30 December 2022

Clinical Trials of Medicinal Products in Russia: Legal Regulation

December 30, 2022

BRACE Law Firm ©

Any medicinal product for medical use must be effective and safe. However, for a long time in the history of medicine, there were no serious scientific trials of the efficacy and safety of medicinal products. Even in the early 20th century, such trials were unregulated and evaluative in nature.

The catalyst for developing rules for conducting clinical studies (hereinafter "clinical trials", "clinical studies") involving humans was the tragedy involving the medicinal product Thalidomide, which was launched on the market in 1954 by the German pharmaceutical company Chemie Grünenthal. Initially, the product was considered a safe sleeping pill and sedative. However, no studies on humans were conducted, as the legislation of that time did not require it. Subsequently, in countries where this product was used, there was a mass birth of children with developmental anomalies ("seal limbs") and other deviations caused by pregnant women taking this product. Furthermore, the earlier Nuremberg trials of Nazi doctors who conducted medical experiments on prisoners highlighted the need for legislative consolidation of the rights of patients participating in clinical studies.

Currently, the registration of a new medicine and its market launch is impossible without conducting long-term clinical studies involving humans.

This article discusses the procedure for conducting clinical studies of medicinal products for medical use and the guarantees provided to their participants.

Concept and Types of Clinical Studies of Medicinal Products

The basic regulatory act determining the legal basis for conducting clinical studies of medicinal products in the Russian Federation is Federal Law No. 61-FZ dated April 12, 2010, On Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products", "Law No. 61-FZ"). Chapter 7 of the said law is dedicated to the regulation of clinical studies of medicinal products for medical use.

According to Article 4 of the Law on Circulation of Medicinal Products, a clinical study is understood as the study of diagnostic, therapeutic, prophylactic, and pharmacological properties of a medicinal product in the process of its use in humans or animals using scientific assessment methods to obtain evidence of the safety, quality, and efficacy of the medicinal product, data on adverse reactions of the human or animal organism to the use of the medicinal product, and the effect of its interaction with other medicinal products and (or) food products or feed.

Thus, clinical studies are used to assess the safety and efficacy of a medicinal product.

The objects of clinical trials are:

The pharmaceutical form of the pharmacologically active substance or placebo (a substance without obvious therapeutic properties used to simulate a medicinal product) studied in the clinical study;
A registered medicinal product, if the method of its use differs from that approved during state registration, or when used for a new indication, or to obtain additional information on the approved indication.

The organization of clinical trials of a medicinal product for medical use may be initiated by:

The developer of the medicinal product;
Educational organizations of higher or additional professional education;
Scientific research organizations.

Clinical trials of medicinal products for medical use are carried out in medical organizations. Part 7 of Article 38 of the Law on Circulation of Medicinal Products previously stipulated that a medical organization must have accreditation to participate in a clinical trial. Effective January 1, 2021, the Accreditation Rules [1] were repealed, and therefore, according to clarifications from the Ministry of Health of Russia, accreditation of a medical institution for participation in a CS and the extension of the accreditation certificate are not required [2]. To eliminate the conflict of laws, the Ministry of Health of Russia has developed a draft of amendments to the Law on Circulation of Medicinal Products.

Furthermore, it is permitted to involve other legal entities of any organizational and legal form in conducting clinical trials, provided that these trials comply with the established requirements.

Law No. 61-FZ identifies the following types of clinical trials depending on the number and composition of the conducting entities and the territory of the study:

Single-center – conducted in one medical organization under a single protocol for the clinical study of a medicinal product;
Multicenter – conducted in two or more medical organizations under a single protocol for the clinical study of a medicinal product;
International multicenter – conducted in various countries under a single protocol for the clinical study of a medicinal product;
Post-registration – conducted after the state registration of a medicinal product to collect additional data on its safety and efficacy, expand indications for the use of the medicinal product, and identify adverse reactions of patients to its action.

In addition, the Law on Circulation of Medicinal Products identifies the following types of clinical trials:

Bioequivalence study of a medicinal product – a type of clinical trial of a medicinal product conducted to determine the rate of absorption and excretion of one or several active substances possessing pharmacological activity, and the amount of the medicinal product reaching the systemic circulation, the results of which allow concluding on the bioequivalence of a generic medicinal product in a certain pharmaceutical form and dosage corresponding to the form and dosage of the reference medicinal product;
Therapeutic equivalence study of medicinal products – a type of clinical trial of medicinal products conducted to identify identical properties of medicinal products of a certain pharmaceutical form, as well as the presence of identical safety and efficacy indicators of medicinal products, and identical clinical effects during their use.

Note that by virtue of Part 2 of Article 38 of the Law on Circulation of Medicinal Products, conducting clinical trials in full is not required for generics (medicinal products containing the same pharmaceutical substance or combination thereof in the same pharmaceutical form as the original medicinal product that entered circulation after the original medicinal product). A bioequivalence study and (or) therapeutic equivalence study is sufficient. During these trials, the rate of absorption, the degree of delivery to the site, and the rate of excretion are compared with the original product, and identical properties, safety indicators, and efficacy of medicinal products are identified, etc.

Authorization to Conduct Clinical Trials

Clinical trials begin only after obtaining authorization for their conduct issued by the Ministry of Health of the Russian Federation (Article 38 of the Law on Circulation of Medicinal Products). The procedure for obtaining it, deadlines, and the list of documents are regulated by the Administrative Regulation of the Ministry of Health of Russia[3].

To obtain authorization to conduct a clinical study, the applicant submits a package of documents to the Ministry of Health of Russia:

Application;
Protocol of the clinical study of the medicinal product for medical use;
Investigator's brochure;
Patient information sheet;
Information on the experience of investigators in relevant specialties and their experience in conducting clinical trials;
Information on medical organizations where the clinical study of the medicinal product for medical use is supposed to be conducted;
Information on the estimated dates for conducting the clinical study of the medicinal product for medical use;
A copy of the compulsory insurance contract indicating the maximum number of patients participating in the clinical study of the medicinal product for medical use;
Information on the composition of the medicinal product for medical use;
A document compiled by the manufacturer of the medicinal product containing the characteristics of the medicinal product;
Information on the license for the production of medicinal products (if production is carried out in the Russian Federation), or information on the manufacturer's compliance with Good Manufacturing Practice (GMP) requirements issued by the authorized body of the country of manufacture of the medicinal product.

A state duty must be paid for actions performed during the consideration of the application (examination of documents, ethical review, actual issuance of permits). The amount of the state duty is determined in Article 333.32.1 of the Tax Code of the Russian Federation depending on the types of actions performed.

Before deciding on the possibility of issuing an authorization, the Ministry of Health of Russia sends documents for examination:

Documentary expertise – to the FSBI "Scientific Center for Expertise of Medicinal Products" of the Ministry of Health of the Russian Federation.
Ethical expertise – to the Council on Ethics under the Ministry of Health of Russia.

The examination of documents is performed in accordance with Order of the Ministry of Health of Russia No. 558n dated August 24, 2017[4]. During its conduct, a commission of experts assesses the scientific validity and scope of preclinical trials, the properties of the medicinal product, and the content of the clinical study protocol. Based on the results of the expertise, a conclusion on the possibility (impossibility) of conducting the clinical study is issued within 30 working days.

The procedure for conducting ethical expertise is regulated by Order of the Ministry of Health and Social Development of Russia No. 753n dated August 26, 2010 [5]. During the ethical expertise, an assessment is made regarding the ethical feasibility of conducting the clinical study: the justifiability of the estimated risk compared to the expected benefit, the justification for canceling or suspending standard treatment of patients participating in the CS, the amount of compensation and conditions for it in the event of the patient's death or harm to their health, etc. The conclusion is also issued within a period not exceeding 30 working days.

Within 5 working days from the date of receipt of the expert conclusions, the Ministry of Health of Russia issues an authorization to conduct the clinical study or makes a decision to refuse to issue the said authorization indicating the reasons for the refusal. The register of issued conclusions is posted on the website of the Ministry of Health of Russia on the Internet.

A refusal to conduct expertise and (or) to issue an authorization for a clinical study may be appealed in court. The challenge is carried out according to the rules of Chapter 24 of the Arbitration Procedure Code of the Russian Federation (Challenging Non-Normative Legal Acts, Decisions and Actions (Omissions) of State Bodies). For example, in Case No. A40-94161/11-149-579, a CJSC applied to the arbitration court with a statement to declare invalid the decision of the Ministry of Health to refuse to issue an authorization for conducting a clinical study of the medicinal product for medical use Algeron. The basis for the refusal was the conclusion of the FSBI Scientific Center for Expertise of Medicinal Products, according to which the data submitted for expertise did not allow assessing the safety of the clinical study or the toxicological properties of the product. Courts of all instances refused to satisfy the application. They indicated that the Ministry of Health of Russia does not re-evaluate the conclusions of expert examinations, and the presence of a negative expert conclusion is sufficient to make a decision on refusal [6].

Procedure for Conducting Clinical Studies

Clinical studies authorized by the Ministry of Health of Russia are conducted in accordance with the Rules of Good Clinical Practice, approved by Order of the Ministry of Health No. 200n dated April 1, 2016 (the "National Good Clinical Practice Rules"). The Rules of Good Clinical Practice of the Eurasian Economic Union were approved by Decision of the Council of the Eurasian Economic Commission No. 79 dated November 3, 2016 (the "Eurasian Good Clinical Practice Rules"). In addition, when conducting a CLINICAL TRIAL, it is necessary to be guided by GOST R 52379-2005 "Good Clinical Practice", approved by Order of Rosstandart No. 232-st dated September 27, 2005.

In practice, clinical trials consist of several phases, each of which takes considerable time:

Phase I – testing the medicinal product on healthy volunteers to assess primary safety and tolerability;
Phase II – testing on a small number of patients with a specific disease for which the product was developed to select optimal dosages of the medicinal product and the course of treatment;
Phase III – testing on a large number of patients of various ages, at various stages of the disease, with various concomitant pathologies to assess the safety and efficacy of the medicinal product and select optimal doses;
Phase IV – post-registration trials to explore possibilities for expanding indications for use, improving dosing regimens, and identifying previously unknown side effects.

Let us examine the procedure for conducting clinical studies in more detail.

A clinical study is conducted based on a contract for conducting a clinical study of a medicinal product for medical use, concluded between the organization that received the authorization to conduct the study and the medical organization directly carrying out such study. The contract for conducting a clinical study of a medicinal product for medical use must contain:

Conditions and terms of conducting the study;
The total cost of the study program, indicating the amount intended for payments to investigators and co-investigators;
The form of presentation of the results of the study.

The head of the medical organization conducting the clinical trial appoints an investigator responsible for its conduct. The investigator must have a medical specialty corresponding to the clinical trial being conducted and at least 3 years of work experience in study programs; co-investigators may also be appointed.

The investigator selects patients who can be recruited to participate in the clinical study based on medical indications. Patient participation in a clinical trial is strictly voluntary. The patient or their legal representative has the right to refuse participation in the clinical study at any stage of its conduct. Article 43 of Law No. 61-FZ establishes restrictions on the recruitment of certain categories of persons for a CS. Thus, it is prohibited to conduct a clinical study of a medicinal product involving as patients:

Orphans and children left without parental care;
Women during pregnancy, women during breastfeeding (except for the study of a medicinal product intended for such women and provided that all necessary measures are taken to exclude the risk of harm to the woman and the child);
Military personnel (except for the study of a product developed for use in conditions of hostilities, emergencies, prevention and treatment of diseases and injuries resulting from exposure to adverse chemical, biological, and radiation factors. This exception does not apply to military personnel undergoing military service by conscription. The ban on their recruitment is absolute);
Law enforcement officers;
Persons serving sentences in places of deprivation of liberty or held in custody in pre-trial detention centers.

Conducting a clinical study involving children is permitted:

If its conduct is necessary to promote the health of children or prevent infectious diseases in childhood;
If the purpose of the study is to obtain data on the best dosage for treating children.

Prior to its conduct, a clinical study must be conducted on adults (except cases where the product is intended exclusively for children) and with the written consent of their parents or adoptive parents.

A CS of a medicinal product intended for the treatment of mental illnesses is permitted involving persons with mental illnesses only with the written consent of their legal representatives.

Clinical studies are conducted in accordance with strictly defined study protocols regulating the procedure for their conduct. The head of the medical organization informs the Ministry of Health of Russia within 3 working days from the start of the clinical trial. Making changes to the CS protocol is carried out exclusively by decision of this body.

A clinical study is suspended or terminated if a danger to the life or health of patients is discovered during its conduct.

A report on the CS results must be submitted to the Ministry of Health of Russia within a period not exceeding 3 (three) months from the date of its completion, suspension, or termination (according to Art. 40 of Law No. 61-FZ).

Guarantees of Rights of Patients Participating in Clinical Studies

Conducting clinical studies on humans necessitates establishing a mechanism for protecting the rights of patients participating in them. Articles 43 – 44 of the Law on Circulation of Medicinal Products are dedicated to this.

Firstly, a mandatory condition for conducting clinical studies is obtaining voluntary informed consent of patients by signing an information sheet.

The law establishes a list of information that participants must receive before the start of clinical studies:

Regarding the medicinal product and the essence of the clinical study of this medicinal product;
Regarding the safety of the medicinal product, its expected efficacy, and the degree of risk to the patient;
Regarding the conditions of the patient's participation in the clinical study;
Regarding the goals and duration of the clinical study;
Regarding the patient's actions in case of unforeseen effects of the medicinal product on their health status;
Regarding the conditions of compulsory insurance of the patient's life and health;
Regarding the guarantees of confidentiality of the patient's participation in the clinical study.

Consent for the participation of incapacitated persons and children may be given by the legal representative of the clinical study participant. The procedure for obtaining it is regulated in more detail in the National Good Clinical Practice Rules. Thus, by virtue of clauses 53–55 of the National Good Clinical Practice Rules:

Information about the clinical study should contain as few special terms as possible and be understandable to the clinical study participant or their legal representative;
Before obtaining consent, the investigator must provide the clinical study participant or their legal representative with the time necessary to make a decision on participation or refusal of such participation;
The clinical study participant or their legal representative has the right to receive exhaustive and reliable answers to all questions regarding the clinical study;
The clinical study participant or their legal representative must receive a signed and dated copy of the patient information sheet and other materials concerning the conduct of the clinical study. During the clinical study, the participant is informed of all changes to documents and clinical study data concerning their participation.

However, the stated requirements cannot guarantee the patient's correct understanding of the information; therefore, the investigator must approach the information procedure conscientiously, excluding a formal approach, and especially deception or misleading the patient.

Secondly, the law provides for a mechanism of compulsory insurance of the life and health of a patient participating in a clinical study. The rules for compulsory insurance were approved by Decree of the Government of Russia No. 714 dated September 13, 2010.

The policyholder is the organization that received the authorization to organize the clinical trial. The term of the compulsory insurance contract cannot be less than the term of the study.

An insured event under the compulsory insurance contract is the death of the patient or deterioration of their health, including that entailing the establishment of disability, given a causal link between the events that occurred and the intake of the medicinal product.

The insurance payment amount is:

In the event of the death of the insured person: 2 million rubles;
In the event of establishing disability:

Group I: 1.5 million rubles;
Group II: 1 million rubles;
Group III: 500,000 rubles.

In the event of deterioration of the health of the insured person not entailing the establishment of disability: not more than 300,000 rubles.

The amount of insurance payments may be increased based on a court decision.

The following persons have the right to receive an insurance payment:

Disabled persons who were dependents of the deceased insured person or had the right to receive maintenance from them by the day of their death;
A child of the deceased insured person born after their death;
One of the parents, the spouse, or a family member, regardless of their working ability, who does not work and is occupied with caring for the deceased insured person's dependent children, grandchildren, brothers, and sisters who have not reached the age of 14, or who have reached the said age but need outside care due to their health condition according to the conclusion of medical bodies;
Persons who were dependents of the deceased insured person and became disabled within 5 years after their death;
In the absence of the said citizens: parents, spouse, children of the deceased insured person;
In the event of the death of an insured person who did not have an independent income: citizens on whom the insured person was dependent; regarding reimbursement of funeral expenses for a patient who participated in clinical studies of a medicinal product: the person who incurred such expenses.

Despite the insurance payment guaranteed by law in the event of death or damage to health, in practice, it is not so simple to obtain it. Often, the insurance company refuses payment, citing the lack of a causal link between participation in clinical studies and harm to the patient's health or life.

Of course, establishing the presence or absence of such a link is difficult for a court due to the specifics of medical studies, as a result of which the appointment of a forensic examination is necessary for such cases.

Let us cite examples from judicial practice. In Case No. 33-20545/2019, a charitable organization acting in the interests of a CS participant filed a lawsuit against an insurance company to recover 2 million rubles of insurance indemnity and 2 million rubles of penalty. In justification of the claim, it indicated that patient G. took the investigational medicinal product for 5 years and then died. In the pre-trial order, the payment of insurance indemnity was refused due to the lack of a causal link between the intake of the medicinal product and the death of the insured person.

Examining the submitted medical death certificate, the court concluded that G.'s death occurred not as a result of taking the medicinal product, but as a result of a disease diagnosed in him before the start of the clinical studies. Relatives refused a pathological-anatomical examination of the corpse. At the same time, the investigators neither confirmed nor refuted the link between the death and G.'s participation in the study. The court concluded that there was no causal link between G.'s death and his participation in the clinical study of the product and dismissed the lawsuit [7].

Relatives of patients have attempted to challenge the burden of proving the causal link in the Constitutional Court of the Russian Federation. The Court indicated that the presence of a causal link is a necessary element of insurance. It refused to recognize the provisions of Part 3 of Article 44 of the Law on Circulation of Medicinal Products as contradicting the Constitution of the Russian Federation [8].

It is worth noting that contrary judicial practice also exists. For example, in Case No. 33-1354/2019, the court established that patient E. participated in a clinical study for psoriasis treatment. At the 74th week of participation in the clinical study, she was diagnosed with breast cancer. The forensic medical examination concluded that the malignant neoplasm arose during the period of taking the experimental product when its side effects were highly probable. Furthermore, defects were identified in the conduct of the study, which did not provide for a proper assessment of oncogenicity. Insurance indemnity in the amount of 500,000 rubles was recovered from the insurance company, as well as a fine in the amount of 250,000 rubles for failure to satisfy the consumer's requirements voluntarily [9].

Control over Conduct of Clinical Trials

State control over compliance with the Rules of Good Clinical Practice during clinical trial is exercised by Roszdravnadzor. The list of control questions for conducting inspections of clinical studies was approved by Order of Roszdravnadzor No. 8700 dated September 16, 2022.

Despite the apparent regulation of the procedure for conducting clinical trials, given the special importance of the problem, it is necessary to continue improving the norms of legislation. In particular, it is necessary to regulate in more detail the rights of patients during clinical studies and measures to ensure them. Furthermore, it is necessary to expand legal support for the entire process of clinical studies and carry out work to improve the legal literacy of both patients participating in clinical trials and investigators.

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References

[1] Decree of the Government of Russia No. 683 dated September 3, 2010, On Approval of the Rules for Accreditation of Medical Organizations for the Right to Conduct Clinical Trials of Medicinal Products for Medical Use.

[2] Letter of the Ministry of Health of Russia No. 25-2/3045274-4400 dated April 12, 2022, On Cancellation of Accreditation of Medical Organizations for the Right to Conduct Clinical Trials of Medicinal Products for Medical Use.

[3] Approved by Order of the Ministry of Health of Russia No. 20n dated January 19, 2018.

[4] Order of the Ministry of Health No. 558n dated August 24, 2017, On Approval of the Rules for Conducting Expertise of Medicinal Products for Medical Use and Specifics of Expertise of Certain Types of Medicinal Products for Medical Use (reference medicinal products, generic medicinal products, biological medicinal products, biosimilar medicinal products (biosimilars), homeopathic medicinal products, herbal medicinal products, combinations of medicinal products), Forms of Conclusions of the Commission of Experts.

[5] Order of the Ministry of Health and Social Development of Russia No. 753n dated August 26, 2010, On Approval of the Procedure for Organizing and Conducting Ethical Expertise.

[6] Ruling of the Supreme Arbitration Court of the Russian Federation No. VAS-12712/12 dated October 4, 2012, in Case No. A40-94161/11-149-579.

[7] Appellate Ruling of the Moscow City Court dated May 14, 2019, in Case No. 33-20545/2019.

[8] Ruling of the Constitutional Court of the Russian Federation No. 2468-O dated September 30, 2019, On Refusal to Accept for Consideration the Complaint of Citizen Alexander Yuryevich Potapov regarding the Violation of His Constitutional Rights by Part 3 of Article 44 of the Federal Law "On Circulation of Medicinal Products" and Clause 7 of the Standard Rules for Compulsory Insurance of Life and Health of a Patient Participating in Clinical Trials of a Medicinal Product.

[9] Appellate Ruling of the Stavropol Regional Court dated February 19, 2019, in Case No. 33-1354/2019.