home Audience 1 Research and development for generic companies. Generics on the Russian pharmaceutical market. What is the validity period of a patent for original medicines?

Research and development for generic companies. Generics on the Russian pharmaceutical market. What is the validity period of a patent for original medicines?

Samvel Grigoryan about the complex “relationships” between original drugs and generics

The progress of mankind is ensured by discoverers, and the development of the pharmaceutical industry is ensured by developers of new medicines and technologies for their production. Each of their discoveries is another hope for patients and another contribution to modern medical practice. According to WHO, since 1950, life expectancy at the global level has increased by more than 20 years. This unprecedented social impact has been achieved largely thanks to new drugs. It would not be an exaggeration to say that innovations have paved the way from incurability to treatability, to greater effectiveness and safety of treatment.

Hot on the trail: original drugs and their copies

Being a pioneer is always more difficult. The development of original (innovative) medicines is a knowledge-intensive, lengthy process that requires large intellectual, financial and organizational resources. Hundreds of millions of dollars spent on obtaining a new pharmaceutical substance determine the high cost of the drug created on its basis. This is the price we all pay for the opportunity to not only have pharmaceutical science, but to develop it.

Market laws cannot be abolished, and it is hardly possible to deprive other manufacturers of the right to repeat (legally, of course) the original drug and offer this “copy” (generic) to the consumer under their trade name. In a word, competitors are ready to rush on the “hot trail” laid by innovative companies without delay. And not only to rush, but also to “overtake”, having achieved - due to a lower price - an advantage (sometimes quite significant) in sales volumes. Examples when a generic drug is bought more often than the original drug from which it is “copied” are known to every pioneer.

Rivalry between market participants is a useful phenomenon if only competitors are placed on an equal footing. In this case, those following the trail have a gigantic advantage - they do not have to spend huge amounts of money on creating a “new formula”. And the funds are really large. For example, according to Yuri Mochalin, director of corporate relations and government affairs at AstraZeneca, the international biopharmaceutical company AstraZeneca annually invests more than $4 billion in research and development. Unencumbered by this level of costs, generic companies can offer their product at a significantly lower price, and the market position of the corresponding original drug will inevitably suffer from unequal competition.

If the products of innovative companies stop paying off and become low-profit, this will lead to a curtailment or slowdown of the already long process of developing new pharmaceutical science products. Such a prospect is disadvantageous not only to the creators of original medicines themselves, but also to patients, doctors, and also - oddly enough - to formal competitors, generic companies, since in this case they will have nothing to reproduce.

Protective measures: patent protection of medicines

In order to avoid this, it is necessary to compensate innovative companies for unequal conditions of existence in the market. One of the tools of patent law allows this to be done - a ban on the reproduction of the original formula for a period established by law. Thanks to it, the holder of a patent for a new drug is temporarily freed from obviously unequal competition. This exceptional measure gives innovative companies the opportunity to recoup the costs of creating the drug and generate the profit necessary for further investment in drug development.

The duration of this compensatory privilege of the copyright holder in our country, in accordance with paragraph 1 of Art. 1363 of the Civil Code is 20 years. The countdown, of course, does not start from the moment the drug appears on the market, but from the date of filing the initial patent application. But from the beginning of the development of the original formula to its “premiere”, sometimes up to 10-15 years pass. Thus, in practice, innovative companies do not enjoy the benefits of patent protection for as long as it seems at first glance. At the same time, manufacturers, as a rule, strive to warm up interest in their new brand in advance, so that the “premiere” of the drug on the market is immediately marked by a high level of sales.

In the United States, there is a 12-year patent protection period for drugs of biological origin and a 20-year term for drugs obtained by chemical synthesis. In the European Union, the validity period of a patent can be increased to 25 years.

Another form of intellectual property protection in the field of pharmaceutical inventions is the exclusivity of research data from the developer company. Russia's recent accession to the WTO (August 23, 2012) means the entry into force of a new norm. Commenting on it, Vladimir Shipkov, executive director of the Association of International Pharmaceutical Manufacturers (AIPM) , notes that now, for 6 years from the date of registration of the original drug, no other company can use the results of its preclinical and clinical studies to bring their (reproduced) product to the market. True, according to Yuri Mochalin, director of corporate relations and work with government agencies at AstraZeneca (part of the Association), this provision of the federal law does not yet have by-laws and therefore is not yet applied. The Ministry of Health and Social Development is currently working on writing such acts, and the Association is taking an active part in this work so that the rule on data exclusivity becomes alive.

It is clear that the first, almost instinctive desire of any buyer is to purchase medicine as cheaply as possible. Therefore, it would seem that he would not benefit from such a formally “protectionist” measure as patent protection. But this is only at first glance. The consumer, who is also the patient, is indirectly interested in the continuation of pharmaceutical research, the appearance on the market and the immediate introduction into medical practice of new generations of medicines - increasingly effective, safe, selectively acting. By “overpaying” for the brand, he cares (in the vast majority of cases unconsciously) about his future, about the day when some medicine, not yet created, will help him, his children, grandchildren, maybe even save them.

Moreover, the “drug portfolio” of many innovative companies contains orphan drugs that take a long time to pay off and do not bring much profit. Their development and production are a consequence of awareness of responsibility to each patient individually. Competing companies rarely show interest in reproducing medicines for the treatment of rare nosologies. It turns out that patent law is a tool for protecting not only innovative companies and their investments in pharmaceutical research, but also the vital long-term interests of the consumer.

Competitive “symbiosis”: the role of generics in the development of the pharmaceutical market

On the other hand, a reasonable limitation on the term of patent protection protects both industry participants and patients from an unjustifiably prolonged monopoly of the copyright holder. This is the meaning and benefit of the presence of generic companies on the market: they create a competitive environment in the drug sector, the presence of which is in the interests of the consumer.

Manufacturers of generic drugs, as a rule, prepare in advance for that significant day when the copyright holder loses its exclusive right. Their activity is especially great when it comes to a widely sought-after drug. The appearance of legal "copies" on the market usually occurs almost immediately after patent protection expires. Two or more trade names containing the same pharmaceutical substance begin to compete, the market for this medicinal product (previously entirely owned by the original) is distributed between the subjects of competition, and this can lead to a drop - sometimes quite significant - in sales of the more expensive original drug.

And yet, it is wrong to reduce the relationship between innovative and generic companies solely to competition. Both parties need each other to some extent, and the consumer of their products needs healthy competition between them. Manufacturers of generic drugs, as noted above, have a vested interest in developing innovations so that they have something to reproduce.

The benefit to the creators of original drugs from the well-being of their competitors is less obvious, but it should be taken into account that the lack of competition always has a negative impact on the market and its participants. The realities of the pharmaceutical industry in the form of the inevitably approaching expiration of patent protection and generic companies ready to launch do not allow original manufacturers to relax and lose the momentum of new developments, resting on the laurels of previous achievements. For the consumer, this competitive “symbiosis” is doubly beneficial. He has the opportunity to choose, taking into account a combination of factors such as the quality and brand of the drug, the doctor’s prescription or recommendations, the advice of a pharmacist, the patient’s habit of a specific name “that helps him,” and the price of the drug.

Selection and statistics

The ranking of these factors in terms of importance in our country strongly depends on geography. In Moscow and other large cities, brands are more often preferred, especially if they are recommended by pharmaceutical workers. The consumer’s attachment to a specific pharmacy or pharmacy chain, that is, a pharmacy brand, often implies his trust in the recommendations of the first capitalists and the products they offer. For buyers on a budget, no matter where they live, price is usually key.

One of the factors listed above still stands apart and claims to be the relative palm. We are talking about a doctor's prescription. Most patients are little aware of such professional matters as “original drug”, “generic”, and do not really understand what an “analogue” is. Even specialists sometimes have to remember which of the drugs of the same INN is the original, and which are its “copies” (especially when we are talking about names that have been on the market for more than a decade).

Buyers, as a rule, ask the pharmacy for the trade name that the doctor prescribed (recommended) and which is printed on the packaging in capital letters. The mass consumer usually does not focus on another name, which is printed in small print (INN). Thus, in many cases of outpatient treatment and especially in hospital practice, the choice between the original drug and the generic is made by the medical professional.

The realized preferences of consumers, medical workers, and healthcare organizers collectively form statistics. According to the marketing agency DSM Group, in value terms, the share of original drugs (drugs that are protected by a patent or were protected by a patent, that is, the first in the INN) in the Russian pharmaceutical market has not changed significantly over the past 3 years and is approximately 41%. In physical volume, the share of originals is much lower - about 12%. Of course, this is due to the fact that they are more expensive than generics. At the same time, again according to the DSM Group, the average cost of an original drug is approximately 500 rubles, while a generic drug is about 100 rubles. DSM Group predicts that there will be no significant redistribution of market shares in favor of generic drugs this year or next. A wave of changes is possible after 2014, when many original drugs will come out of patent protection.

Brand generics

Various trends are taking place in the global generics sector. Many preparations of generic drugs, of course, cannot be considered fully (therapeutically, pharmacologically) equivalent to their originals. But there are many opposite examples. The quality of the product of the leaders in the generic sector is high enough for the name of these companies to be perceived as a brand.

In addition, in an effort to provide additional sustainability to their business, some innovative companies are diversifying their activities by creating and developing a generic line. A case in point is Sandoz, the generics division of the Novartis group of companies. That is, the market for drugs based on generic drugs is heterogeneous, and from it a segment of “branded” generics can be distinguished, provided with the trademark and quality of technology from leading manufacturers. It follows that the reality of the pharmaceutical industry is not only competition between original drugs and their “analogues,” but also a price “war” in the generic sector, usually “driven” by those market participants whose products can be called “unbranded.”

If this process takes on a “dumping” character, then the knowledge-intensive pharmaceutical industry, unlike many other areas of the economy, suffers rather than benefits from such trends. Every unit of profit lost by those who invest it in the research base, new developments, improving the production of original drugs and high-quality generics results in a slowdown in the pace of development of the innovative and technological potential of pharmaceutical science and industry. But it is hardly possible to limit these trends or introduce lower price thresholds.

Balance and perspective

It is not only innovative companies that are diversifying their activities. The policies of some leaders in the generics sector demonstrate a more or less pronounced turn towards the development of research and development, development and acquisition of know-how. Rustam Iksanov, Vice President for Strategic Development at Akrikhin, draws attention to the fact that all manufacturers have to solve the question: how to maintain growth when the number of “new formulas” in the world decreases from year to year. That is why Akrikhin is focusing its efforts on creating so-called “generic plus” products, that is, generics with added value (generics with signs of originality). At the same time, of course, it should be borne in mind that a generic company cannot transform into an originator; these are fundamentally different business models

Alexey Kovalev, sales director of the pharmaceutical company Vertex, sees the future in relying on innovation, production of know-how, and products with elements of originality. This will ensure the stable existence of the company, strengthen its position in the market and create a manageable part of the product range, free from the influence of external factors and the economic situation. Other priority measures, according to Alexey Kovalev, are monitoring the validity of patents for original drugs and the production of branded generics. Compared to unbranded ones, their life cycle is longer and their price is higher. It remains stable for a long time and even grows. Among the measures contributing to the successful promotion of branded generics are: Alexey Kovalev denotes increased consumer awareness of this class of medicinal products.

However, not all manufacturers consider it possible and advisable to develop both directions. As Yuri Mochalin, director of corporate relations and government affairs at AstraZeneca, notes, there are industry participants who decide not to diversify their activities, and AstraZeneca is one of them. It looks quite attractive to have your own generics division, which would allow you to use new opportunities. However, AstraZeneca remains committed to its strategic decision to remain in the innovation sector. This decision was made after the merger of the two companies Astra and Zeneca in 1999, and it has not changed since then. “We don’t expect any deviations in our global strategy,” concludes Yuri Mochalin.

As the above data from the marketing agency DSM Group shows, the ratio of market shares of originals and generics has been quite stable in recent years. Time will tell whether Russia's recent accession to the WTO can influence this peculiar balance. There are currently insufficient grounds for a positive answer to this question. The ratio of original drugs to generics may be affected by the introduction of a drug insurance system. This is a separate big question, depending on which model of this social security mechanism will be taken as a basis in our country.

Demand for generic medicines is growing worldwide and pharmaceutical companies are realizing their significant potential. In the near future, the global generics market is projected to grow by 8.7% per year, that is, in the period from 2016 to 2021. The global market volume will increase from 352 billion US dollars to 533 billion. The European Pharmaceutical Review has prepared a rating of the largest generic drug manufacturers according to their revenues received in 2018.

1. Teva Pharmaceutical Industries– $18.9 billion

Teva, which is based in Jerusalem, is the world's leading manufacturer of generic drugs. The company, founded in 1901, began as a small wholesale seller of imported drugs. In the 1980s Teva has entered the global market, including the US market. Currently, the company has 43 thousand employees. In 2018, Teva produced 120 billion tablets; every ninth prescription in the United States was written for drugs from the Israeli company.

As noted by Teva President and CEO Kare Schultz, the implementation of a business restructuring plan began in 2018, but this did not prevent the company from achieving all the goals set for the company. “During this time, we were able to reduce costs by $2.2 billion, and in 2019, savings should be $3 billion compared to the 2017 baseline.”,” Schultz emphasized.

2. Mylan NV– $4 billion

This pharmaceutical company operates in more than 165 countries, Mylan employs about 35 thousand people. The company's portfolio includes more than 7,500 products and 12 research centers.

The company was founded in 1961 in West Virginia and is currently registered in the Netherlands. The Mylan brand sells not only generics, but also registered and biosimilar drugs. Most of the company's products are sold and manufactured in the USA. Through the acquisition of a number of smaller players, Mylan has become one of the leading suppliers of generic drugs in the world.

3. Sandoz– $9.9 billion

Sandoz is the generics and biosimilars division of Novartis. The Munich-headquartered company merged with Ciba-Geigy in 1996 to form the Novartis Group.

Sandoz is one of the leading suppliers of biosimilars and generic antibiotics in the world. In January 2019, the company announced it had received Top Global Employer certification.

4. Sun Pharmaceuticals– $4 billion

Headquartered in Mumbai, Sun Pharmaceuticals offers over 2,000 products. In addition to being one of the leading manufacturers of generic drugs, the company also produces a number of active pharmaceutical ingredients.

Sun Pharmaceuticals was founded in 1983, until 1996 it sold its products only in India, but in 1996 it entered the global market. The company has formed a portfolio of 10 specialized drugs, five of which have already been brought to market. Sun Pharmaceuticals expects generics to be a key driver of success in the new financial year.

5.Lupin Pharmaceuticals– $2.3 billion

Lupine Pharmaceuticals is based in Mumbai and is a subsidiary of Lupine Limited and one of the top five pharmaceutical companies in the country, making it a key player in the industry. The company was founded in 1968, although its main focus is generics, it also produces original drugs and active pharmaceutical ingredients.

The company's research program covers the entire pharmaceutical product chain, and Lupine Pharmaceuticals' R&D department employs 1,400 people. According to various estimates, the company's products are sold in 70 countries around the world; Lupine Pharmaceuticals is currently making attempts to enter the American market.

Traditional pharmaceutical development is like the old fable of the elephant and the blind man. During the development of the GLS, we touch different aspects of its quality, just as a blind man touches different parts of a large elephant. Therefore, it is quite natural that as a result, we, just like a blind person, generalize contradictory information and often get the wrong idea about the influence of various factors on the quality of the product we have developed. Many important factors remain unknown to us, just as an elephant remains invisible to a blind man. This is often the reason why bioequivalence studies, technology transfer and associated validation fail in commercial production.

At the same time, the pace of development of the global pharmaceutical industry and growing competition among domestic companies require that generic drug developers not only respond quickly, invest significant effort, and produce quality identical to the original drug, but also the use of modern concepts. One of these concepts in drug development has been rightfully considered over the last few years to be the Quality-by-Design concept, stated in the ICHQ8 guideline “Pharmaceutical Development”. Its main advantage is the ability to increase the efficiency of pharmaceutical production while maintaining high quality standards due to:

Organizations of quality control in real time *;
Reducing the percentage of defects and non-conforming series;
Reducing time losses during routine production by reducing the number of deviations and inappropriate quality control results (OOS, Out-of-Specification);
Transition from a reactive decision-making system to a proactive system based on timely risk assessment.

What is Quality-by-Design?

There are still several interpretations of the translation of this term into Russian. This includes “Quality through development”, and “Planned quality”, and even “Development quality”. By and large, all interpretations of the translation are similar in essence.

Quality-by-Design (QbD) is a systematic approach to drug development that begins with clearly defined goals through drug product development, understanding of its manufacturing process and control strategy, based on sound science and quality risk assessment. The ICHQ8 Pharmaceutical Development Guidelines introduce the QbD concept as an improved approach to pharmaceutical development.

In contrast to the traditional approach, the QbD concept initially suggests focusing on the finished product and its consumer (patient). In other words, we first strive to deeply understand the risks to the consumer associated with the use of the drug, and only then, in reverse order of development, we eliminate all possible critical hazards associated with the raw materials used and the parameters of the production process.

Compared to the traditional one, the improved approach to generic drug development additionally includes the following elements:

Determining the properties of raw materials that may affect the critical properties of the drug using an in-depth risk assessment;
Determination of the degree of influence of variability in the properties of raw materials and technological process parameters on the critical properties of the drug using full-factorial mathematical modeling;
Formation of a control strategy based on the results of a comprehensive risk assessment and conducted experiments. For example, defining the design space;
Shifting emphasis from episodic revalidation to continuous confirmation of the suitability of process parameters, and organizing release by parameters.

The main advantages of the Quality-by-Design concept in relation to traditional pharmaceutical development are presented in the table taken from ICHQ8.

Aspect	Traditional approach	Improved approach Quality-by-Design
All pharmaceutical development	· Mostly empirical · Development studies are often conducted with one variable at a time	· Systematic, relatively mechanistic understanding of the properties of the raw materials used and process parameters in relation to critical product quality parameters · Multivariate experiments to understand product and process · Creating a development space · Application of PAT tools
Manufacturing process	· Constant · Verification is primarily based on original full-scale samples · Focus on reproducibility and optimization	· Adjustable within the development space · Validation throughout the life cycle and, ideally, a continuous monitoring process · Focus on control strategy and product reliability · Using statistical process control methods
Process Controls	· Testing during production mainly for "complies - does not match" · Offline mode ( off - line ) analysis (control of samples in laboratories)	· PAT tools are used with feedforward, response-based controls · Process activities are monitored and directed to support ongoing attempts to improve and improve the product after approval
Aspect	Traditional approach	Improved approach Quality-by-Design
Product Specifications	· Basic controls · Based on series data available at the time of registration	Part of a total product control strategy Based on the desired performance of the product with essential information required
Control strategy	· The quality of a medicinal product is mainly controlled by intermediate and final product testing	· Product quality is ensured by a risk-based control strategy designed for an understandable product and process. · A strategy aimed at quality control with the possibility of real-time release or reduced testing of the final product
Product Lifecycle Management	· Reactive (that is, there are actions to correct and solve problems)	· Mainly preventive actions · Facilitates continuous improvement and improvement of the product

Success factors for the QbD concept

Statistical analysis, including full factorial experimental design
Defining the design space (DesignSpace)
Automation of in-production control, organization of production according to parameters

Implementation of the QbD approach

In practice, the implementation of a QbD program looks like this:

Studying the nature of variability (variation) that is inherent in the product being created;
Determination of critical properties of a drug (based on its target profile)
Determination of critical parameters of the technological process and the nature of the relationship between their variability and the quality of the drug;
Definition of the development space or, as it is sometimes called, the area of design solutions (DesignSpace);
Formation of a quality control strategy;
Automation of in-production control;
Organization of release according to parameters.

Studying the nature of variability (variation) that is inherent in the product being created

First, you need to imagine the profile of the target product. In other words, you need to answer the questions:

“What exactly do we want to get?”
“What characteristics should this something have?”
“Are there any restrictions (regulatory requirements, consumer expectations, etc.)”?

The second is to understand the nature of variability. In other words, answer the questions:

“What can change in the product?”
“What influences what can change”?
“What influences what influences”?

At this stage, it is necessary to use existing knowledge and experience, including retrospective data on similar drugs. And since all means are fair in war, the use of benchmarking tools helps.

Determination of critical properties of pharmaceutical products and critical process parameters

Scientific rationale and risk assessment methodology are used to select critical quality parameters and critical process indicators. This is due to the fact that there is a direct relationship between risk and criticality:

Risk includes the severity of the harm, the likelihood of development, and detectability (or the degree to which it evades control). In this way, risk management can change the level of its criticality (unacceptable, serious or minor).
The criticality of a quality indicator (in other words, the criticality of one of the properties of a drug) is primarily based on the severity of harm and does not change as a result of risk management.
The criticality of a process parameter is related to its impact on some critical quality indicator. It is based on the probability of occurrence and detectability of harm and can change as a result of risk management.

Accordingly, even at the initial stages of development, using the risk assessment methodology (by identifying harm, the severity of its consequences and the likelihood of its occurrence), we can predict critical indicators for the product and critical process parameters. As we gain new knowledge and experimental data at subsequent stages of development, when transferring technology and scaling up production, our assessment will only be refined based on the results of validation.

Determining the nature of the relationship between the variability of drug quality parameters and the variability of critical process parameters

Existing scientific data and the results of risk assessment at the drug development stage will allow us to draw up a multifactorial experimental design. An experiment based on the statistical principles of orthogonality, reference distribution, and randomization is an effective way to identify interactions between process and product variables. Its result will be identified mathematical dependencies and models of the type y=f(x1,x2,...,xn) - where y is a critical quality indicator, and xi is the critical i-th process parameter.

Description of the design space (DesignSpace)

The Design Space (or Design Space) is some combination of one or more process parameters that affect a desired product property. Based on the results of a multifactorial experiment, acceptable ranges of variability for each process parameter are established based on the degree of its influence on the expected product quality specification.

The scope of design solutions is expressed either as a simplified mathematical relationship y=f(x1,x2,…,xn), or as a range of parameters (to simplify work in production).

Formation of a quality control strategy

The control strategy includes critical process parameters and product quality indicators that model downstream process parameters to produce a product of a given specification. In other words, this is the same input, interoperational and acceptance control - only based on an algorithm built on mathematical models of the dependencies y=f(xi).

Knowing the nature of variability, knowing the degree of influence of process parameters on product quality indicators when forming a strategy, it will not be difficult to determine:

Type of control (continuous, selective);
Sampling points (to ensure representativeness of the sample);
Required test accuracy;
Possibility of using express methods;
Automation capabilities.

Automation of in-production control

Control requires resources. And above all, it’s time and people (staff). The logic of control automation is a significant reduction in control time, elimination of the human factor and reduction in the cost of control operations. The time is reduced due to the continuity of monitoring and the absence of downtime in the “pending decision” status. Eliminating the human factor has undeniable advantages. Firstly, there are not many good analysts, secondly, they are not cheap, and thirdly, no one is immune from an erroneous control result due to absent-mindedness caused by a bad mood, migraine, or simply the analyst’s thoughtfulness.

Automation of control is carried out mainly by equipping production equipment with process analyzers, which primarily carry out non-destructive measurements of critical indicators (properties) of the product. Such measurements can be carried out:

In-line, when the sample is not removed from the process flow;
On-line, when the sample is redirected from the flow to the analyzer, and can then be returned to the process;
At-line, where a sample is removed, isolated and analyzed in close proximity to the process stream.

Process analyzers (NIR spectrometers, metal detectors, dynamic weighing balancers, etc.) typically generate a large amount of data. Using this data and established mathematical relationships, a flexible process is developed that takes into account the variability of the processed materials. In this case, the end point of the process is not a point in time, but the achievement of the desired property of the product (compliance of the indicator with a given specification).

Production system validation

At this stage, we need to show that maintaining specified process parameters, for example, temperature, flow rate of a humidifier solution in the manufacture of tablet mass, gives us, etc.) allows us to obtain, for example, flowability in a certain narrow range, which, with appropriate tableting parameters (speed and pressing pressure) gives the necessary homogeneity of the tablet mass. The validation result is usually presented in the form of statistical characteristics, for example using process capability indices Cp>=Cpk>= 1.67.

Organization of release according to parameters

The release parameters are comparable with the use of alternative analytical methods. This approach involves assessing the quality of the finished product not on the basis of control of samples selected from a product series, but on the basis of data on the production process, obtained continuously at each stage of production. The PAT concept develops the practice stated in Appendix 17 of GMP for making decisions about the sterility of a product based on the parameters of the heat sterilization regime (121 °C, at least 15 minutes). Only now does this become applicable to any indicator of the quality of a drug with proper justification.

And most importantly, the role of the Authorized Person is changing. Now its function is not so much making a decision on the possibility of releasing a series to the market on the principle of “control at the end of the pipe”, but rather “creating this very pipe”, establishing the rules for the behavior of the production process to achieve product quality.

Conclusion

The QbD concept itself is not considered complex, but its implementation requires deep knowledge and a strong evidence base based on multiple full-factorial experiments. And if our (domestic) manufacturers and regulatory authorities do not soon adopt the approaches of the world market leaders, we will inevitably lag behind in innovation for many years. Accordingly, we will never be able to compete with the global pharmaceutical community. And not so much in terms of quality (which we are obliged to ensure regardless of the approaches and resources expended), but rather in terms of the efficiency of organizing the production of medicines.

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08/05/2019 Temperature compliance is a stumbling block for participants in the supply chain
The number of litigations related to the thermolability of drugs is increasing. Alexander Panov, head of the Healthcare practice at the Pepeliaev Group law firm, stated this during the round table “Validation of the drug transportation process,” organized by the Council of Supply Chain Professionals.

The event took place as part of the third meeting of the Pharmaceutical Logistics working group and brought together heads of logistics companies, as well as representatives of pharmaceutical manufacturers and distributors.

The head of the Vialek Group of Companies, Alexander Alexandrov, drew attention to the fact that deviations in temperature conditions do not always lead to a product not meeting the required level of quality. According to him, transportation without deviations does not happen, as evidenced, among other things, by foreign experience.

“It is impossible to ensure that the temperature regime does not go beyond the limits even for a minute,” he emphasized. “The other issue is that we should not allow long-term deviations, and from a legal point of view this still needs to be finalized, because now this issue is often equated.” Another common mistake is to measure the air temperature rather than the temperature of the product during transport, he added.

Continuing the topic of inaccuracies in definitions, the expert noted that the manufacturer and the holder of the registration certificate are responsible for the quality of the product. And in this regard, there is no need to manipulate the concepts of “efficiency and safety”.

“Safety and effectiveness are confirmed at the stage of preclinical and clinical studies,” he recalled. - Logisticians ensure this through the application of good practices. But to say that during transportation it is necessary to ensure the safety and effectiveness of the drug is incorrect - carriers must ensure that transportation of the goods does not have any impact on the quality of the product.”

Read the details in “FV” No. 23 (978) dated July 23, 2019 in the publication “How lucky you are.”

In 2014, the growth rate of the Russian pharmaceutical market will be at the level of 3-6%, then the market will grow and develop steadily, which will allow the economy in general and the pharmaceutical industry in particular to recover. According to the rating, by 2018 Russia will be among the ten largest pharmaceutical manufacturers. How will the pharmaceutical industry grow, what are the prospects for the development of the market for reproduced generic medicines, and how proven is their effectiveness and quality? These issues were discussed during the round table “Generic Medicines: Challenges and Prospects” at the International Conference “Quality of Medicines and Medical Products”, held in Moscow under the auspices of the Federal Service for Surveillance in Healthcare (Roszdravnadzor) at the end of May. G.

THERE IS A STRONG GROWTH TREND IN THE GENERIC DRUGS MARKET IN RUSSIA

Denisova Maria Nikolaevna
Leading manager of IMS Health, Doctor of Pharm.D.

What is driving the growth of the global pharmaceutical industry, and who is driving it? The undisputed leader is the United States (60%), there is a temporary lull in the European pharmaceutical market, the growth rate for the main powers in the European market is just over 2%. The traders include a segment of countries with fast-growing economies, to which Russia belongs, and according to our forecasts, this segment will increase at the level of 9-12% in the next five years.

According to the rating, by 2018 Russia will be among the top ten largest pharmaceutical manufacturers also because the Russian market is the most attractive among all pharmaceutical markets in Eastern Europe. If you look at the ranking of pharmaceutical companies in the prescription segment, the leaders here are Novartis pharm, Roche, Sanofi Aventis, Gedeon Richter, KRKA pharma. At the same time, there is an increase in the level of drug consumption by the Russian population. Compared to the countries of the European Union, we consume prescription drugs in a different price aspect.

If you look at the structure of costs in healthcare and take the segment of countries with sustainable developed economies as a starting point, you can identify the following leaders: the USA, Japan, five European countries and the UK. Their expenses, incl. and for drug provision, amount to about 19%. In rapidly growing countries, the cost of drug supply is about 30%; this record is explained by the lack of money for the stable development of the pharmaceutical industry, so the above countries are striving to reduce the cost of drug supply. This happens by regulating the range of medicines at the state level.

Generic drug production will increase due to sponsorship from insurance and private companies. The Eastern European market currently offers generics, branded (sold under their trade names) and unbranded (sold under their international nonproprietary names). Branded generics dominate in Eastern European countries.

What about in Russia? Our country ranks 113th in the world in terms of healthcare costs per capita, and 130th in terms of efficiency of spending budget funds. Annual costs for the development of the pharmaceutical industry amount to 650 billion rubles. Some of the generics consumed by the Russian population are without patent support (according to research, up to 49%), unbranded ones make up 19%. Today, on the Russian pharmaceutical market, the share of protected generics (with a patent) is 65%, and those with an unrenewed patent are 35%.

Over the past 5 years, there has been a consistent trend toward an increase in the share of generics; Thus, in 2008, the share of branded generics was 71%, unbranded - 17%, in 2013 - 74 and 19%, respectively. Let me assume that the share of unbranded generics will increase even with the advent of insurance medicine, which is explained by their relative cheapness. The state wants to save on drug supplies, which will undoubtedly affect both the income of manufacturers and the health of patients.

QUALITY OF ORIGINAL AND REPRODUCED DRUGS: THE SCORE IS EQUAL

Dubinin Konstantin Viktorovich
Director for interaction with government agencies and corporate policy of JSC Teva

According to experts from the World Health Organization (WHO), not a single country has sufficient funds for drug supply, therefore, in order to reduce the cost of pharmacotherapy, WHO and other international organizations recommend implementing generic substitutions in medical policy. Today, in the ever-growing generic market, the consumer expects to see evidence of the effectiveness and compliance with the quality of the generic drug (GMP) - the generic and the original drug. This raises the question: how do generics differ from original medicines (OLM)?

If we evaluate generics and generic drugs by quality and effectiveness of use, then the answer is clear: nothing. A generic is a reproduced innovative drug for which the patent protection period has expired. The generic has the same composition of active ingredients and a similar dosage form as the OLS. Generics benefit from OLS in terms of price, because their cost is significantly lower. Manufacturers of VLS do not incur costs for the development and testing of drugs; they copy the chemical formula, so the production of generics is cheaper. It has been established that 50% of ODS manufacturers are engaged in the production of generics.

To obtain permission to market a particular drug in a particular country, the manufacturer must provide data on the bioequivalence of the generic drug in relation to its branded analogue. In addition, VLS manufacturers invest 6 to 16% of their revenues in research and development activities to ensure the quality, safety and effectiveness of their products. Manufacturers of generic drugs conduct independent research and develop their own formulations, since the EML data is not disclosed to third parties. Like brand-name drugs, generics are produced in factories that meet Good Manufacturing Practice (GMP) standards and are periodically inspected by patent organizations. Practice has shown that the use of generics contributes to the full supply of medicines to the population with low and middle incomes. VLS provide a choice for the doctor and the patient.

In connection with the speedy transition to international GMP standards, it is necessary to ensure accurate reproduction of the EML, which guarantees the quality of the generic at the stage of its creation. GMP standards guarantee, for both OLS and VLS, responsible handling of raw materials, including excipients, and competition at every stage of the life cycle. All that I have stated allows me to conclude: in terms of their pharmacological properties, generics can replace OLS.

THERE IS NO UNIFORM APPROACH TO PATENT RIGHTS FOR GENERIC DRUGS

Zalesov Alexander Vladimirovich
Deputy General Director, Head of Legal Service of Soyuzpatent LLC

Russian patent legislation is in full compliance with international standards, incl. and on trade aspects. At the same time, Russian legislation and judicial practice are quite different when it comes to the area regulating the circulation of pharmaceutical products. In particular, in Russia there is almost no regulatory procedure that guarantees the entry of VLS into the pharmaceutical market, so that the legitimate interests of the patent holder are taken into account. Hence the conflict between VLS and OLS. There is a provision in the law that allows registration to be canceled if the distribution of certain drugs was considered a failure. You can apply for registration of a generic medicinal product only after the patent has expired. In Russia, it is easy to exercise your patent rights, and therefore the legitimate interests of the patent holder will be respected, but illegal ones will not be satisfied.

Registration of a pharmaceutical drug is a long process that begins with manufacturing and research, during which industrial batches are produced, the technological process for drug production is being developed, serious preclinical, pharmacological and toxicological clinical studies are carried out, and a large number of documents are drawn up. At the same time, a ban on registration of a drug containing a patented invention is an additional guarantee against patent infringement. Its absence opens up wide scope for abuse in the drug market.

Any patent holder strives to ensure that the term of his patent lasts as long as possible. To obtain a primary patent, registration of a molecule of the active substance is typical; for its application, it is important to prove that there is a proven method for its synthesis, and to obtain a preliminary assessment of its activity. The primary patent has a validity period of 20 years. It may be extended if registration took more than 5 years. It is known that the cancellation of the state registration of a VLAN does not entail the automatic cancellation of the decision to extend the validity of the patent. An application for extension of the patent term may be received after the expiration of the main 20-year patent term and will be considered if the patent was still valid at the time of receipt.

Abuse of a patent in international practice, according to the Paris Convention for the Protection of the Rights of the Patent Holder, is prohibited and entails its cancellation. Patent abuse can be considered an illegal monopoly or a violation of the rules of healthy competition. To ensure a timely response to the case of patent abuse, the patent holder should carry out constant monitoring and promptly notify the relevant authorities of the extension of the patent term.

ABOUT THE TERMS OF PROTECTION OF PRE-CLINICAL AND CLINICAL STUDIES

Plieva Madina Robertovna
Director of Legal Affairs of the Association of International Pharmaceutical Manufacturers (AIPM)

WTO protection affects, among other things: Agreement on the Protection of Intellectual Property Rights (TRIPS), the provisions of which are already partially reflected in Russian legislation. The protection of preclinical and clinical research data, which is equated to intellectual property, is subject to Federal Law No. 323-FZ “On the fundamentals of protecting the health of citizens of the Russian Federation.” According to this document, a number of regulations prohibit the registration of generics within 6 years from the date of registration of the original drug, citing data from preclinical and clinical studies of the reference drug.

In EU countries, the protection period for data from preclinical and clinical studies is 10 years. The period consists of 8 years, during which it is impossible to submit an application for registration of a drug, and during the next 2 years it is impossible to bring the drug to the market. If a new drug is used in pediatrics, then 5 years are added to the time it takes to bring the drug to market. In the USA, for small-molecule drugs, the period of data protection for preclinical and clinical studies with subsequent procedures is 5 years, it increases for drugs used in pediatric practice. For biological products, the time period for bringing them to market is 12 years. In Canada, a similar period of validity lasts 8 years, of which 6 years the drug cannot be registered and introduced into the pharmaceutical market.

For more successful competition between generics and VLS, the state can adjust the terms of drug protection, which is quite feasible in accordance with Federal Law No. 61-FZ “On the Circulation of Medicines,” which provides for transition points from research to practice. Probably, the terms of protection of data from preclinical and clinical studies for 4 years for chemical products, and up to 3 years for biological products, can be considered more optimal. Guarantees of such protection will help increase the investment attractiveness of the Russian market for leading foreign pharmaceutical companies and will make their work in Russia more predictable. Data protection will provide an additional incentive for costly research to develop innovative medicines.

All over the world, the number of people saving on medicines is growing. In Russia, more than half of the market is accounted for by generics - inexpensive copies of original drugs whose patent has expired. Is there a noticeable difference between a patented product and an analogue?

And the originals

At the beginning of November, the State Duma should submit for consideration the bill “On Amendments to the Federal Law “On the Circulation of Medicines” and Article 333.32.1 of Part Two of the Tax Code of the Russian Federation.” For the first time in the history of Russian pharmaceuticals, legislators are trying to provide a legal definition of interchangeable drugs. Such close attention to the problem is the best evidence that copies of original drugs whose patent has expired (generic) have become firmly established in our lives. Moreover, first of all, the near future of healthcare is associated with them, and not only in Russia, where, according to some estimates, they already account for more than half of the market. If you believe the PwC forecast, by 2020 Russia will annually spend $10.9 billion on generics and no more than $3.9 billion on innovative drugs.

The functioning of the pharmaceutical market is simple. Manufacturers from time to time release new ones to the market, which are based on original molecules and new production technologies. Since their development required significant funds and a lot of time, for the first two decades the manufacturer’s right to produce the original drug was protected by a patent. After this period, other companies have the opportunity to make copies - generics. In this case, you will no longer have to spend resources on development, research and promotion, so the drug will be cheaper. The price of the original drug and the generic differs by an average of 30-40 percent.

To appear on the market, a generic manufacturer must prove pharmaceutical, pharmacokinetic and therapeutic equivalence to the original drug. Pharmaceutical equivalence means that the generic contains the same active ingredients in the same dosage form, is intended for the same route of administration and is identical to the original in terms of potency or concentration of active substances. Pharmacokinetic, or bioequivalence, suggests that the same amount of the active ingredient of both drugs is absorbed into the body at the same rate.

A generic drug is considered therapeutically equivalent if it acts on the patient’s body in the same way as the original.

In Russia, generics are tested only for bioequivalence. It is believed that there is no need to prove the identity of the effect of their active substance on the body: the chemical formula of the original drug and the analogue is the same.

When announcing special auctions for public procurement at tenders, the Ministry of Health indicates the international nonproprietary name (INN) in the documentation; companies submit applications for the supply of both original drugs and their analogues. After comparing several criteria, including price, the ministry selects the most suitable drug.

President of the Patient Advocates League Alexander Saversky believes: if we talk about the national scale of solving the problem of drug supply, then generics are necessary. For example, when the Ministry of Health began purchasing drugs under the “7 nosologies” program, due to the lower cost of generics, competition arose between pharmaceutical manufacturers and prices for hemophilia therapy fell by 40 percent. As a result, using the budget allocated for the program, the state will provide medicines to a larger number of people in need.

Head of the Department for Control of the Social Sphere and Trade of the Federal Antimonopoly Service (FAS) Timofey Nizhegorodtsev says that the state uses the funds saved as a result of this approach for new health care programs. In his opinion, the introduction and expansion of drug insurance programs in the United States became possible precisely thanks to the active use of generics.

Indeed, in the treatment of many chronic diseases, especially cardiovascular diseases, regular medication intake in the proper dosage is important. It is important that the patient can constantly buy the drug at affordable prices. And in this case, generics, due to their low prices, guarantee constant use of drugs and the effectiveness of treatment.

In addition, Mr. Nizhegorodtsev believes, the development of the generics market encourages manufacturers of original drugs to continue development and create new ones: “If there were no guardians in the form of generic companies, then the originators could indefinitely exploit outdated developments and not engage in innovation.” Moreover, according to the FAS representative, the originators “recoup” their costs while the patent protection for their drug is in effect, since the price for it is practically not controlled.

Expert opinions agree on one thing: generics are a good idea, very relevant for Russia, which today is forced to save even on healthcare. However, perhaps only a few of them recommend completely trusting these drugs.

According to a number of experts, generic drugs differ from each other, it depends on the raw materials, technological components, packaging, and fillers. Sometimes these are completely different drugs that are combined under one INN. “We see this in patients,” says the psychiatrist Valery Zarubin.

Indeed, in an effort to cut costs, unscrupulous generic manufacturers buy cheaper raw materials. The product manager of a large foreign pharmaceutical company assures: original drugs are distinguished by a stable concentration of the active substance, while for generics the concentration is not strictly regulated, but within a certain range. When treating with certain drugs, dosage fluctuations are unacceptable.

A classic example is . An unstable concentration can negate the bactericidal effect, the infection will manifest itself again, but it will already adapt to this antibiotic. In addition, there are no inert excipients, and low-quality substances can cause adverse reactions.

Professor of the Department of General Pharmaceutical and Biomedical Technology of RUDN University Doctor of Science Praskovya Mizina notes that excipients are one of the most important pharmaceutical factors influencing the therapeutic effect of a drug and its equivalence: “An excipient ultimately can, I’m not saying that it always does, but it can have an impact on therapeutic equivalence; there are no absolutely indifferent excipients exists".

The director of the Institute of Health Economics at the National Research University Higher School of Economics shares a similar point of view about the need for a more careful selection of generics. Larisa Popovich: “The problem is not the diseases, but the individual reaction of the body to the generic drug. Bioequivalence of a generic does not mean therapeutic equivalence.” The selection of the dose and nature of a drug with a very narrow therapeutic index (for example, in the field of organ transplantation) is purely individual. In such situations, replacing the drug (with a generic or, conversely, the original) is undesirable if there is positive dynamics on the chosen drug, Larisa Popovich is sure.

In our country, only the lazy ones do not say that generics are of low quality, ineffective drugs, but there is no evidence, there are only personal impressions. We need real investigations and conclusions, he says Timofey Nizhegorodtsev, who is convinced of the safety and effectiveness of generics. - The perception of the issue of interchangeability lies more in the plane of education, ethics, requirements, rather than science. Some doctors say that generics contain a different stabilizing substance - a molecule that affects the therapeutic effect of the drug. This is nonsense, because if the stabilizing substance has at least some effect, there will be other indications for use, this is a different drug.

Given the growing preference for copies, it may seem that pharmaceutical manufacturers will gradually switch exclusively to the production of less expensive drugs - generics, and the future of innovative developments will be in question. Experts assure: there is no threat to new original drugs.

Vice President for Strategic Development at Akrikhin Rustam Iksanov I am sure: the market for innovative drugs is simply changing. “If earlier innovations were concentrated in the field of new chemical molecules, today they are developing around molecules of biological, gene technologies, and drug delivery vehicles.”

Every year in Europe and America the same number of new molecules is registered - approximately 25-30, says the head of the business solutions department at Zentiva. Vadim Ryabokon: “This means that over the past 5-7 years all originators are in a stable situation. Every year, legislation imposes more and more restrictions on them - registration becomes more expensive, and it becomes more difficult to come up with a molecule. However, we must admit: the originators are coping with this task so far.”

After the crisis of 2008 and to this day, there has been a rapid growth in sales of generics, copies of original drugs whose patent has expired: with an identical effect on the body, copies are much cheaper than the original.