Not in Accordance with the Official Instructions: How the Use of Off-Label Drugs is Regulated

Maria Nikonova

In June, the State Duma is planning plans to consider a bill that will allow doctors to prescribe off-label medications for the treatment of pediatric oncology and hematological diseases.

This topic has been widely discussed for a long time. For instance, in December 2020, the Federation Council held a meeting of the Expert Council on Healthcare dedicated to OLDU. At the same time, several charities sent an open letter to the Minister of Health on the need to include off-label medicines in the standards of medical care.

The bill submitted to the State Duma was the response to the issue.

What is an off-label?

In 1997, the FDA gave the following definition of off-label drug use: “the use for indication, dosage form, dose regimen, population or other use parameter not mentioned in the approved labeling.” And in 2016, the Eurasian Economic Union also adopted a definition. The Rules of good pharmacovigilance practice (GVP) of the Eurasian Economic Union, approved by the Decision of the EEC Council of 03.11.2016 No. 87, establish that  “off-label” is the deliberate use of a medicinal product for a medical purpose not in accordance with the general characteristics of the medicinal product or the instructions for medical use.”

Off-label use may deviate from the instructions in different ways [1]:

• the indications for use are different from those stated in the instructions;
• the use of the pharmaceutical product despite contraindications;
• use in populations for which it is not allowed according to the instructions (e. g., age, pregnancy, lactation, etc.);
• the use of the method of administration not provided for in the instructions;
• use of a medicinal product without prior administration of a test dose;
• use of doses different from those specified in the Instructions;
• using a dosage frequency different from that stipulated for in the Instruction;
• using the medical product beyond the established duration of its administration;
• using fractures of a solid indivisible dosage form;
• administration of a combination medicinal products that is prohibited;
• using the principle of analogy, e. g., when:
• a medicinal product is used for the treatment of a disease which is not included in the instruction,
• there is another medicinal product, with a different trade name but with the same INN, and the instructions for that product include the disease.

Off-label kids

Most off-label prescriptions take place in pediatrics. And this situation is typical not only for Russia, but also for the European Union.

In the “Study on off-label use of medicinal products in the European Union”, it is said that off-label use in paediatric populations in the hospital setting showed a range of 13-69% of the investigated prescriptions being off-label, and in the outpatient setting, a range of 2-100% was found. Similar data are also found in the articles of Russian pediatricians [2].

1. V. Glagolev, Deputy Minister of Health, stated the following figures of off-label use at a meeting of the expert council: 20% in the total volume of prescriptions for medicines, and more than 70% in pediatrics.

The main reason for the absence of pediatric indications for many medicinal products is the lack of clinical studies. Most clinical trials are conducted in adult populations, and pharmaceutical companies cannot apply such results in respect of children.

How are off-label medicines prescribed now?

For children, OLDU is currently allowed, but it must be approved by a decision of a medical commission.

According to Part 1 of Article 37 of the Law No. 323-FZ, “On the Basics of Public Health Protection in the Russian Federation,” medical care is organized and provided “with due account for the standards of medical care.” Part 14 of Article 37 No. 323-FZ provides that “the standard of medical care <…> includes the average indicators of the frequency of provision and frequency of administration <…> of medicines registered in the Russian Federation <…> in accordance with the instructions for the use of the medicinal product.”

Clinical recommendations may include off-label drugs. Thus, the Requirements for the structure of clinical recommendations approved by the order of the Ministry of Health of the Russian Federation No. 103n of February 28, 2019 state:  “… a ” # ” sign before the name of the medicinal product shall be put, and information shall be provided <…> with references to clinical studies <…> or references to relevant literature if the thesis recommendation applies to medicine <…> used  in the way that is different from the indications, contraindications, the methods of application and doses specified in the instructions for use of the medicinal products“.

However, at present, CRs cannot be used as the basis for prescribing medical products, as the doctor must be guided by the standard.

According to Part 15 of Article 37 of Law No. 323-FZ, “prescription and administration of medicines <…> that are not included in the applicable standard of medical care or are not provided for by the correspondent clinical recommendation are allowed due to medical indications (or due to individual intolerance or urgent life-saving indications), subject to the decision of the medical panel“. This is also confirmed by the Order of Prescriptions of the Medicinal Products approved by the Order of the Ministry of Health of the Russian Federation No. 4n of January 14, 2019.

Thus, to prescribing an off-label drug, a doctor must receive an approval of the medical panel.

Major challenges

If the law already provides a mechanism that allows for off-label prescriptions, why is additional legislative regulation needed? There are several reasons for this.

1. Unclear regulation

The attitude to off-label prescriptions in the professional community varies. For example, there is an opinion that even a medical commission is not authorized to make a decision on the appointment of a medical panel should not approve off-label use. This opinion is based on the fact that the rules cited above do not explicitly provide for the possibility of prescribing an off-label medicinal product.

At the same time, courts recognize it as illegal when patients are deprived of the opportunity to receive drugs that are not included in the standard of medical care, or off-label, which were prescribed by the medical panel. This practice has been established both at the level of courts of general jurisdiction [3] and at the level of the Supreme Court of the Russian Federation [4]. But the discussions continue.

2. Problems related to medical panels

Obtaining a prescription through a medical panel takes time and not always an effective solution for the patient.

Roszdravnadzor report for 2020 notes that inspections revealed more than 80 cases when medical panels failed to consider the issue of medicines prescription in the presence of medical indications.

This means that the only way for a young patient, i. e., the medical panel, only results in a loss of precious time.

What problems is the bill intended to solve?

The bill provides for:

1. the possibility of prescribing off-label drugs specified in the clinical guidelines. Now doctors do not have an opportunity to prescribe an off-label medicinal product, even if it is explicitely stated in the clinical recommendations;
2. the right of the medical panel to prescribe an off-label medicinal product due to the need to help the patient. Thus, the current ambiguity of the regulation on the powers of the medical panel is eliminated;
3. the establishment of insurance coverage based not only on the standards of medical care, but also on the basis of the clinical recommendations or the decision of the medical commission;
4. the competence of a specialized medical organization to form a list of effectively applied off-label medicines for their subsequent inclusion in the standards of medical care and clinical recommendations.

There is a mechanism that will make it possible to include off-label use in the standards of medical care. It should be noted that this mechanism contradicts the current version of Part 14 of Article 37 of Law No. 323-FZ, which states that medicines may only be included in the standards of care based on the instructions for use. In order for off-label drugs to be introduced in medical care standards, it is necessary to introduce additional amendments. The problem may be solved by another billthat supplements Law No. 323-FZ with the provision that  “the standard of medical care for children <…> allows for the inclusion of <…> medicines that do not have provisions for their pediatric application in their instructions for use <…>“.

Safety first

Have these proposals undergone an appropriate critical consideration? After all, the administration of off-label drugs to children is associated with the risk of serious adverse reactions. Thus, the conclusion in the article entitled “Safety study of the use of medicinal products in children” is that children are at a higher risk of developing complications as a result of medical therapy.

The European Medicines Agency (EMA) issued the Declaration on Good Off-Label Use Practices (GOLUP).

The declaration sets out the criteria for off-label drug use:

1) Presence of a medical therapeutic need based on a current examination of the patient by a suitably qualified health care professional;

2) Absence of authorised treatment and licensed alternatives tolerated by the patient or repeated treatment failure;

3) A documented review and critical appraisal of available scientific evidence favours offlabel use to respond to the unmet medical need of the individual patient;

4) Patients (or their legal representative) must be given sufficient information about the medicines that are prescribed to allow them to make an informed decision;

5) Presence of established reporting routes for outcomes and adverse events linked to off-label use.

The bill generally takes these criteria into account.

But it would also make sense for the legislator not to limit the consideration to oncological and hematological diseases and pediatric applications and approach the issue in a more systematic manner, i. e., to provide for the possibility of prescribing off-label drugs to patients with other life-threatening and chronic diseases, when necessary. Such proposal was recently made by 32 public and patient organizations, which sent an open letter to the President and the Government of the Russian Federation.

[1] Classification based on the speech of S. V. Glagolev, Deputy Minister of Health.

[2] For example, in the article “Safety study of the use of medicinal products in children”, in the review “The off-label problem: Russian Pediatric Clinical Hospital Experience”.

[3] For example, the decisions of the Sverdlovsk District Court of Irkutsk (Irkutsk region) of January 23, 2020 in case No. 2-1/2020, the Prioksky District Court of Nizhny Novgorod (Nizhny Novgorod Region) of February 18, 2020 in case No. 2-2642/2019 explicitly refer to off-label drugs

[4] For example, the Definition of the Supreme Court of the Russian Federation of December 2, 2019 No. 11-КГ19-24, the Definition of May 29, 2018 No. 11-КГ18-8.