The regulatory regimei Classification
The Pharmaceutical Law defines medicines as substances or their combinations that have the following classification features:
- capable of contact with the human or animal body, or penetrating into the organs and tissues of the human or animal body;
- applied for the prevention, diagnosis (except for substances that do not make contact with the human or animal body) and treatment of disease, rehabilitation, or preservation, prevention or interruption of pregnancy; and
- obtained from the blood, blood plasma, organs or tissues of a human being or animal, from plants, minerals using synthetic methods or using biological techniques.
Medicines fall into two categories:
- pharmaceutical substances – active ingredients of biological, biotechnological, mineral or chemical origin, with pharmaceutical activity, intended for the manufacturing and production of pharmaceutical medicines and determining their effectiveness; or
- pharmaceutical medicines – pharmaceutical products in dosage form, used for the prevention, diagnosis or treatment of disease, rehabilitation, or preservation, prevention or interruption of pregnancy.
Further classifications defined by the Pharmaceutical Law are: referential (original), generic, biosimilar and interchangeable medicines; biological, immunobiological, biotechnological, gene therapy medicines; botanical and homeopathic medicines, narcotic and psychoactive medicines, radiopharmaceutical drugs; and adulterated and counterfeit medicines.
Medical devices have the following classification features:
- they are instruments, apparatus, tools, equipment, materials and other products, applied for medical purposes, separately or in combination, as well as with other accessories, that are necessary for application, including special software;
- they are intended by the manufacturer for prevention, diagnosis, treatment and medical rehabilitation, health monitoring, medical research, recovery, substitution, change of anatomical structure or physiological functions of the body, or prevention or interruption of pregnancy; and
- their function is achieved not by pharmacological, immunobiological, genetic or metabolic influence.
The new Federal Law No. 180-FZ on biomedical cell products (adopted on 23 June 2016) has been in effect since 1 January 2017. This law regulates development, trials and other aspects of commercialisation of biomedical cell products for treating diseases, as well as citing various types of such products and the biological material necessary for the production of such products.
Occasionally, problems arise because of the distinction between medicines or medical devices and food products (including biological food additives) and cosmetics. In the event of a dispute, it should be borne in mind that all these products have different regulatory regimes, and it is necessary that they be governed by the criteria stipulated in the related legislation. Apart from the specific regulatory issues, there may be different consequences in terms of import duties (e.g., some products may attract a higher rate of state customs duty), advertising requirements and terms of sale. Judicial practice has seen the customs authority, for example, refusing to classify silicone gel as a medical device (classified by the company as a type of bandage), claiming that the gel was cosmetic and therefore subject to the increased rate of import duty; however, in subsequent litigation, the company managed to prove that this gel was, in fact, a medical device, used during the treatment of burns and scars in specialised institutions, which was also confirmed by the related marketing authorisation (MA) from the competent state authority, and by expert opinions. Cosmetic products, pursuant to the effective legislation, are used for rendering a more pleasant appearance to the skin. In this case, the courts agreed with the applicant and revoked the customs authority's classification decision.ii Non-clinical studies
Pre-clinical trials are held for the use of chemical, physical, biological, microbiological, pharmacological, toxicological and other experimental research on the substance, drug and physical effect, means, methods and technologies of preventive measures, diagnostics and treatment by applying scientific methods of evaluation for the purpose of researching a specific effect and or proof of safety for health.
Pre-clinical trials are governed by good laboratory practice, the specific focus of which is, among other things, requirements for research laboratories and related documents.
Use of the information in the results of pre-clinical trials for commercial purposes is not allowed within the first six years without the consent of the owner of the information. However, in the case of generic medicines, the applicant is allowed to use a review of scientific publications on the results of pre-clinical trials of the original product.iii Clinical trials
A clinical trial is defined as the study of diagnostic, therapeutic, prophylactic and pharmacological features of the drug during its use on human beings and animals, including the processes of absorption, distribution, excretion and changes by scientific methods to obtain evidence for the safety, quality and efficacy of the drug, data on adverse reactions in the human or animal body and the effect of its interactions with other drugs and food or feed. The Pharmaceutical Law also encompasses multi-institutional, international multi-institutional and post-registration clinical trials.
Clinical trials are undertaken upon filing an application for drug registration and approval from the quality and ethics committee. Compliance with the rules of clinical practice as approved by the MoH is obligatory.
Use of the information in the results of pre-clinical trials for commercial purposes is not allowed within the first six years without the consent of the owner of the information.
For generic drugs, full-scale clinical trials may not be undertaken – in this case the applicant is allowed to submit bioequivalence trial results.
The management of a clinical trial may be exercised by the sponsor itself, educational facilities or research institutions, but clinical trials as such should be undertaken in medical institutions duly accredited by the MoH in accordance with the requirements as approved by the Russian government. Relations between the clinical trial authorisation (CTA) holder and the accredited medical institution are regulated by a private contract between them. This contract should contain certain essential features: the terms of the trial; an indication of the total costs, including remunerations to the researcher (co-researcher); and a description of the form of report for submission to the MoH.
The chief officer of the medical institution appoints the researcher (co-researcher), who selects patients for the clinical trials. Patients should participate in the trials voluntarily.
The Pharmaceutical Law provides the outline of the requirements that are set out for patients. Requirements are also set out regarding the information that should be included on the written consent form completed by the patient, namely:
- details of the drug, its safety and risks;
- the terms of participation;
- what the patient should do in the event of side effects;
- insurance conditions; and
- confidentiality guarantees.
Informed consent is obligatory, which is confirmed by the patient's signature (or the signature of his or her duly authorised representative) on an information list for the patient. Patients have the right to terminate their participation in a trial at any time.
Minors may act as patients only with the written consent of their parents and on condition that the trial is specifically focused on the aspects of using the drug on minors.
People with mental afflictions may participate in clinical trials for drugs intended for the treatment of mental afflictions on the condition that their representatives give their written consent.
Certain sections of the population cannot participate in clinical trials, such as:
- law enforcement officers;
- military officers (except for trials of drugs developed specifically for use in warfare, emergency situations or other similar circumstances);
- pregnant women (except for trials of drugs intended only for pregnant women);
- orphaned children; and
- imprisoned people.
The CTA holder is obliged to insure the patients against death (cover of 2 million roubles) or disability (cover ranges from 300,000 to 1.5 million roubles, depending on the degree of impairment to health) as result of the clinical trial. A patient cannot participate in a trial should the CTA holder fail to obtain insurance for that person.
Clinical trials results must be recorded and safety reporting is obligatory. Should the trial be terminated, the CTA holder must inform the MoH of the reasons for the termination.iv Named-patient and compassionate use procedures
In Russia, the general rule is that an MA is required for administering medicine, although the following exceptions exist when an MA is not required:
- drugs produced by pharmacies according to the prescriptions and requirements of medicinal institutions;
- drugs purchased by individuals abroad and intended for personal use;
- drugs imported to Russia for providing medical help owing to the life-saving necessity of the patient based on the regulator's decision;
- drugs imported to Russia based on the regulator's permission for holding clinical trials or for holding examinations for state registration;
- pharmaceutical substances;
- radiopharmaceutical drugs produced directly by medical institutions as per the established regulations; or
- drugs manufactured for export.
Marketing of a drug is allowed only once the MA is approved (except for those circumstances described in Section II.iv). The stages of the pre-marketing procedure are as follows:
- Development stage: the search for new pharmaceutically active ingredients, their subsequent examination, pre-clinical trials and development of manufacturing technologies. It is not possible to determine the specific timing of this stage, as it depends on the activity of the sponsor.
- State registration: the application for CTAs (if necessary) and examination of the quality, efficacy and safety of the drug. The general timing for original drugs is approximately 160 business days (excluding the time for clinical trials) and 80 days for medicines under the fast-track examination procedure. The following stages may be discerned:
- the applicant files an application with the MoH and the registration dossier is prepared;
- the registration dossier is reviewed by the specialised institution by the MoH, considering whether the CTA may be issued – an ethics committee also participates at this point;
- based on the results of this examination and ethics committee review, a decision on the issuance of the CTA by the MoH;
- the CTA holder launches clinical trials (by entering into an agreement with the accredited medical institution, arranging insurance for the patients, etc.);
- the results of the clinical trials are submitted to the MoH;
- the examination of the drug's quality, efficacy and safety, as well as a risk-benefit analysis is undertaken by the specialised institution approved by the MoH; and
- based on the results of the examination, the MoH issues the MA, requests a re-examination or refuses to issue the MA.
Similar stages exist for the registration of medical devices, depending on their class.Special procedures
An expedited (fast-track) procedure is applicable to the following types of drugs:
- orphan medicines;
- the first three medicinal products for registration in Russia as generic products; and
- medicines for use exclusively by minors.
The fast-track procedure does not apply to:
- biosimilar medicines;
- original medicines (except for orphan medicines);
- generic medicines, except for:
- the first three medicinal products for registration in Russia as generic products; and
- medicines for use exclusively by minors;
- new combinations of previously registered medicines; and
- medicines, registered previously, but manufactured in other pharmaceutical dosage forms in accordance with the list of pharmaceutical dosage forms and in the new dosage.
For generic drugs, reference to a review of scientific publications on the results of pre-clinical trials of the original product (instead of pre-clinical trials of a generic drug) and bioequivalence trials (instead of clinical trials) is allowed.
All the aforementioned tests (quality, safety, etc.) are undertaken during the expedited procedure, except for clinical trials, and the requirements during the examinations are the same as in the general procedure.Fees
The specific fees depending on the type of the CTA or depending on the medicine at issue, as well as depending on the registration forum (Russia or EAEU) are provided in the Russian Tax Code. The following are examples of applied fees: 110,000 roubles for Russian examination to issue the CTA; and 325,000 roubles for risk-benefit examination to issue the MA.
For medical devices, the fees for examination, depending on the class, may range from 45,000 to 115,000 roubles. The fee to issue an MA is 7,000 roubles.vi Regulatory incentivesPatent protection
Pharmaceutical products may be protected by a substance patent, a process patent or a use patent. Patent protection is effective for 20 years starting from the priority date. Regular renewals are required to keep the patent in force.
The patentee has the exclusive right to import the patented product into Russia, manufacture, use, offer for sale, sell or otherwise commercialise the product; this matches with the patentee's right to forbid other persons from infringing that exclusive right.
The list of activities that fall under the scope of a patent is non-exhaustive. The following types of activities are specifically mentioned:
- importation into Russia, manufacturing, working, offering for sale, sale or other commercialisation or storage of the product according to the purpose for which the subject of the patent is used;
- the same actions in (a) in respect of a product, manufactured directly from the patented process;
- the same actions in (b) in respect of:
- a device, if such a device automatically functions using the patented process; and
- a product working in accordance with the purposes indicated in the manufacturer's claims; and
- implementation of a process in which the invention is used, including by means of using the process.
Research on a product or process in which the patent is used, or experimentation on it, is not a patent infringement, but if the defendant's activities extend beyond the scope of research or experimentation (e.g., the defendant starts commercialisation), its activities may be considered an infringement.
In judicial practice, the principle is followed that submission of a drug for an MA before the expiry of a patent does not as such constitute infringement of a patent, but further commercialisation of a drug before the patent expires is viewed as an infringement. Furthermore, if the generic MA is filed a significant amount of time prior to expiry of the patent, the patentee may argue that there is a threat of patent infringement, and an example of this has been seen in judicial practice, where the court recognised the activities of early filing of an MA and subsequent maximum sale price registration as constituting a threat of infringement.
If the court adjudicates that the commercialisation of a specific drug is a breach of the patent legislation, the MoH is obliged to revoke the MA.Extension of patent protection
Extension of a pharmaceutical patent is possible for no more than five years if more than five years elapse between the filing date and the date when the MA is issued.Data exclusivity
It is not permitted to use (without consent), for commercial purposes, the information in the results of pre-clinical trials and clinical trials, submitted by an applicant for the original product within six years of the registration of the original medicine in Russia.
It is permitted to file for the MA four years after registration of the original product (three years for biosimilars). Non-compliance with the term results in the MoH dismissing a generic drug application.vii Post-approval controls
The MoH and Roszdravnadzor are competent for monitoring the safety of drugs. There are specific rules on monitoring safety, as well as guidelines introduced by the Roszdravnadzor with regard to in-house monitoring of drugs safety.
As part of pharmacovigilance, the MA holder and other entities involved in product commercialisation are obliged to report any side effects not listed in the instructions for use of the drug, serious adverse reactions, unexpected adverse reactions in the application of drugs, and the peculiarities of drug interactions with other drugs that have been identified in clinical trials. The MoH is entitled to suspend commercialisation of a product in the event of any such report.
Furthermore, as of 1 January 2016, the MA holder is obliged to report regularly to the regulator with the results of pharmacovigilance.
The MA may be revoked in the following cases:
- if, as result of state safety monitoring, it is evident that a risk to health exists;
- a voluntary revocation application is filed;
- if an MA was issued for five years, but upon expiry of that term no confirmation of state registration exists;
- in the event that the registration dossier needs to be amended, but the MA holder fails to respond to the related request within 30 days;
- if an MA is issued for a trade name that has already been registered for another drug with a different combination of active ingredients;
- if one and the same drug has been registered under various trade names;
- if a court renders a decision on infringement of IP rights during commercialisation;
- if the drug is not commercialised within three years;
- when there has been a failure to comply with pharmacovigilance obligations; or
- if there has been a refusal to amend an instruction for use if the risk of taking the drug exceeds the effect of using the drug.
Any amendments or changes regarding the MA holder should be notified to and approved by the MoH.viii Manufacturing controls
The manufacturing of a drug is allowed once the appropriate licence is obtained by the manufacturer in Russia; licence control is exercised regularly.
The manufacturing procedure should comply with the rules of good manufacturing practice approved by the Ministry of Industry and Commerce, which set out specific technical requirements depending on the type of pharmaceutical product.
The manufacturer is obliged to develop internal regulations that include a list of the pharmaceutical substances and auxiliary ingredients, the data on the equipment used in manufacturing and a description of the technological process and control methods for each stage of manufacturing.ix Advertising and promotion
Advertising and promotion of drugs (and the following points (c) to (j) also relating to medical equipment) is subject to general advertising and competition rules (such as restrictions on unfair advertising and unfair completion, including incorrect comparisons) and specific restrictions and prohibitions, under which it should not:
- be addressed to minors;
- cite specific cases of cure or improvement of health (not applied to advertising intended only for medical professionals in specialist publications or events);
- use expressions of gratitude by specific individuals (not applied to advertising intended only for medical professionals in specialist publications or events);
- invoke the results of obligatory clinical trials or examinations as evidence of any advantages of the drug;
- contain the assertion that consumers have certain diseases or health problems;
- give the impression that a healthy person should use the drug (not applied to advertising of preventive drugs);
- give the impression that by using the drug, it is not necessary to consult a doctor;
- guarantee favourable effects of the drug, its safety and effectiveness, and the absence of side effects;
- imply that the drug is a biologically active additive or food supplement or any other product that is not a medicine; and
- imply that safety or effectiveness of the drug is explained by its natural origin.
The description of the features and characteristics of the drug should not go beyond the scope of the instructions for use. A special notice is also required that instructs the user to read the instructions for use and of the need to consult a doctor (except for advertising aimed at medical professionals).
The advertising of prescription medicines or medical devices for use where special knowledge is required is allowed only if the advertising is aimed at professionals (i.e., only at the related conferences or in specialist publications). Promotional events at which drug samples that contain narcotic and psychotropic ingredients are distributed are forbidden.
Special rules on promotional communications between representatives of pharmaceutical companies and hospital or pharmacy employees are also established to prevent conflicts of interest (such as a restriction on the distribution of promotional merchandise among doctors).x Distributors and wholesalers
The initial distribution of drugs and medical devices is exercised by the holders of the MA and the related licences (to manufacture drugs and medical devices). Wholesale and retail sales of drugs are subject to licensing (sales of medical devices are not licensed).
In the sale of drugs, it is possible to apply for both wholesale and retail licences.
As part of the government incentive to have an increased level of localised manufacturing, restrictions on state procurement of foreign pharmaceuticals were imposed at the end of 2015.
Furthermore, the wholesale and retail of medicines are subject to good distribution practices and good pharmacy practices, and compliance with these practices is subject to state control.xi Classification of products
A distinction is made between drugs that may not be sold to end consumers without a prescription from a doctor (prescription drugs) and drugs that may be sold over the counter. The MoH regulates the procedure of doctors issuing prescriptions. There is also a limit on the total number of medicines that may be covered by one prescription. Classification of a drug as a prescription drug affects its advertising in that it is only allowed if aimed at professionals.xii Imports and exports
The import of drugs into Russia is regulated in detail by the government within the framework provided by the Pharmaceutical Law.
The precondition of importation is that there should be a certificate from the manufacturer confirming the compliance of the drugs being imported with the requirements of the pharmacopoeia monograph or – in its absence – with the regulatory documents.
There are specific categories of entities that may import drugs (such as sponsors, wholesale companies and medical institutions). Importation for personal needs by individuals is also allowed.
As a general rule, there should be a Russian MA for imported drugs, but exceptions are made for clinical trials and their import by individuals for personal use, or cases when there is a decision by the regulator to allow use of a specific medicine for a specific individual. A permit to import, issued by the MoH, is generally required.
The export of drugs from Russia may be exercised without restriction, although a special procedure is provided for drugs being exported for use in humanitarian aid or emergency situations.xiii Controlled substances
Narcotics and psychotropic drugs are subject to detailed control over commercialisation (manufacturing and storage) and use. Every aspect of their commercialisation is subject to specific requirements as set out in the Pharmaceutical Law. The list of substances to which this applies is provided by the government.xiv Enforcement
While the MoH is the main regulatory authority, enforcement is mainly undertaken by Roszdravnadzor. Monitoring is exercised and compliance with licence requirements is observed. Penalties may range from administrative fines to criminal punishments. Revocation or suspension of product commercialisation may also take place as a sanction.