Legal Issues Regarding Off-Label Use of Medicinal Products

 

May 15, 2019

Anna Ivanova, Associate at BRACE Law Firm ©

Roman Shabrov, Partner at BRACE Law Firm ©

 

Off-Label Use of Medicinal Products in Russian Practice

The Good Pharmacovigilance Practice (GVP) of the Eurasian Economic Union (the "Union" or "EAEU"), approved by Decree of the Council of the Eurasian Economic Commission No. 87 dated November 3, 2016, defines the concept of "off-label" use. According to these Rules, "off-label" use represents the intentional use of a medicinal product for a medical purpose not in accordance with the summary of product characteristics or the instructions for medical use.

To ensure compliance with the laws of the Union member states, international treaties, and acts constituting Union law, Marketing Authorization Holders (MAHs) must implement quality assurance processes to scientifically evaluate all information regarding the safety profile of a medicinal product. This includes information on adverse reactions arising, inter alia, from use not in accordance with the approved summary of product characteristics or instructions for medical use.

A previous version of Article 37 of Federal Law No. 323-FZ dated November 21, 2011, On the Fundamentals of Health Protection of Citizens in the Russian Federation (as amended by Federal Law No. 323-FZ dated August 3, 2018) (the "Law on Health Protection") indirectly addressed the possibility of using medicinal products off-label. Specifically, it established that the prescription and use of medicinal products not included in the relevant standard of medical care are permitted in cases of medical indications (individual intolerance or for life-saving reasons) by decision of a medical commission. Notably, following significant changes to current legislation aimed at integration with Union law, this paragraph underwent relatively minor changes by indicating the possibility of using medicinal products not in accordance with clinical recommendations. According to Federal Law No. 489-FZ dated December 25, 2018, On Amendments to Article 40 of the Federal Law On Compulsory Medical Insurance in the Russian Federation and the Federal Law On the Fundamentals of Health Protection of Citizens in the Russian Federation Regarding Clinical Recommendations, these recommendations should become the basis for providing medical care (while previously approved clinical recommendations are subject to revision [1]). Currently, the provision of Part 15 of Article 37 of the Law on Health Protection is formulated as follows: "The prescription and use of medicinal products, medical devices, and specialized health food products not included in the relevant standard of medical care or not provided for by the relevant clinical recommendation are permitted in cases of medical indications (individual intolerance or for life-saving reasons) by decision of a medical commission".

At the same time, Order of the Ministry of Health and Social Development of Russia No. 502n dated May 5, 2012, On Approval of the Procedure for the Creation and Activity of the Medical Commission of a Medical Organization (the "Procedure for Medical Commission Activity") has not undergone similar changes. According to this order, the medical commission decides on the prescription of medicinal products in the presence of medical indications (individual intolerance or for life-saving reasons) that are not included in the relevant standard of medical care (Clause 4.7).

Pursuant to Clauses 6 and 8 of the Procedure for Prescribing Medicinal Products, Prescription Forms for Medicinal Products, the Procedure for Executing Said Forms, Their Accounting and Storage, approved by Order of the Ministry of Health of Russia No. 4n dated January 14, 2019, medical workers are prohibited from issuing prescriptions in the absence of medical indications for the patient; for unregistered medicinal products; for medicinal products which, according to the instructions for medical use, are intended for use only in medical organizations; or for narcotic drugs and psychotropic substances included in Schedule II of the List, registered as medicinal products, for the purpose of treating drug addiction. However, in the presence of medical indications (individual intolerance or for life-saving reasons), the prescription and documentation of medicinal products not included in the standards of medical care are carried out by decision of the medical commission of the medical organization. The medical commission's decision is recorded in the patient's medical records and in the medical commission's log.

Although the development of the draft amendments to the Procedure for Prescribing and Issuing Medicinal Products suggested that the process of off-label use would be regulated at the legislative level [2], the provisions in said document do not differ significantly from the superseded Procedure for Prescribing and Issuing Medicinal Products, as well as Prescription Forms for Medicinal Products, the Procedure for Executing Said Forms, Their Accounting and Storage, approved by the Ministry of Health of the Russian Federation No. 1175n dated December 20, 2012.

It is important to note that the concepts of "standard of medical care", "clinical recommendations", and "instructions for use of a medicinal product" are not identical.

Current legislation provides no precise definition for the term "standard of medical care". The Procedure for Developing Standards of Medical Care, approved by Order of the Ministry of Health of Russia No. 53n dated February 8, 2018, establishes that the Ministry of Health of the Russian Federation develops the Standard of Medical Care in accordance with the nomenclature of medical services. The standard consists of a passport section and a main section. The main section includes averaged indicators of the frequency of provision and the frequency of use of medicinal products registered in Russia (indicating average doses) in accordance with the instructions for use of the medicinal product and the pharmacotherapeutic group according to the Anatomical Therapeutic Chemical (ATC) classification recommended by the World Health Organization. From the content of this document and the meaning of currently effective standards, one can conclude that standards of medical care are documents defining the list of diagnostic and treatment procedures to be performed when providing medical care, indicating averaged indicators (including medicinal products for treating specific diseases by their International Nonproprietary Name). Clinical recommendations are documents containing structured information based on scientific evidence regarding prevention, diagnosis, treatment, and rehabilitation, including patient management protocols (treatment protocols), medical intervention options, and a description of the sequence of actions by a medical worker, taking into account the course of the disease, the presence of complications and comorbidities, and other factors affecting the results of medical care.

Instructions for use of a medicinal product is a document for a specifically defined medicinal product, including the name of the product, a description of its properties, and indications and contraindications for use [3].

However, the aforementioned legal acts specifically provide for the prescription of medicinal products with a deviation from the standards of medical care and clinical recommendations. In our view, this inaccuracy must be eliminated at the legislative level.

Nevertheless, the term "off-label" has recently begun to be applied directly in Russian legislation. Explanations regarding the off-label use of certain medicinal products have started to appear. Below are some examples of such formulations in a number of recently approved legal acts.

Name of Legal Act	Content of the "Off-Label" Formulation
Clinical Recommendations (Treatment Protocol) for Ectopic Pregnancy (Set out in the Letter of the Ministry of Health of the Russian Federation No. 15-4/10/2-729 dated February 6, 2017).	In the Russian Federation, the instructions for use of methotrexate do not provide for indications and treatment regimens for ectopic pregnancy; therefore, its off-label use may be considered only as an alternative to organ-removing surgery when it is necessary to preserve reproductive function, following a decision by the ethics committee, and only in gynecological hospitals of group 3 medical organizations after obtaining the patient's informed voluntary consent [4]. Methotrexate should not be prescribed at the first visit, except in cases where the diagnosis of ectopic pregnancy is absolutely clear and a viable intrauterine pregnancy has been excluded.
Federal Clinical Recommendations for Providing Medical Care to Children with Bronchopulmonary Dysplasia (BPD), approved by the Union of Pediatricians of Russia on February 14, 2015.	Further studies are needed to evaluate the efficacy/safety ratio of using inhaled corticosteroids (ICS) in this category of patients. Budesonide is an "off-label" drug (use according to indications after obtaining informed consent from parents, as well as the consent of the Local Ethics and Formulary Committees in a specialized hospital setting) in children with BPD under 6 months of age. The prescription of budesonide may be considered in the following clinical situations: 1) only in children with severe BPD, i.e., those who are or were on mechanical ventilation at 36 weeks of post-conceptual age or 56 days of life (depending on gestational age at birth); 2) in the classical form of BPD; 3) in the presence of respiratory symptoms (shortness of breath, wheezing); 4) when BPD is complicated by pulmonary hypertension; 5) in the absence of immunoprophylaxis for RSV infection; 6) upon the development of bronchial asthma or obliterating bronchiolitis in a child with BPD. Inhaled steroids should not be prescribed to children with mild BPD, its "new" form, or in cases where broncho-obstruction symptoms are absent, including during acute respiratory viral infections.
Federal Clinical Recommendations for Providing Medical Care to Children with Mucocutaneous Lymph Node Syndrome (Kawasaki), approved by the Union of Pediatricians of Russia on February 15, 2015.	Use of the drug in children off-label — outside the indications registered in the instructions for the medicinal product — with the permission of the Local Ethics Committee [5] of the medical organization, in the presence of signed informed consent from one of the parents (guardian) and a child over 14 years of age.

Thus, based on the aforementioned legal acts, actual off-label use of medicinal products occurs despite the vagueness of formulations at the federal legislative level. This is particularly relevant for the treatment of oncological diseases, as well as when prescribing treatment for pregnant women and children [6].

Moreover, a number of court cases have found the refusal to provide a patient with drugs not included in the standard of medical care but prescribed by a medical commission to be illegal.

For example, as established by a Ruling of the Supreme Court of the Russian Federation, which protected the medical commission of a medical institution and the patient, the fact that the applicant (patient) has a socially significant disease and disability, as well as a life-saving need for treatment with the medicinal product "Pomalidomide" (which is not provided for by the relevant standard of medical care), requires the prescription of this drug by decision of a medical commission. The relevant medical institution adopted this Commission decision. Consequently, such a decision imposes an obligation on the Department of Health and Social Protection to provide the patient with this medicinal product [7].

In one of its rulings, the Supreme Court of the Russian Federation concludes that the standard of medical care is the main guideline determining which medicinal products should be used when providing medical care according to the nomenclature. However, in the case of medical indications (individual intolerance or for life-saving reasons) and by decision of a medical commission, the use of medicinal products other than those included in the standard of medical care is permitted [8].

Accordingly, one can conclude that it is necessary to change the practice of prescribing off-label medicinal products and to provide such drugs free of charge when a relevant medical commission decision exists, since such use and prescription of drugs often have a decisive influence on the course of a patient's disease, and the need for treatment with a particular drug is often significantly limited by time frames.

The Procedure for Medical Commission Activity establishes the procedure for its convening. A medical commission is created based on an order from the head of the medical organization. The head of the medical organization approves the regulations on the medical commission, which govern its work procedure and composition. The medical commission consists of a chairman, one or two deputy chairmen, a secretary, and commission members. The head of the medical organization or a deputy head whose job duties include resolving issues within the commission's competence is appointed as the chairman of the medical commission. The medical commission includes heads of structural units of the medical organization and specialist physicians from among the medical organization's employees.

Meetings of the medical commission are held at least once a week based on schedule plans approved by the head of the medical organization. If necessary, extraordinary meetings of the medical commission may be held by decision of the head of the medical organization.

A medical commission decision is considered adopted if two-thirds of the members support it. The secretary of the medical commission (or medical commission subcommittee) enters the adopted decision into the patient's medical documentation and the log. An extract from the protocol of the medical commission's decision is issued to the patient or their legal representative based on a written application [9].

Thus, the specified Procedure for Medical Commission Activity establishes the basic rules for such a commission's operations. Furthermore, Articles 19 and 20 of the Law on Health Protection establish the rights of patients to receive information about their rights and obligations, their state of health, the choice of persons to whom information about their health status may be transferred, and the performance of medical intervention upon obtaining the patient's or their legal representative's informed voluntary consent for such intervention. Article 22 of the specified law establishes that everyone has the right to receive information available in the medical organization about their state of health in an accessible form, including information on the results of medical examination, the presence of a disease, the established diagnosis, methods of medical care, the associated risk, possible types of medical intervention, its consequences, and the results of medical care. Based on the aforementioned legal norms, we believe that the attending physician is entitled to initiate the procedure for the medical commission to consider prescribing off-label medicinal products, and the patient is entitled to raise the issue of such a prescription with the physician and receive timely and reliable information regarding decisions made concerning further treatment.

Most regulations on medical commissions approved in medical organizations establish the possibility of inviting any interested persons and parties at the initiative of the commission chairman, as well as at the initiative of the person responsible for preparing the issue (in the latter case, by prior agreement with the Chairman) [10]. Often, commissions for additional drug provision are created in medical institutions, which include attending physicians [11]. Nevertheless, the procedure for the attending physician to initiate the inclusion of an off-label prescription issue on the medical commission's agenda remains not fully regulated. Furthermore, it follows from the legal norms cited above that the issue of the patient's presence at the medical commission meeting is resolved directly by obtaining the relevant consent from the chairman of the medical commission. At the same time, the question of how a patient should request the prescription of "off-label" drugs is not unequivocally settled. We believe that these procedures should be regulated at the legislative level to more detailed define patient rights and the capabilities of the attending physician.

We believe that, based on the general norms of health protection legislation, a patient has the right to raise questions about their further treatment, including the prescription of off-label medicinal products, and the attending physician, if necessary, may initiate the procedure for the medical commission to consider the issue of prescribing an off-label drug.

Current legislation also lacks clear regulation regarding the relationship between the powers of a medical organization's local ethics committee and the medical commission. As seen from the examples of clinical recommendations cited above, they contain references to the need to obtain informed consent and permission from a local ethics committee for the prescription of a particular off-label drug.

In accordance with the Good Clinical Practice (GCP) rules, approved by Order of the Ministry of Health of the Russian Federation No. 200n dated April 1, 2016, an independent ethics committee must include a sufficient number of persons possessing the necessary experience and qualifications to provide an expert assessment of the scientific, medical, and ethical aspects of a planned clinical trial. Typically, this consists of five persons, with the interests of at least one person lying outside the sphere of science. The independent ethics committee operates in accordance with requirements it approves regarding the composition and qualifications of members, information about the founder, and the organization of meetings and decision-making. The independent ethics committee immediately informs the investigator and the clinical trial organizer in writing of its decisions concerning the clinical trial and the reasons for such decisions.

According to Letter of the Department of State Control of Quality, Efficiency, and Safety of Medicinal Products and Medical Equipment of the Ministry of Health of the Russian Federation No. 291-22/101 dated August 23, 2001, On Local Ethics Committees, local ethics committees (LECs) are created and function at medical, research, and educational medical institutions and are intended to ensure compliance with ethical norms and the interests of clinical trial participants. An LEC must possess sufficient competence, the necessary total experience, and qualifications in matters of biomedical ethics and the conduct of quality clinical trials.

The composition of an LEC is formed on a multidisciplinary basis with representation from various sectors of society to reduce administrative and economic dependence on the institution's management. Factors such as the professional training of candidates for Committee membership (scientists, medical workers), balanced gender representation, and the inclusion of public representatives are taken into account. An LEC has the right to involve independent experts. An employee of the institution who has a higher medical education and understands ethical problems, human rights issues, and the legislative and regulatory acts concerning human participation in biomedical research may serve as the LEC Chairman. The head of the institution or their deputy cannot be the LEC Chairman.

Thus, a number of clinical recommendations provide for the need to obtain additional permission from an LEC as a committee that is as independent as possible from the medical organization's management.

At the same time, we believe that the indication in several cited clinical recommendations of the need to obtain permission from local ethics and Formulary committees does not comply with Part 15 of Article 37 of the Law on Health Protection. This provision is formulated such that it clearly stipulates that the only document required for the prescription and use of medicinal products, medical devices, and specialized health food products not included in the relevant standard of medical care or not provided for by the relevant clinical recommendation is the decision of the medical commission. In our opinion, this conflict should be resolved based on Part 3 of Article 3 of the Law on Health Protection, which provides that in the event of a conflict between health protection norms contained in other federal laws, other regulatory legal acts of the Russian Federation, or laws and other regulatory legal acts of the constituent entities of the Russian Federation and the norms of the Law on Health Protection, the norms of the Law on Health Protection shall apply. Thus, a decision of the medical commission is sufficient for the prescription and use of an off-label medicinal product.

Nevertheless, when prescribing off-label medicinal products, concerns arise within the medical community and among patients regarding their side effects.

We believe that in this case, the medical commission, consisting of medical workers with the relevant knowledge and practical skills for treating specific diseases, is called upon to consider the possibility or impossibility of using a particular medicinal product. A critical factor is the impossibility of prescribing substitute treatment with medicinal products and/or resistance to drugs whose use complies with the instructions, clinical recommendations, and standards of medical care. Furthermore, we consider it reasonable to officially establish at the legislative level the right of the medical commission, when deciding on the prescription of off-label drugs, to be guided by clinical trial data and other information regarding the experience of using a particular medicinal product. The Ministry of Health of Russia has put forward such initiatives previously [12].

Additionally, we believe it is appropriate, when prescribing off-label medicinal products, to apply an approach analogous to the norms of the Regulations on the Procedure for the Use of Medicinal Products in Patients for Life-Saving Reasons, approved by Order of the Ministry of Health of the Russian Federation No. 494 dated September 9, 2005. Specifically, before starting the use of a medicinal product, the attending physician must inform the patient about the medicinal product, the expected effectiveness of the proposed therapy, the safety of the medicinal product, the degree of risk to the patient, and the actions to be taken in the event of unforeseen effects of the medicinal product on their health status.

Off-Label Use of Medicinal Products within the European Union

Within the European Union, opinions are also expressed that regulating the prescription of off-label medicinal products is a pressing issue. Specialists in this field suggest that using drugs for purposes other than their intended ones can bring real benefits to patients in cases where no alternative treatment options exist [13].

In 2016, the European Medicines Agency (EMA) published the Good Off-Label Use Practices (GOLUP). According to Clause 1 of GOLUP, the off-label use of medicinal products is performed provided that criteria such as the following are met:

1. The presence of medical indications, the conclusion of which is based on the expertise of a medical worker with relevant qualifications.
2. The absence of alternative drugs that can be used for their intended purpose, or in cases where the results of treatment were unsuccessful after the repeated use of existing medicinal products (used in accordance with their purpose).
3. Compliance with the requirement for critical study and scientific research of medicinal products used off-label.
4. Informing patients and their legal representatives regarding medicinal products prescribed off-label.
5. Prescribing off-label only after a thorough assessment by qualified medical personnel.
6. Developing a process for collecting and analyzing reports on the adverse consequences of using off-label medicinal products.
7. Freedom of action for qualified medical personnel, while prioritizing the patient's interests and complying with ethical norms.
8. Support from authorized state bodies for medical workers who prescribe off-label in compliance with all the principles listed above [14].

We believe this document is very well-developed and could serve as a foundation for the national legislation of EU member states to establish practically applicable and viable mechanisms for implementing and monitoring the off-label prescription process.

In particular, the official website of the European Medicines Agency (EMA) pays special attention to research on adverse reactions to the off-label use of medicinal products (including in children) [15]. Furthermore, there are a significant number of clarifications regarding the procedure for collecting and providing information on the results of off-label medicinal product use [16].

Research on both positive and negative indicators resulting from off-label medicinal product prescriptions is also actively conducted within the EU. For example, one study concludes that the highest prevalence of off-label medicinal product use was found in therapeutic areas such as cardiology, neurology, psychiatry, and respiratory diseases (asthma) [17].

According to all interested parties (patients and medical personnel), there are significant positive aspects to prescribing off-label medicinal products in cases where no alternative treatment with medicinal products having the appropriate purpose and indications exists.

Another positive aspect is the development of the healthcare system and the economic component.

Nevertheless, interested parties classify the risks of negative consequences from drug use, as well as the lack of harmonization of national laws among EU member states, as negative elements of off-label medicinal product prescriptions [18].

Thus, we believe that due to the long history of addressing off-label medicinal product use within the European Union and the availability of a significant amount of scientific research, some borrowing of legal features for prescribing off-label drugs is possible for forming the legal framework of the Eurasian Economic Union.

Off-Label Use of Medicinal Products in the USA

The issue of prescribing off-label medicinal products is regulated by the Food and Drug Administration (the "FDA"). Specifically, it is established that when prescribing a medicinal product, such a product must first be approved by the FDA. Such approval is carried out based on clinical recommendations. At the same time, it is noted that medical workers must explain cases of off-label medicinal product prescriptions to the patient. The main criterion for such a prescription is the absence of alternative treatment options or cases where treatment with drugs having the relevant indications did not yield the necessary results.

Different forms of off-label medicinal product use are envisioned:

1. Use for a disease for which the treatment is not intended by the indications of a particular medicinal product. For example, when chemotherapy is approved for treating one type of cancer, but medical workers use it to treat another type of cancer;
2. Use of a medicinal product in a different way; for example, when a drug is approved in capsule form, but it is given as an oral solution instead;
3. Use of a medicinal product in a different dosage [19].

Examples of results from prescribing off-label medicinal products are provided on the official website of the National Center for Biotechnology Information (NCBI) in the USA.

For example, the use of sodium oxybate for an 11-year-old patient with narcolepsy (this drug is prescribed for patients 18 years and older) yielded a significant positive result in treatment [20].

In February 2019, the results of a study on off-label prescriptions in pediatric practice were published: At least one medicinal product was prescribed off-label in 779,270 out of 2,773,770 (28.1%) patient visits during the study period. Younger age, long hospitalizations, and mortality were associated with higher rates of off-label drug use. The off-label use of certain medicinal products varied among care settings. Rates of off-label medicinal product use were higher in observational (single visit) (45.5%), inpatient (53.9%), and outpatient (54.2%) settings [21].

Thus, we believe that the practical use of off-label medicinal products in Russia and foreign countries is currently dictated by objective necessity. Specifically, a rapidly changing pharmaceutical market, an increase in cases of orphan diseases, the ineffectiveness or exhaustion of the effect (resistance) of medicinal products provided for by standards of medical care and clinical recommendations, and the focus on developing an individual approach to patients require additional legislative regulation of off-label medicinal product prescriptions. In our opinion, within the framework of Russian legislation, additional development of existing terminology and the detailing of procedural aspects for prescribing off-label medicinal products are necessary.

May 15, 2019

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References

[1] According to Federal Law No. 489-FZ dated December 25, 2018, clinical recommendations (treatment protocols) on issues of providing medical care approved by medical professional non-profit organizations prior to the effective date of said Federal Law shall apply until their revision and approval in accordance with parts 3, 4, 6–9, and 11 of Article 37 of Federal Law No. 323-FZ dated November 21, 2011, On the Fundamentals of Health Protection of Citizens in the Russian Federation, but no later than December 31, 2021.

[2] Sergey Zyryanov, Going Beyond. Situations with the Use of Drugs Not According to Instructions are Ambiguous, Rossiyskaya Gazeta – Special Issue No. 7377 (211).

[3] Requirements for Instructions for the Medical Use of Medicinal Products, approved by Order of the Ministry of Health of the Russian Federation No. 724n dated September 21, 2016.

[4] Legal Aspects in the Work of a Neonatologist (didactic materials), Diana Myadkhatovna Mustafina-Bredikhina, lawyer of the Association of Neonatologists IPO.

[5] The Regulations on the Ethics Committee of the Ministry of Health of the Russian Federation, approved by Order of the Ministry of Health of the Russian Federation No. 435n dated July 10, 2015, established that the ethics committee of the Ministry of Health of the Russian Federation is a permanent body created by the Ministry of Health of the Russian Federation to issue a conclusion on the ethical justification or ethical groundlessness of the possibility of using methods of prevention, diagnosis, treatment, and rehabilitation when providing medical care within the framework of clinical testing of methods of prevention, diagnosis, treatment, and rehabilitation. In accordance with the Rules of Good Clinical Practice approved by Order of the Ministry of Health of the Russian Federation No. 200n dated April 1, 2016, an independent ethics committee created at the level of a medical organization (local ethics committee) or regional level and functioning as an independent body ensures the protection of rights, safety, and health protection of clinical trial participants.

[6] O.A. Tsyganova, MD, Analysis of Regulatory and Legal Regulation of Off-Label Therapy in the Russian Federation and Abroad, Medical Law Journal, No. 4, July–August 2018, pp. 9–13.

[7] Ruling of the Supreme Court of the Russian Federation No. 57-KG18-13 dated September 10, 2018.

[8] Ruling of the Supreme Court of the Russian Federation No. 11-KG18-8 dated May 29, 2018.

[9] Procedure for the Creation and Activity of the Medical Commission of a Medical Organization, approved by Order of the Ministry of Health and Social Development of Russia No. 502n dated May 5, 2012.

[10] Regulations on the Medical Commission of LLC Center for Interdisciplinary Dentistry and Neurology, Appendix No. 1 to Order No. 12-01-01 dated January 12, 2015.

[11] Order On the Organization of the Activity of the Medical Commission (MC) and Medical Subcommittees of the Medical Commission (MC) of the Livenskaya Central Regional Hospital of the Orel Region (2015).

[12] Sergey Zyryanov, Going Beyond. Situations with the Use of Drugs Not According to Instructions are Ambiguous, Rossiyskaya Gazeta – Special Issue No. 7377 (211).

[13] Piernicola Pedicini, EU Needs Guidelines on Off-Label Use of Medicines, The Parliament. Politics, Policy and People Magazine, June 16, 2017.

[14] Declaration on Good Off-Label Use Practice.

[15] Evidence of Harm from Off-Label or Unlicensed Medicines in Children, European Medicines Agency, Pre-authorisation Evaluation of Medicines for Human Use, October 2004, EMEA/126327/2004.

[16] Collecting and Reporting Information on Off-Label Use, 7th Industry Stakeholder Platform on Operation of EU Pharmacovigilance Legislation – April 4, 2016, European Medicines Agency.

[17] Report from the Commission to the European Parliament and the Council, Better Medicines for Children — From Concept to Reality; General Report on Experience Acquired as a Result of the Application of Regulation (EC) No. 1901/2006 on Medicinal Products for Paediatric Use, 2013.

[18] Study on Off-Label Use of Medicinal Products in the European Union.

[19] Understanding Unapproved Use of Approved Drugs "Off Label", Content current as of February 5, 2018.

[20] A Case of Off-Label Sodium Oxybate in an 11-Year-Old with Narcolepsy, The National Center for Biotechnology Information.

[21] Katelyn Yackey, Kristin Stukus, Daniel Cohen, David Kline, Sonia Zhao, Rachel Stanley, Off-Label Medication Prescribing Patterns in Pediatrics: An Update.