|Year : 2022 | Volume
| Issue : 3 | Page : 302-310
Pharmacoeconomic aspects of pharmaceutical ethics
Huk Karina Ruslanivna1, Bespalova Olena Yaroslavivna2
1 Department of Industrial Biotechnology and Biopharmacy, Faculty of Biotechnology and Biotechnics, National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Kyiv, Ukraine
2 Department of Translational Medical Bioengineering, Faculty of Biomedical Engineering, National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Kyiv, Ukraine
|Date of Submission||14-May-2022|
|Date of Acceptance||14-Jul-2022|
|Date of Web Publication||17-Sep-2022|
Bespalova Olena Yaroslavivna
Asst. Professor, Department of Translational Medical Bioengineering, Faculty of Biomedical Engineering, National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Kyiv
Source of Support: None, Conflict of Interest: None
Nowadays, ethical standards of marketing, pricing, and safety strategies conducted by pharmaceutical manufacturers have declined significantly, which raises the question of health-care quality. The company's main objective has become to maximize profit and it is often done by unethical and deceptive marketing, implementation of direct-to-consumer ads, and educational meetings with a promotional character. One of the modern health-care areas, which aims to solve the ethical issues of the drug market, is pharmacoeconomics. The goal of pharmacoeconomics is not only the economic evaluation of various medical programs and pharmacological drugs but also the development of recommendations for the most efficient use of health resources and determining the right pricing and reimbursement strategy. Moreover, the use of the formulary system, which is the functioning tool of the evidence-based medicine (EBM), aims to provide an access to a wide range of certified and high-quality medicines that are recognized on the world market. Generics are considered a great substitutional option to the “ordinary” drugs due to their affordable price as the cost of prescription drugs in the world continues to be a source of concern. Another tool for providing affordable drug's prices is the reimbursement system, which offers a range of essential medicines at the reduced cost and can be product, disease, population, or consumption specific.
Keywords: Ethical issues, evidence-based medicine, formulary system, generic drugs, pharmaceutical market, pharmacoeconomics, reimbursement system
|How to cite this article:|
Ruslanivna HK, Yaroslavivna BO. Pharmacoeconomic aspects of pharmaceutical ethics. Biomed Biotechnol Res J 2022;6:302-10
| Ethical Issues of the Medicinal Market|| |
In recent years, the pharmaceutical industry has been accused of indulging in unethical practices concerning the marketing, pricing, and safety of medicines around the world. However, it is the tactics and methods that the pharmaceutical industry employs in their marketing endeavors that raise the most concern.
Pharmaceutical companies are moneymaking corporations just like any other; thus, in order to exist, they have to create a profit. This market-driven approach fuels unethical drug promotion in several ways. The most common violations include:
- Promoting misleading or false claims about a drug
- Deliberately suppressing risks and side effects of a drug
- Providing financial incentives to physicians for prescribing drugs
- Using disease awareness campaigns for the promotion of pharmaceutical products rather than promotion of health and positive aspects of leading healthy lifestyle.
Providing scientifically valid, accurate, and balanced information on medical products should be paramount for any pharmaceutical company. Promotion must, therefore, be ethical, balanced, accurate, and not deceptive. The information in promotional materials must support an adequate estimation of the risks and benefits of the drug use and must also inform on its proper and timely use.
The developing direct-to-consumer ads are often persuasive, as ads connect to their target audiences by means of emotions and visual complexity on processing and by emphasizing pharmacological efficacy, simple use, adequate symptom control, and innovative features, although not the costs.
Moreover, as a result of unethical relations between pharmaceutical industry and medical profession, there is an inappropriate drug prescribing. It is largely the result of the aggressive drug promotion, such as organizing various forms of educational meetings with a promotional (not always a scientific) character and even paying money for particular drug prescription.
What is more, an exacerbating ethical question for the pharmaceutical market has been the aggressive and poorly controlled pricing policies pursued by drug companies. This results in unreasonably high company's profits; however, research and development of the drug stays unimproved.
| Pharmacoeconomics|| |
One of the modern health-care areas, which aims to solve the ethical issues of the drug market, is pharmacoeconomics. The use of pharmacoeconomic principles allows to determine the economic feasibility of certain drugs or biomedical technologies' consumption to rationally spend money as an individual consumer and the state as a whole. The name of the science comes from the words: The name of the science comes from the words: «pharmacy» a drug and «economy» -household management.
The main task of pharmacoeconomics is not only the economic evaluation of various medical programs and pharmacological drugs but also the development of recommendations for the most efficient use of health resources.
The period of origin of modern pharmacoeconomics dates back to the end of the 20th century, when the first monograph on pharmacoeconomics “Principles of Pharmacoeconomics” was published by Raymond Townsend et al. in 1991. It defines, “pharmacoeconomics describes and analyzes the costs of pharmacotherapy for the medical system and society as well as the quality of life due to treatment associated with the use of new drugs.”
Since 1995, the International Society for Pharmacoeconomics and Outcomes Research has been developing and coordinating pharmacoeconomic research in the world. The main goal of the ISPOR is to implement the results of pharmacoeconomic research into health-care practices to ensure that society allocates limited health resources wisely, fairly, and efficiently.
The establishment of pharmacoeconomics as a separate science within health care is determined by several factors. The first factor is the general global disparity between the limited financial resources of states and the ever-increasing amount of funding for health care. The second is a significant increase in the number of medicines on the world's pharmaceutical market and the search for approaches that would promote their rational use, reduce, and optimize budget expenditures on health care as well as costs of insurance companies and patient's choice.
The subjects of pharmacoeconomic research are:
- Investigation of the medical technology's effectiveness, when the therapeutic results of one treatment scheme can be compared to another or placebo (alternative medical technology)
- Expenditures spent on prevention, diagnosis, pharmacotherapy of diseases by alternative medical technologies
- Safety and efficacy of new drugs introduced into the market
- Documentation of randomized clinical trials of drugs
- Pharmacoepidemiological statistics study the therapeutic efficacy and number of side effects / reactions to drugs in a large population of patients under normal conditions of medical practice after the introduction of the drug on the market.
The main consumers of the pharmacoeconomic research results are medicinal professionals, who use them for inclusion in the relevant lists/forms of medicines; heads and specialists of state and regional health departments; and specialists from pharmaceutical and distribution companies.
The main pharmacoeconomic categories are:,
- Effectiveness: The proven effect of the drug, stated in controlled conditions (clinical trials of phase I and II) before its registration
- Therapeutic efficacy: The effectiveness of the drug after its registration and introduction to the pharmaceutical market, which is stated among a large (over 10,000 people) number of patients in real clinical practice in pharmacoepidemiological studies
- Safety: The frequency, number, and severity of side effects
- Usefulness: An indicator of the effectiveness of medical technology, which is measured by the rate of improving the quality of patient's life after receiving the prescribed treatment
- Economic efficiency: An indicator of cost-effectiveness of financial resources (profit per invested currency).
The purpose of pharmacoeconomic research is to identify the most effective, safe, and cost-effective medical technology.
According to the [Figure 1], conducting pharmacoeconomic analysis is appropriate when the transition from technology A to technology B increases efficiency and cost-option 1 or option 2 (costs are reduced, but the efficiency of A will not be lower than the efficiency of technology B). At the same time, pharmacoeconomic research should become the basis for examination, which of the two medical technologies could be more effective.
Determining the right pricing and reimbursement strategy in the drug development process is also a critical point of pharmacoeconomics. The question, 'What is the highest price I can charge for this product,' is obviously incorrect. The right question is, “What pricing strategy meets the business objectives of the company or the product” or “What price results in fast reimbursement or formulary listing in major markets.”
Strategic pricing includes strong health economic elements. The economic value of new medications can be calculated based on the comparator price and the differential value [Figure 2]. The comparator is usually the most likely gold standard therapy at the time of the expected launch of the product.
| Evidence-Based Medicine|| |
During the last decade, concept of evidence-based medicine (EBM) caused great interest among health-care professionals. EBM is an interdisciplinary approach, which uses techniques from science, engineering, biostatistics, and epidemiology, such as meta-analysis, decision analysis, risk–benefit analysis, and randomized controlled trials to deliver “the proper care at the most relevant time to the patient that requires help.”
The term “evidence-based medicine” was proposed by a group of Canadian scientists from McMaster University (1990). The formation of EBM at the modern stage of society's development is associated with the rapid scientific and technological progress, rising health-care costs, high cost of new medical technologies for diagnosis and treatment of various diseases, medical, and other reasons.
EBM is formed on testing the effectiveness and safety of diagnostic methods, prevention, and treatment in clinical trials. In most countries, some of the rules for conducting clinical trials set out in the good clinical practice standard, as well as the rules for the production of medicines (GMP standard) and laboratory tests (GLP standard), have become generally accepted.
The main principle of EVB is “Each clinical decision should be based on scientific facts that are statistically proven on a large representative group of patients and any new medical technology/treatment cannot be acknowledged by scientific field without mandatory testing during randomized controlled trials”.
The main methods of EVB (gold standard) are randomized controlled trials in which patients are distributed into randomized groups.
EBM aims to solve the following problems:
- Increase the effectiveness of pharmacotherapy and treatment of acute diseases and syndromes (especially emergencies), and for chronic diseases, to stabilize long-term remission, reduce mortality, and improve the quality of life of patients
- Increase the safety of treatment and reduce the risk of complications of the disease through the rational appointment of drugs and treatments
- Optimize the activities of national health systems
- Optimize the cost-effective treatment, giving preference to less expensive and at the same time sufficiently effective drugs, methods of diagnosis, and treatment.
The methodological basis of EBM is clinical epidemiology, which studies the patterns of spread of any disease, as well as predicts them for each patient based on the study of the clinical course of the disease.
EBM uses four general steps in medicinal practice: prepare accurate and distinct questions after observing patient's problem; investigate the literature (especially recently wrote and scientifically acknowledged) for the clinical articles, that are relevant to the patient's problem; critically appraise previously obtained arguments for their validity; and use the results in clinical practice under vigilant control.
In Ukraine, EBM has been developing rapidly recently: modern principles of health-care organization are based on the most important provisions of EBM, the rate of making publications on the topic of EVB has increased significantly, and the center for EBM has been established as well as medical universities.
| Formulary System|| |
The mechanism for implementing the principles of EBM in clinical practice is the introduction of a formulary system.
The form of medicines is a guide to the rational use of medicines, which contains a list of medicines registered in Ukraine and includes quality, effective, safe, cost-effective medicines as stated by EBM, and medical practice. In addition, regional and local forms are also used; however, they differ in the area of their scope.
The main principle of the formulary system is the use of drugs with proven effectiveness of their action in a certain pathological process.
Functions of the formulary system are the following:
- Medical: Definition and development of methods of rational pharmacotherapy
- Pharmacological: Ensuring control over the proper use of drugs and taking measures to prevent and correct errors
- Social: Providing patients with drugs with proven clinical efficacy
- Economical: The use of clinically and economically effective drugs
- Informational: Dissemination of objective information about the effectiveness and safety of medicines
- Professional and educational function: Improving the competence and skills of doctors of various profiles, clinical pharmacists, pharmacists, paramedics, and pharmaceutical staff.
Foreign experience shows that the formulary system exists for the needs of the general practitioner and it should be free from external influences and commercial pressure, especially insurance companies.
The principles and recommendations of formulary system (FS) are based on the results of meta-analysis, accumulated in the treatment of thousands of patients and world's recently gained experience.
In general, FS began to be used in countries, where medical standards had already been established, and formulary lists appeared only after the development of a health insurance system (in the United States since 1930 and in Europesince 1945).
Nowadays, FS requirements are mandatory only in 3 countries: France, Italy, and Austria. In other countries, the FS is of a recommendatory nature.
The history of the form system is closely connected with the creation of the British National Health Insurance Form in the 1930s, which with the beginning of World War II had merged into the National Military Form, which contained the composition of medicines with the definition of substances intended for replacement of scarcely imported ingredients. The first form was compiled in 1949 after the establishment of the National Health Service of Great Britain, and since that time, it had undergone many changes. A new British form, which included a wide range of drugs and provided scientifically sound advice on the benefits of some drugs over others, was published in 1981.
The experience of the United Kingdom progressed rapidly and was implemented in Australia, Canada, Sweden, Germany, and other European countries. These countries still have the most effectively developed formulary system.
| The Problem of Accessibility of Original and Innovative Medicines to the Population|| |
The use of the formulary system aims to provide an access to a wide range of certified and high-quality medicines that are recognized on the world market.
According to the World Health Organization, the availability of medicines to the society should be considered in terms of not only physical but also economic accessibility. From that point, physical accessibility implies providing consumers with high-quality, effective, validated, and safe drugs. Considering the aspect of affordability, it should include a state regulation of prices as well as the system of demand investigation.,
However, the Ukrainian pharmaceutical market still has a large number of counterfeit drugs that contain toxic substances and ineffective active pharmaceutical ingredients that do not have a therapeutic effect. Thus, consumption of counterfeit drugs leads to undesirable consequences in the human body, causing an increase in infectious and oncological diseases.
In order to effectively solve the emerged problem, the Government of Ukraine contrived a State Strategy for the implementation of state policy on providing the population with medicines for 2017–2025. This strategy aims to ensure the proper selection of essential medicines to the National List, ensure the availability and quality of medicines, and improve governmental regulation.
The problem of ensuring the availability of medicines is expected to be solved by:
- Improving the system of state regulation of prices for medicines, the purchase of which is fully or partially financed from state and local budgets;
- Intensification of price competition between manufacturers, distributors of medicines, and pharmacies.
The problem of ensuring the availability of original (innovative) medicines for the population is expected to be solved by:
- Establishing the specifics of testing inventions (medicinal products) for compliance with the conditions of patentability, in order to avoid the issuance of new patents for inventions that are not innovative, but contain only minor modifications of existing patents, with slight improvement in efficiency
- Implementation of the necessary measures to increase the level of availability of innovative expensive medicines (applying, if necessary, the flexible terms of the TRIPS Agreement);
- Optimization of the procedure for compulsory licensing to innovative medicines
- Implementation in the legislation of Ukraine of the so-called “Bolar provision”, according to which companies are allowed to apply for state registration of a generic medicinal product before the expiration of the patent for the original medicinal product. After the expiration of the patent, the company can immediately start the introduction of a generic drug, which allows to reduce the time.,
| Generic Drugs|| |
Generic medicine is a product of the pharmaceutical market that is bioequivalent to the innovator product in terms of dosage form, strength, route of administration, quality, safety, performance characteristics, and intended use. Generic medicines are a cornerstone for providing affordable medicines to patients. The major generic markets in the world include United States of America followed by European Union, Canada, Japan, and Australia.
Nowadays, the use of generic products represents over a half of the global volume of pharmaceutical products.
There are many legal and regulatory issues along with quality concerns associated with the use of the generic products. These issues need to be solved to optimize the use of generic medicines. The sustainability of generic medicine sector is crucial for improving access to essential medicines worldwide.
Generics are considered to be a great substitutional option to the “ordinary” drugs due to their affordable price as the cost of prescription drugs in the world continues to be a source of concern.
For instance, in 2016, the U.S. spent $450 billion on prescription medicines, accounting for 14% of total health-care spending and projected to increase to $610 billion by 2021. Much of this increase in drug spending is due to brand-name drugs that are protected from generic competition by patents and regulatory exclusivity.
Generic medicines constitute only 10% of prescriptions dispensed in the U.S., and brand-name drugs account for 74% of drug spending.
Prices typically decrease rapidly with the entry of subsequent generic manufacturers. Generic drugs that entered the market between 2002 and 2014 reduced drug prices by 51% in the first year, and after a plateau in drug prices during the 180-day exclusivity, when only the first generic drug manufacturer can market its drug, nearly all reductions in the price of oral medications occurred in the first eight months after generic entry. As the number of generic manufacturers within specific drug markets increases, drug prices continue to decline.
The Food and Drug Administration analysis found out that after patent and exclusivity expiration, the introduction of one generic manufacturer into the market reduced the price of the drug by only 6%. With two generic manufacturers, the price reached 52% of the brand-name drug's price. Additional studies have found that at least four generic manufacturers are required to achieve substantial price reductions and it is shown in [Figure 3].
From the other perspective, the confirmation of bioequivalence is the main issue of generic drug approval and validity on the global pharmaceutical market. Two medicines, which are compared pharmaceutically, can be considered bioequivalent if the statistical confirmation of bioavailability can be seen between them.
Taking immediate-release drugs with systemic action as an example, the evaluation is mostly based on two points: the area under the plasma concentration–time curve (AUC) as well as the maximum plasma concentration (Cmax). Those indicators reflect the extent of exposure and the peak exposure. Current guidance dictates that, generally, confidence intervals for ratio of Cmax and AUC for the two pharmaceutical products that are compared should lie within the interval from 80% to 125%.
According to the recent research, the concerns about therapeutic equivalence of generic drugs do not have a profound basis. The study mathematically modeled the bioequivalence of generic drugs using data drawn from the Dutch regulatory database.
The mean deviation of the generic-to-generic PK ratios from 1.00 (representing the ideal) was 6.1% for Cmax and 5.4% for AUC. The 90% confidence interval for both AUC and Cmax met the regulatory criteria for bioequivalence in 80.5% of comparisons. Separately, the criteria for bioequivalence were met in 90.1% of comparisons for AUC and in 87.0% of comparisons for Cmax.,
According to another research,, unsurprisingly, the appropriate and science-based knowledge about generic drugs was the main correlate of the preference for purchasing generic drugs. It was stated that among analyzed people, the preference for purchasing generic drugs was 63.2%. Among those who preferred to purchase generic drugs, 55.1% have reported accepting to replace the prescribed drug (if not a generic) with the equivalent generic drug.
| Regulation of Drug Prices|| |
Price regulation is a set of public authorities' actions aimed at establishing or limiting the amount of money paid by the buyer or received by the seller.
There are three main principles of drug price regulation:
- Direct control over the cost of drugs, which includes:
- Setting discounts (provided by the manufacturer or pharmacies for certain groups of drugs)
- Rebaits (return of a certain part of the funds by the pharmaceutical provider to the health insurance fund, hospital)
- Payback (return of a certain part of the excess profit to the buyer, if sales exceeded previously established, which is done by the manufacturer)
- Implementation of price–volume agreements between the manufacturer and public authorities (applicable to new drugs, when the price is taking into account sales volumes).
- Control over the profits of drug companies
- Price regulation.
Retail mark-up on drugs is set in all EU countries. As for the wholesale mark-up, it is either the subject of negotiations between manufacturers and distributor or regulated by the state.
A multitude of methods are used in order to determine the price of the medicine.
The cost-plus pricing method is a pricing procedure that calculates the “rational” price of products, taking into account production costs, sales costs, research and development, administrative costs, indirect costs, and profits.
Internal price referencing: A method of comparing prices for identical drugs (drugs with the same active ingredient) or similar drugs (drugs of one therapeutic/pharmacological group) or even for therapeutically equivalent treatment (not necessarily drugs) in the country to examine the basic or reference price.
External price referencing: The practice of comparing a price of a certain level (manufacturer's price, wholesale price, and retail price) for medicines in one or more countries in order to determine the base or reference price of the same level or negotiating a price level for a product in a given country.
Regarding price-regulating bodies, in most countries, this function belongs to the Ministry of Health; however, this function might also be done by the Ministry of Economy, the Ministry of Finance, or the Ministry of Social Policy [Table 1].
According to [Figure 4], indirect influence on the price of drugs is carried out through the reimbursement system. The latter is an important tool for ensuring the rational use of drugs, both from the standpoint of therapeutic efficacy and from the standpoint of rational use of funds in terms of insurance medicine.
Although each country's system of regulating manufacturer prices of drugs is different, countries can be categorized into those with strict price or reimbursement regulation for individual drugs (France, Italy, and Japan), those with indirect or limited price regulation (Canada, the UK, and Germany), and the largely unregulated US.
In the first group, France and Italy require regulatory approval of the manufacturer's launch price before a drug can be reimbursed by the social insurance scheme. Postlaunch price increases are usually not allowed and decreases may be mandated.
Moreover, in France, Italy, Japan, and Canada, except for truly innovative drugs, prices of established products serve as a regulatory benchmark for setting new products' prices. The relationship is approximate: some comparator products are more relevant than others; the new product may obtain a mark-up for improved efficacy or usefulness; and the regulated launch price may be higher if a firm makes a significant local investment, comarkets the product with a domestic firm, or has other influence.
Among the less regulated countries, postlaunch price increases are limited to the rate of inflation. In the US, manufacturer prices are unregulated, but competitive pressures have increased with the growth of managed pharmacy benefits since the mid-1980s, through health maintenance organizations.
Thus, the European Consumer Organization came to the conclusion that the prices for medicine in the United Kingdom and the USA were, respectively, 20 and 54 percent above the EEC average. However, the prices in France and Italy lied, respectively, 30 and 28 percent below the EEC average.
The empirical analysis of drug prices assumes drug markets to be imperfectly competitive, and prices may be affected by quality attributes. Specifically, the price of a drug is expected to be positively related to quality attributes such as effectiveness and convenience; negatively related to the number of generic competitors, with greater impact from post-patent 'true' generics than from licensed, comarketed products; and negatively related to the number of substitute molecules in the therapeutic category, although the competitive effect of therapeutic substitutes is expected to be less than for generic substitutes.
| Mechanisms and Experience of Reimbursement in Different Countries|| |
European countries have developed pharmaceutical reimbursement systems with the aim of proposing a wide variety of essential pharmaceurical products to their citizens at the reduced cost (sometimes even for free) and with a special focus on access for vulnerable groups of population.
Reimbursement system is considered a combination of supply- and demand-side actions that target different stakeholders (for instance, doctors and patients) with the aim of reducing or providing stable medicine prices as well as their responsible use.
Different schemes may be implemented for reimbursement of the drug costs:
- Product-specific reimbursement: The decision on reimbursement is based on the specific medicinal product
- Disease-specific reimbursement is linked to the illness that will be treated. This type of reimbursement implies that specific medicinal product can be reimbursed at different reimbursement rate and sum for the treatment of divergent illnesses
- Population group-specific reimbursement implies that specific groups of population (such as infants, children, and pensioners) can be considered eligible for free medicines, or pharmaceuticals at higher reimbursement rates, whereas others cannot
- Consumption-based reimbursement implies that the rate of reimbursement depends on the expenditures for pharmaceuticals within a clearly stated period of time (increase in reimbursement sum is connected with rising rates of drug's consumption).
It is a generally accepted practice that the competent authority for the medicinal pricing determines the reimbursement status of the pharmaceutical product. The decision is usually based on the wide range of criteria (for instance, therapeutic benefit, cost-effectiveness, and others).
Sweden can be considered a good example of effective reimbursement system. The country has an autonomous regional structure and the decisions on reimbursement are taken through the Dental and Pharmaceutical Benefits Agency.
Another example is consumption-based scheme of reimbursement in Denmark. According to the scheme, to the moment when a patient can become eligible for reimbursement, he/she has to pay the full cost of his/her pharmaceutical product up to a threshold of 950 Danish kroner (DKK) in a period of 360 days (the reimbursement period). When the first threshold is passed, the reimbursement rate grows as expenditures for reimbursable drugs increase.
In the EU, pharmaceutical pricing and reimbursement remains the competence of the Member States. While all EU Member States need to be obedient to the rules, settled by the Transparency Directive, which aims to guarantee pricing and reimbursement decisions to be taken in a transparent way within specific time-frames, it is up to the country how they shape their pharmaceutical pricing and reimbursement system.
Europe has higher health service coverage, as a result, reimbursement of health expenditure by a social health insurance or a national health service is also higher compared with the rest of the world. This is reflected in the share of the public funding of health and pharmaceutical expenditure. In the EU, around 75% of health expenditure and two-thirds of pharmaceutical expenditure is on average covered by the public payers.
The Government of Ukraine has also recognized reimbursement as the area of priority for ensuring the availability and acessability of medicines.
Determination of the amount of drug reimbursement and the formation of the register of drugs, the cost of which is reimbursable, is entrusted to the Ministry of Health of Ukraine. The register is expected to be updated twice a year, as of January 1, and July 1, every year.
The range of medicines included in the government's Affordable Care Act demonstrates an increase in medicines with each update of the Register of Medicines. For example, the number of drugs for the treatment of bronchial asthma increased in the fifth edition of the register by 133% compared to the first. It was found that 87% of drugs are imported, and only 13% domestic. Spain (32%) and Sweden (23%) predominate among the leading producer countries. Analysis of the dynamics of the amount of compensation and the amount of surcharge for packaging revealed that the percentage of drugs without surcharge is about 50%. By 75% of the drugs for the treatment of bronchial asthma, the amount of surcharge per package with each edition of the register of drugs subject to reimbursement increased.
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Conflicts of interest
There are no conflicts of interest.
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