The article describes the modern legal aspects of conducting research on real clinical practice both in the countries of the European Union and the United States, as well as in Russia and the EAEU member states.

INTRODUCTION

Despite the fact that abroad real-world studies, as a phenomenon and as a legal institution, have been known for a long time, even in the United States and European countries, their legislative and sectoral regulation differs in detail from country to country. However, in many countries, only the most general references to actual clinical practice trials may exist in legislation. Given the importance of research on actual clinical practice for scientific purposes, this disregard by legislators is surprising. Firms - developers and manufacturers of pharmaceutical products wishing to conduct research on actual clinical practice are faced with the need to be guided by the Good Epidemiological Practice (GEP) rules developed in the United States for use in the tobacco industry when conducting research on the effects of tobacco smoking. requirements of international medical communities and industry associations, as well as its own internal standard operating procedures. That is, special requirements for such research in most countries operate at the level of self-regulation and are aimed at ensuring the quality of projects and their ethics [1].

In the field of law enforcement practice of regulation of this group of studies, the most advanced in the United States and the European Union.

Let's take a closer look at them.

USA

The legal framework in the United States is based on three main documents. The first, the Health Information Technology Act (HITECH, 2009), has facilitated the wider adoption of electronic health records. Further, the 21st Century Cures Act (2016 Public Law 114-255) indicates that the FDA must use a body of evidence from actual clinical practice when registering a new indication for a drug. In general, this law was intended to accelerate the development of medical products in order to deliver innovation faster and more efficiently to patients who need it.

Among other provisions, the Prescription Drug User Fee Act (1992) was amended in 2017 to add article 505F Utilizing real world evidence ) [2], which provided a basis for assessing the potential use of the body of evidence from real clinical practice. Thanks to these amendments, it is necessary to use the body of evidence from real clinical practice to make regulatory decisions.

In 2018, the Framework for the FDA's Real-World Evidence Program was proposed [3]. It includes demonstration projects, stakeholder engagement in internal processes to provide senior management input from pharmaceutical development and manufacturing firms in assessing real-world clinical evidence, and to promote collaborative learning and policy consistency. In addition, this Framework will include guidance documents to assist developers interested in using real-life clinical practice data to generate a body of evidence to support FDA regulatory decisions.

In 2019, the FDA prepared a project "Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics" [4], which describes the sources of such data. This is data obtained from:

• electronic medical archives;
• databases of insurance companies and billing activities;
• data from the pharmacovigilance system;
• patient registers by nosological forms;
• studies of patient-reported outcomes;
• other sources that may provide information about the patient's health, such as wearable medical mobile devices.

From the FDA perspective [4], pragmatic clinical trials or large simplified randomized trials can be helpful in the registration of a new drug.

Data from real clinical practice can be used as a control in non-comparative studies. Observational studies can be used to collect information to support data on drug efficacy. To assess the safety of medicinal products, post-marketing safety studies can be used.

EUROPEAN UNION
In 2016, the European Union (EU) adopted the recommendations "Scientific guidance on post-authorization efficacy studies" [5], according to which randomized clinical trials (for example, pragmatic clinical trials) and non-randomized clinical trials (comparative studies in parallel groups and studies with historical control).

Two main approaches to data acquisition are described, i.e. primary data collection or reuse of existing data (eg from electronic health records). Clinical research in general will rely on the collection of primary data, and on the contrary, the use of electronic health records to facilitate clinical research is a secondary source of data [5].

Patient recruitment, informed consent, confidentiality, patient anonymity and proper documentation of patient information are areas that still need to be addressed in accordance with applicable (local) legal and ethical requirements for clinical research. It is emphasized that pragmatic clinical studies and observational studies can play a special role in the study of drugs in real clinical practice [5].

EU regulators may require drug registration certificate holders to create or work with an existing registry to support post-marketing data collection on the effectiveness and safety of drugs in routine medical practice. It is recommended that existing nosology registries be used as they allow the continued assessment of disease outcomes and the comparison of different treatment options using a similar methodology. Data from existing registers can be supplemented by links to external data sources.

If it is necessary to initiate the creation of a new register, then it should be based on the relevant methodological standards and described in the protocol [5].

THE RUSSIAN FEDERATION
Analysis of studies of real clinical practice in Russia indicates the growing interest of the scientific and medical community and pharmaceutical manufacturers in this topic. However, this attention is faced with a lack of understanding of the basic principles, rules and standards for conducting this kind of research. If the conduct of interventional clinical trials in the Russian Federation (RF) is regulated quite strictly and uniformly, then this cannot be said with respect to studies of real clinical practice.

Federal Law No. 86-FZ "On Medicines" dated 22.06.1998 defines requirements only for interventional clinical trials of medicinal products.

The national standard "Good Clinical Practice" (GOST R 52379-2005) [6], as well as those introduced by the Order of the Ministry of Health of the Russian Federation of 01.04.2016 No. 200n "Rules of Good Clinical Practice" [7], applies only to interventional clinical trials.

Federal Law No. 61-FZ of 12.04.2010, in Article 4, Clause 44 "On the Circulation of Medicines" (hereinafter referred to as Law No. 61-FZ), for the first time defined a post-registration clinical trial - a clinical trial of a medicinal product for medical use conducted by the manufacturer of the medicinal product, the civil circulation of which is carried out after state registration, in order to additionally collect data on its safety and efficacy, expand the indications for the use of this medicinal product, as well as identify undesirable reactions of patients to its action [8].

If we carefully read the above goals: collecting additional data on the efficacy and safety of a medicinal product, identifying adverse reactions, we will see that they largely coincide with the goals of research in real clinical practice.

However, Law No. 61-FZ, in principle, does not permit research on actual clinical practice, since the rule “everything that is not prohibited is allowed” is not applied in healthcare regulation.

To date, the Ministry of Health of the Russian Federation or Roszdravnadzor of the Russian Federation have not created procedures for registering studies of real clinical practice as a post-registration clinical trial. There is no significant data on the specific actions of the Ministry of Health of the Russian Federation or Roszdravnadzor of the Russian Federation aimed at challenging or suppressing the conduct of studies of real clinical practice. Despite this, by virtue of the letter of the law, until recently, this issue is considered unresolved, and if the regulatory authorities decided to take a tough stance and challenged the studies of real clinical practice conducted in the Russian Federation, pharmaceutical companies could face difficulties in justifying the legality of their conduct.

It should be noted that proposals have been made to introduce into the draft Law No. 61-FZ the definition of “non-interventional research”, which partly includes studies of real clinical practice. So, in January 2010, the Association of Clinical Research Organizations (ACOI) proposed to introduce the following definition into the draft Law No. 61-FZ: “observational (non-interventional) research is a post-registration clinical trial in which the use of a medicinal product is carried out on the basis of the general characteristics of the medicinal product, the prescription of a medicinal product does not depend on the decision to include the patient in the study, and the study procedures do not imply the allocation of patients to a specific treatment group and the use of additional diagnostic and treatment methods that are not provided for by standard medical practice ”[9].

The term “real clinical practice” we are introducing in the AOKI proposals sounds like “standard medical practice”.

In addition, the AOKI proposals indicate that non-interventional research does not imply any medical intervention in standard medical practice, and the point is only to collect the necessary information; the same regulation is not required as in interventional clinical trials, since the use of drugs outside the registered indications for use or any additional procedures for the subjects of such studies is not expected.

Therefore, such studies do not require special permission from the regulatory authorities, but only the approval of the Ethics Committee is required if the personal data of the subjects are used, and insurance is not required for patients and other things.

In a letter from the Federal Antimonopoly Service (FAS) dated July 1, 2013 on amendments to Law No. 61-FZ, a very similar wording was proposed: a medicinal product after its registration and entry into the pharmaceutical market, in which 

Therefore, the prescription of a medicinal product does not depend on the decision to include a patient in the study, the use of a medicinal product is based on the general characteristics of the medicinal product, and the research procedures do not imply the allocation of patients to a specific treatment group and the use of additional diagnostic and treatment methods not provided for by standard medical practice ”[ 10].

The term “real clinical practice” introduced by us in the FAS proposals sounds like “standard medical practice”.

It also contained proposals on the procedure for conducting such studies with their federal regulation [10].

Pharmaceutical companies, medical organizations, professional medical associations, educational institutions of higher and additional professional education, research organizations, executive authorities of a constituent entity of the Russian Federation, local government bodies performing functions in the field of public health [10].

To obtain permission to conduct a post-registration observational (non-interventional) clinical trial, it was proposed to submit the following documents and data to the authorized federal executive body [10]:

1) an application for obtaining permission to conduct a non-interventional study;

2) a document confirming the payment of the state fee for the consideration of the application;

3) research protocol, including a statistical estimate of the sample size required for reliable confirmation of the main purpose of the research;

4) the form of the informed consent of the research subjects to the processing of personal data, unless such processing is carried out exclusively by the research doctor;

5) a list of medical organizations located on the territory of the Russian Federation, in which it is planned to conduct a non-interventional study.

The decision to conduct a non-interventional study was supposed to be made within 30 days from the date of receipt of the documents [10].

The grounds for refusing to issue a permit could only have been the applicant's submission of an incomplete set of documents and / or the provision of inaccurate information [10].

This was the standard procedure for the ethical review of non-interventional research [10].

The list of organizations that received permission to conduct post-registration observational (non-interventional) clinical trials, as well as data on the maximum allowed number of patients who can be included in a non-interventional study, was proposed to be published and posted on the official website on the Internet by the authorized federal executive body, which also was supposed to maintain a register of issued permits [10].

It was proposed to limit the number of patients taking part in a non-interventional study to 10% of the number of patients diagnosed with the disease under study at the start date of the study (30% for patients with orphan diseases) [10].

The initiator of the non-interventional research was asked to submit a Report on the results to the authorized federal body that issued permission for their conduct, indicating information about all medical organizations in which the research was conducted, with the attachment of a list of medical workers who conducted the research, and the number of patients, separately by each medical organization that took part in non-interventional studies, and the criteria for inclusion and / or exclusion of patients [10].

It should be emphasized once again that in the currently valid version of Law No. 61-FZ, the proposals of AOKI and FAS are absent.

EURASIAN ECONOMIC UNION
The Eurasian Economic Union (EAEU) has put three dots in this issue. In 2016, by the decision of the Council of the Eurasian Economic Commission (hereinafter referred to as the EAEU Commission), at the regulatory level for the Russian Federation, a detailed definition of non-interventional research was given [11], which, as we said above, partly includes studies of real clinical practice.

Recall that, by virtue of Art. 15 clause 4 of the Constitution of the Russian Federation and on the basis of clause 13 of the Regulation on the Eurasian Economic Commission, the provisions of international law prevail over the national legislation of the Russian Federation, and the decisions of the EAEU Commission are subject to direct application on the territory of the Russian Federation.

The Rules of Good Clinical Practice of the EAEU Member States (NKP, English Good Clinical Practice, GCP) [12] contain the following definition: non-interventional clinical study (NIS) is a study that meets the following requirements: the drug is prescribed in accordance with the general characteristics of the drug; the decision to prescribe a particular treatment to the patient is not made in advance according to the study protocol, but is consistent with accepted practice and the prescription of the drug is clearly separated from the decision to include the patient in the study; no additional diagnostic or control procedures are applied to patients, and epidemiological methods are used to analyze the data obtained.

The rules of Good Pharmacovigilance Practice of the EAEU Member States (NPF, English Good Pharmacovigilance Practice, GVP) contain a similar definition of non-interventional research [13].

Thus, it seems that at present, the conduct of non-interventional studies of real clinical practice on the territory of the Russian Federation is legal and justified in cases where they meet the following requirements:

• the medicinal product is prescribed in accordance with the general characteristics of the medicinal product;
• the decision to prescribe a certain treatment to the patient is not made in advance according to the research protocol, but is prescribed according to routine medical practice;
• the prescription of the drug is clearly separated from the decision to enroll the patient in the study;
• no additional diagnostic or control procedures are applied to patients;
• epidemiological methods are used to analyze the data obtained.

The question may arise: "Is it necessary to notify or obtain permission from the Ministry of Health of the Russian Federation to conduct a study of real clinical practice?" The answer to this question seems to be no. The law does not provide for such requirements, and the Ministry of Health of the Russian Federation does not have a procedure for accepting such a notification or issuing a permit.

Thus, in order to conduct a study of real clinical practice, it is enough to conclude an appropriate Agreement with the health care institution (or institutions) in which it will be conducted and to enlist the support of the Ethics Committee.

From the above, the following conclusions can be drawn:

1) today, the conduct of non-interventional studies of real clinical practice on the territory of the Russian Federation complies with the applicable legislation;

2) as follows from the above logic, there may be some contradiction between the current legislation of the Russian Federation (in the form of Law No. 61-FZ) and the legislation of the EAEU, in connection with which it may be recommended to bring the national legislation in line with the legislation of the EAEU or at least release an official clarifications on the consistency of the provisions of Chapter 7 of Law No. 61-FZ with the Rules of Good Pharmacovigilance Practice of the EAEU;

3) both in the international arena and in Russia at the moment, studies of real clinical practice are not regulated at the legislative level with an appropriate degree of detail. Given the importance of such research for scientific purposes, it would be useful to develop Rules for the conduct of such research. This would simplify the work of pharmaceutical companies, medical organizations, professional medical associations, educational institutions of higher and additional professional education, research organizations, executive authorities of the constituent entities of the Russian Federation, local government bodies exercising functions in the field of protecting the health of citizens, would remove the excessive nervousness of the participants associated with the fear of violating regulatory requirements, and would contribute to an increase in the number and quality of research in real clinical practice, which, in turn, would be the right step towards the development of effective and safe drug therapy.

References

1. Исследования реальной клинической практики / А.С. Колбин, Д.Ю. Белоусов, С.К. Зырянов и др. - М.: Издательство ОКИ: Буки Веди; 2020. - 208 с.: ил. ISBN 978-5-4465-2902-5. [Research of real clinical practice / AS Kolbin, DYu Belousov, S. K. Zyryanov et al. Moscow: OKI publishing house: Buki Vedi; 2020. Il. ISBN 978-5-4465-2902-5. (In Russ).]. Доступно по: https://clck.ru/QkeeP.

2. 21st Century Cures Act. Режим доступа: https://clck.ru/R5rmY.

3. Framework for FDA’s Real-World Evidence Program. December 2018. Available from: https://clck.ru/R5rog.

4. Submitting Documents Using Real-World Data and Real-World Evidence to FDA fo Drugs and Biologics Guidance for Industry. Druft guidance document. Available from: https://clck.ru/R5rpj.

5. Post-authorisation efficacy studies: questions and answers. Available from: https://clck.ru/R5rrP.

6. Национальный стандарт Российской Федерации. Надлежащая клиническая практика. ГОСТ Р 52379-2005 (утв. Приказом Ростехрегулирования от 27.09.2005 № 232-ст). [National standard of the Russian Federation. Good clinical practice. GOST R 52379-2005 (approved by order of rostekhregulirovaniya No. 232-St of 27.09.2005). (In Russ).]

7. Приказ Министерства здравоохранения РФ от 1 апреля 2016 г. № 200н «Об утверждении правил надлежащей клинической практики». [Order of the Ministry of health of the Russian Federation No. 200N of April 1, 2016 «Ob utverzhdenii pravil nadlezhashchej klinicheskoj praktiki». (In Russ).] Доступно по: https://clck.ru/R5rtX.

8. Федеральный закон «Об обращении лекарственных средств» от 12.04.2010 № 61-ФЗ (последняя редакция). [Federal law «Ob obrashchenii lekarstvennyh sredstv» ot 12.04.2010 № 61-FZ (poslednyaya redakciya). (In Russ).] Режим доступа: https://clck.ru/HXtEH.

9. Предложения и замечания Ассоциации организаций по клиническим исследованиям (АОКИ) к проекту Федерального закона «Об обращении лекарственных средств» 15.01.2010. [Suggestions and comments of the Association of clinical research organizations (AOKI) on the draft Federal law «Ob obrashchenii lekarstvennyh sredstv» 15.01.2010. (In Russ).] Доступно по: https://clck.ru/R5rux.

10. Письмо Федеральной антимонопольной службы от 1 июля 2013 г. № АК/25271-ПР/13 «О проекте федерального закона «О внесении изменений в Федеральный закон «Об обращении лекарственных средств» и в статью 333.32.1. части второй Налогового кодекса Российской Федерации». [Letter of the Federal Antimonopoly service dated July 1, 2013 no. AK/25271-PR/13 «O vnesenii izmenenij v Federal’nyj zakon «Ob obrashchenii lekarstvennyh sredstv» i v stat’yu 333.32.1. chasti vtoroj Nalogovogo kodeksa Rossijskoj Federacii». (In Russ).] Доступно по: https://clck.ru/R5rwJ.

11. Белоусов Д. Ю. Неинтервенционные клинические исследования // Качественная клиническая практика. - 2017. - №1. - С.24-33. [Belousov DU. Non-interventional studies. Kachestvennaya klinicheskaya praktika. 2017;(1): 24-33. (In Russ).] Доступно по: https://clck.ru/R5rzo.

12. Решение № 79 «Об утверждении Правил надлежащей клинической практики Евразийского экономического союза» от 03.11.2016 г. [Decision No. 79 Ob utverzhdenii Pravil nadlezhashchej klinicheskoj praktiki Evrazijskogo ekonomicheskogo soyuza» ot 03.11.2016 g. (In Russ).]

13. Решение № 87 «Об утверждении Правил надлежащей практики фармаконадзора Евразийского экономического союза» от 03.11.2016 г. [Decision No. 87 «Ob utverzhdenii Pravil nadlezhashchej praktiki farmakonadzora Evrazijskogo ekonomicheskogo soyuza» ot 03.11.2016 g. (In Russ).]

Source: Sikachev V.V., Gorin V.V., Kolbin A.S., Belousov D.Yu. Legal aspects of conducting real-world studies. Kachestvennaya Klinicheskaya Praktika = Good Clinical Practice. 2020;(5):64-69. (In Russ.) https://doi.org/10.37489/2588-0519-2020-5-64-69