedures in Turkey. Thirty percent of EU-licensed orphan drugs have also been licensed in Turkey; 70% of EU-licensed orphan drugs are used in Turkey through off-label use approval (Diagram 1, 2).
The above graph shows the therapeutic area distribution of the EU-licensed orphan medicinal products used in Turkey. The majority of orphan drugs used in Turkey are oncology-hematology drugs. There are twenty oncology-hematology orphan drugs, eleven for gastroenterology-metabolism, four for cardiology, two for endocrinology, one for infections, and two orphan medicinal products used for other therapeutic purposes (Graphic 1).
Patients’ access to orphan drugs in Turkey and ethical approach
In Turkey, people can access orphan drugs through licensed sales, even if not authorized in Turkey, by the procurement of approved orphan drugs from the USA and EU. Alternatively, orphan drugs can be accessed though case-by-case prescription approval of medicines whose efficacy and safety are verified with an ongoing clinical trial protocol, or by the clinical use of yet unapproved drugs on patients with severe diseases. In Turkey, regardless of their authorization status, all orphan medicinal products are covered with 100% reimbursement.16
Drug promotion in the pharmaceutical industry
Drug promotion in the Turkish pharmaceutical industry must be performed according to the Regulation on Promotional Activities of Human Medicinal Products as published by the Ministry of Health of Turkey, Turkish Medicines and Medical Devices Agency (TITCK). Promotion covers all the informing activities, all the promotional staff activities about the medical-scientific features of the medicinal products for human use within the scopes of the Regulation held by the owners of the licenses/permits for healthcare professionals, advertisements that are given to medical and professional books and journals, announcements made by direct mailings or through the press or other means of communication, scientific/educational activities, and meetings and other events held by the industry. Promotional materials include printed materials such as books, booklets, and brochures, containing sufficient and necessary information about the product; film and slides; audio /visual materials provided with storage devices such as flash memory drives and CD/DVDs; every kind of publication that may be used as information/data/reference; free samples; programs and materials for patient education; reminder visiting materials such as pens, pencils, notepads, and calendars whose monetary value should not exceed 2.5% of the current monthly minimum gross wage. Product promotional staff pertains to people who have received a certificate of qualification and who promote products to physicians, dentists, and pharmacists via direct visits. Qualification certificate refers to that given directly to university graduates of the medical promotion department and the marketing program by the Turkish Ministry of Health or the certificate provided by examination at the end of the in-service training approved by the Ministry.25
Healthcare professionals includes physicians, dentists, pharmacists, nurses, and midwives. Health professionals must declare all kinds of support given by the owners of the licenses/permits when they write an article at the end of each article, when they talk or present something at the beginning of each speech/presentation. All scientific and educational activities relating to promotions of medicinal products for human use cannot be used, except to transfer existing medical information, and to present new information. The owners of the licenses/permits cannot directly or indirectly cover transportation and accommodation costs of respondents participating in these activities. Meetings at which healthcare professionals attend must be related with their expertise/task fields. A healthcare provider can benefit from this support a total of three times in the same year; two of these three supports can be held by the same license/permit owner and only one can be used abroad. Meetings at which healthcare professionals attend as speakers or report research with the support of license/permit owners are not considered within this scope.25
Pharmaceutical industry inspections
Inspections of the pharmaceutical industry regarding Good Manufacturing Practices (GMP) are performed according to the Regulation on Manufacturing Sites of Medicinal Products for Human Use.26 TITCK inspects manufacturing plants that have manufacturing permission within a program by giving prior notice. In addition, the Agency can inspect manufacturing plants when necessary without further notification. Health inspectors are authorized to examine all documents related to manufacturing, quality control, and quality assurance, and also for sampling when needed, and examining other recordings. The matters required for notification are indicated in the inspection report, and the Agency announces these issues. The Agency may inspect the manufacturing plants of imported drugs. According to TITCK Regulation on Health Inspectors27, health inspectors have to graduate from faculties such as law, political information, economics, business, economics and administrative sciences, health sciences, medicine, dentistry, pharmacy, engineering, biology, and chemistry.
