3. Off-label use

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1. Off-label use

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In some regions, for example in the US, the Summary of Product Characteristics (SmPC) is called ‘label’, therefore the term ‘off-label’. There is no definition on the term ‘off-label use’ of medicines in the EU legislation, but off-label use is commonly understood as the use of a medicine outside the terms of its marketing authorisation (MA), i.e., not in accordance with the approved Summary of Product Characteristics (SmPC).

The reference terms for off-label use thus are the terms of marketing authorisation in the country where the product is used.

Examples for off-label use are:

  • using a different dosage regimen (a different dosage, frequency, route or method of administration),
  • use for an indication (in terms of medical condition) other than that listed in the SmPC,
  • use in a group of patients for which it has not been authorised, such as a certain age group like children (paediatric use),
  • use despite a contraindication, i.e. a specific situation where the medicine should not be given for safety reasons.

The so-called ‘irrational prescription and use of medicines’ could also to a certain degree be considered off-label use. Examples are:

  • the use of too many medicines per patient (polypharmacy), not considering possible interactions between different medicines as per SmPC
  • the inappropriate use of antibiotics for non-bacterial infections,
  • the failure to prescribe in accordance with the best evidence-based clinical guidelines, and
  • inappropriate self-medication

While not optimal, off-label prescribing may remain essential to address unmet medical needs of patients. However, the manner in which countries deal with the off-label use of medicines is not harmonised across the EU as shown in the next section.

2. Legal framework in Europe

The EU pharmaceutical legislation regulates the marketing authorisation framework primarily through Directive 2001/83/EC and Regulation (EC) 76/2004. It includes some exceptions to the requirement of marketing authorisation before a medicine can be marketed (e.g., compassionate use and Named-patient access). Legislation does not, however, regulate the practice of medicine (nor prescription practices at the individual level, either on-label or off-label).

This means that off-label use is not covered by EU pharmaceutical legislation. Off-label use is however recognised as a concept by EU law (recital 2 of the Paediatric Regulation[1] and pharmacovigilance provisions in Directive 2010/84/EU, amending Directive No. 2001/83/EC as regards pharmacovigilance). It imposes on MA holders a responsibility to provide any information of products’ use which might influence the evaluation of the benefits and risks of the medicinal product concerned. Some of the pharmacovigilance requirements extend to off-label use. For example, Member States and marketing authorisation holders are required to collect/report information on suspected adverse reactions arising from the use of medicines outside the terms of the marketing authorisation.

The EMA gives a short definition on off-label use in their glossary of regulatory terms: “Use of a medicine for an unapproved indication or in an unapproved age group, dosage, or route of administration”. And further, in Annex I Definitions (Rev 4) of the European Guideline on Good Pharmacovigilance Practices (GVP), off-label use is defined as: “situations where a medicinal product is intentionally used for a medical purpose not in accordance with the terms of the marketing authorisation”. With the wording ‘intentionally used for a medical purpose’ the EMA clearly distinguishes off-label use from other medicine uses outside the MA such as medication errors (unintentional) and misuse (no medical purpose) or abuse.

Some specific provisions about off-label use might be found in a Member State’s laws. See box below for examples. In other Member States, off-label use is not specifically regulated. An extensive study, commissioned by the European Commission (EC) on off-label use in the European Union[2] revealed that only ten out of the 21 countries that participated in the study had specific policy tools in place for off-label use. However, as stated in this study, “in EU Member States without specific policy tools on off-label use, the dominant view is that off-label use is an issue to be dealt with at the level of the prescriber rather than at the regulatory or healthcare system level. Prescribers are trusted to know what is best for the well-being of the patient, with the medical need of the patient leading their decisions.”.

So, it is important to distinguish the regulation of medicines from their use in medical practice because EU legislation does not encompass the way medicinal products are ultimately used. In other words, the way Member States organise their healthcare system and the way health care professionals (HCPs) conduct their practice is not within the remit of the EU. The use of medicinal products is in the end decided by the doctor and the patient, who can choose to use a medicinal product off- or on-label.

The ultimate responsibility for the definition of health policy and the delivery of health services and medical care (including off-label use) lies with the Member States (Article 168 (7) TFEU). The European Court of Justice indeed confirmed that “off-label prescribing is not prohibited, or even regulated, by EU law” and that “There is no provision which prevents doctors from prescribing a medicinal product for therapeutic indications other than those for which a marketing authorisation has been granted.” Sentence (T-452/14 Laboratoires CTRS vs Commission, paragraph 79).

Nevertheless, even though the European legislation does not forbid or subject off-label use to specific conditions, the rest of the European and national legal framework still applies. This implies that the liability rules, criminal law and the ethical and professional standards remain applicable to prescribers of off-label use. Doctors, therefore, must be aware that, when prescribing an unapproved medicine, they take full responsibility for any harmful consequence for their patients, even if patients have signed an Informed Consent Form.

Examples of policy tools incorporated by EU Member States and the UK are:

- France: Legal framework to issue temporary recommendations for use and permission to prescribe off-label such as the “temporary recommendations for use (RTU), replaced 2021 by (cadre de prescription compassionnelle or “CPC”)

- Hungary: System where prescribers or their organisations have to ask for permission to prescribe a product off-label.

- France and Italy: Measures to regulate reimbursement, explicitly allow for reimbursement of off-label use also when (on-label/authorised/not strictly identical) alternatives exist.

- UK: Policy tool providing guidance for prescribers such as the General Medical Council Guidance (Good practice in prescribing and managing medicines and devices, 2013)

- The Netherlands: Policy tool where professional standards are leading, where off-label prescription is only allowed if the relevant professional body has developed protocols or professional standards with regard to that specific off-label use.

- In many Member States: Policy tools focused on the patient, for example regarding the necessity to give informed consent or the fact that for serious interventions, upon request of the patient, a HCP has to register for what intervention the patient has given consent (The Netherlands).

- Spain: the Royal Decree 1015/2009 establishes that the prescription of medicines off-label must be exceptional, limited to situations where there is no authorised alternative for the patient and subject to his/her consent. Obligations on healthcare professionals (e.g., justify the off- label use, report any suspected adverse drug reactions (ADR) and follow any issued prescription/dispensing restrictions as well as the therapeutic protocol of the medical centre), and on marketing authorisation holders (report suspected ADRs to the authorities and any information that could have an impact on issued recommendations of use).

- Germany: legislation provides for off-label use in the regulation on health insurance (§35c SGB V). Formally, the G-BA (Federal Joint Committee) regulates the access to off-label use.[1] Accordingly, the prescription of medicines for specific non-authorised uses is permitted if the Expert groups issue a positive opinion based on the assessment of available evidence. The consent of the pharmaceutical company concerned to the off-label use is required.



[1]  Recital (2) of Directive 2010/84/EU: Such studies may not have been undertaken for use in the paediatric population and many of the medicinal products currently used to treat the paediatric population have not been studied or authorised for such use. Market forces alone have proven insufficient to stimulate adequate research into, and the development and authorisation of, medicinal products for the paediatric population.

[2] EC-commissioned Study on off-label use of medicinal products in the European Union, NIVEL, Dutch National Institute for Public Health and the Environment, and the European Public Health Alliance, 2017

2.1. Off-label use - advertising

Article 87 of Directive 2001/83/EC prohibits advertising of a medicine for which a MA has not been granted. Since any advertising must comply with the SmPC, advertising the off-label use of an authorised medicine is also prohibited.

Promotion of off-label use would bypass and undermine the rigorous regulatory approval process. It would raise serious concerns over patient safety as it would promote the use of medicines in indications for which the relevant regulatory authorities have not performed a benefit-risk analysis.

Of note: some EU Member States have passed legislation that promotes the off-label use of medicines on economic grounds versus alternative, authorised medicines. Various groups (e.g., EFPIA, EUCOPE and EuropaBio[1]) question whether this trend is in line with EU law and in summary state that by encouraging off-label uses that have not been subject to the same rigorous controls and safeguards as on-label medicines, member states such as Belgium, France, Italy and the UK, bypass the regulatory process and undermine the European Union's underlying objective of guaranteeing patient safety.  Further, the ‘GOLUP declaration on good off-label use practice’ highlights the importance of preserving the European regulatory framework to ensure the safety of patients, while ensuring good off-label use of medicines for patients in need[2].



[1] Statement on bio-pharmaceutical industry complaint to the European Commission against a new Italian law promoting off-label use of medicines for economic reasons. 20 February 2015

[2] Declaration on Good Off-Label Use Practice. European Brain Council 2017

3. Off-label use – reasons (drivers)

Doctors might consider prescribing a medicine outside its approved marketing authorisation when there is no available treatment for the patient (or if an available treatment has not been effective). In certain circumstances off-label use can be medically appropriate and an important element of high-quality patient care. In many cases, off-label prescriptions may be part of best practice or standard of care. An example is Hepatitis C (http://onlinelibrary.wiley.com/doi/10.1002/hep.26903/pdf).

However, it has been reported that healthcare professionals regularly prescribe medicines off-label with levels of evidence considered to be low. This may be problematic because off-label use lacking strong scientific evidence is associated with higher rates of adverse events.

The following part on the reasons/drivers for off-label use is in essence adapted from the findings of the EC-commissioned Study on off-label use of medicinal products in the European Union, already mentioned above. This is complemented by additional information from the literature.

1. Key findings from the study on drivers of off-label use

Various drivers underpin off-label use of medicines. These drivers relate to the marketing authorisation process, post marketing authorisation events, pricing and reimbursement, aspects connected with the work of healthcare professionals, and patient related factors. The scenario is complex and involves many stakeholders, namely regulatory agencies, the industry, physicians, insurers, professional medical associations and patients with distinct and often conflicting interests.

Sometimes, it is not a single driver, but rather a combination of drivers, and the interaction of drivers that stimulate off-label use. Drivers may also change during the lifecycle of a medicine. The relative contribution of, and interaction between, drivers is unknown.

2. World economy / national economy

Economics influences decisions of pharmaceutical companies to develop products and therefore influences, via the marketing authorisation system, the availability of medicines. Economics also influences the healthcare system (e.g., reimbursement) and herewith (indirectly) off- label use.

3. Regulatory level

Marketing authorisation process

  • limited incentives for industry to extend the label of existing medicines (incentives: legislation allows for a one-year extra market protection if a new indication in the first eight years after a marketing authorisation (MA) under specific circumstances; however, off-label sales will continue without investment in such a new indication anyway)
  • no legal power by regulators for extension of label. (no legal power to enforce marketing authorisation holders (MAHs) to include indications in the SmPC, even when adequate (scientific) evidence is available. The same is true for other off-label aspects)
  • long development time and high costs to develop a new indication; moreover, the pre-clinical studies performed for the original/first indication(s) are frequently not suitable for a new indication
  • increasing regulatory requirements (Requirements for MA have increased over the years, being more specific and detailed).
  • more narrow indications and restrictions in SmPC (SmPC only reflects patient categories included in the clinical trials, while neglecting other populations that may benefit from the medicine.)
  • market approval is lagging behind evidence from science and clinical practice (Science and clinical practice are much faster than the regulatory approval processes; the information in the SmPC does not reflect all available evidence: results of clinical trials reported in scientific literature and efficacy/safety information gathered in daily medical practice are not always (immediately) included)
  • lack of adequate information from authorities on non-approved or withdrawn indications

Post marketing authorisation

  • disruption in the manufacturing of a product, leading to medicine shortages and necessity to use other products off-label;
  • withdrawal of a product from the market or deletion of an indication (in case of deletion of an indication the product may still be used off-label for that particular indication if the deletion was not for reasons of safety)
  • product not available in all EU Member States (e.g. economic reasons, especially for lower income countries and countries with a small market)
  • no incentives or obligation to monitor efficacy in case of off-label use neither for MAHs nor for healthcare professionals (HCPs) (monitor only adverse drug reactions; absence of gathering real world data hampers extension of (scientific) evidence).

4. Health care system level

Pricing and reimbursement

  • high costs of on-label therapy; non-affordability (in some MS medicines are sometimes not (fully) reimbursed, which may lead to non-affordability for patients)
  • no reimbursement of on-label therapy (in case the ‘on-label product’ is more expensive than the ‘off-label product’, where the off-label use of a product is reimbursed while use of the on-label product is not, leading to off-label prescribing despite the availability of the on-label product).

5. Professional and patient level

Professionals

  • in absence of a specific authorised medicine when there is a medical need, there is no other choice than prescribing off-label (especially for rare diseases, rare medical situations, (severe) diseases or medical situations that are difficult to treat, and in specific patient groups, such as children and pregnant women. Off-label use may be last resort)
  • more treatment options when off-label is also considered (new research results may be implemented directly even while they are not yet part of a guideline and patients may thereby gain earlier access to a therapy more suitable for their condition)
  • innovation in clinical practice (a path to innovation through which additional indications for an authorised medicine are discovered and a subsequent extension may be filed by a company[1])
  • health care professional guidelines include off-label
  • guidelines not aligned with regulatory approval (sometimes an indication is not approved, but recommended as first choice in HCP guidelines, because for individual patients the benefit-risk balance may be judged as positive by HCPs)
  • favourable practical experience with the off-label product, unwillingness of patients to switch, or unawareness of the on-label alternative (continuation of off-label after on-label product is available)
  • doctor is not aware of prescribing off-label (According to Todd [2], in [3] , a survey of physicians conducted at the University of Chicago Medical Center found that the respondents could identify the regulatory approval status of a medicine just over half the time.)
  • irrational prescribing by doctors (false beliefs that a lower dose will lead to less side effects or personal conviction of higher efficacy compared to other (on label) medicines)
  • economic reasons supported by institutions (for example institution (hospital) is aware that if they prescribe the cheaper option, they can provide the treatment to more patients in need)

Patients

  • no other options available; last resort (e.g., for patients who cannot rely for some reason on authorised medicines)
  • authorised on-label product available, but not effective
  • on-label product causes unacceptable side effects, with the only alternative being off-label use of another medicine
  • economic reasons (especially in lower income countries and when patients have to pay a medicinal product (partly) out- of-their own pocket)
  • patient pressure I: patient insists on pharmacotherapy, despite the fact that no on-label therapy is available (search for the most effective treatment, sometimes based on information on the internet or from exchange with other patients or by participating in patient organisations; self- diagnosing/prescribing and different types of access to prescription medicines over the internet (also outside EU) are of concern)
  • patient pressure II: active involvement in changing label from off-label to on-label
    Example: an HIV combination therapy was often used off-label for HIV prevention. The medicine was only indicated for the treatment of HIV-positive patients, yet numerous patients took it for prevention purposes. Patient organisations have played a key role in requesting an extension of the indication to include prevention in addition to treatment, and the application was finally, with great perseverance from the patient side, submitted by the company. It received the extension of the indication to include prevention in mid-2016.
  • better adherence with the off-label product (for example if the off-label medicine is available in tablets adherence may be better than for an injection)
  • trust in the prescriber

Ethical arguments in addition to the above also favour the off-label use of medicines due to situational supply gaps and necessary medical assistance for patients without adequate treatment options, such as disruption in the manufacturing of a product, the unreasonable withdrawal of a product from the market solely due to commercial purposes or in cases of rare diseases.



[1] R Abbott and I Ayres, “Evidence and Extrapolation: Mechanisms for Regulating Off-Label Uses of Drugs and Devices” (2014) 64 Duke Law Journal 377

[2] A.E. Todd, “No Need for More Regulation: Payors and Their Role in Balancing the Cost and Safety Considerations of Off-Label Prescriptions” (2011) 37 American Journal of Law and Medicine 422.

[3] SOARES JÚNIOR, W. (2020). Off-Label Use of Medicines: A Comparative Study on the Regulation of Medicinal Products in Selected European Union Member States. European Journal of Risk Regulation, 1-22. doi:10.1017/err.2020.104

4. Off-label use - challenges

Off-label use of a medicine poses a range of quite different challenges:

  • ethical and legal issues for healthcare professionals (HCPs). Their choice to prescribe and dispense the medicine off-label should be based solely on therapeutic considerations in the best interest of the patient and ideally supported by evidence-based guidelines.
  • it carries an increased risk for patients. While off-label prescribing may be necessary and justified for medical reasons, an adequate level of evidence in terms of efficacy and safety is required.
  • patient information and consent are especially important. This aims to ensure that the patient is aware of the benefits and risks of off-label use and that both good and bad outcomes are duly reported. Whenever possible, patients should be initially treated following the provisions of the MA of an authorised medicine, and only change to an off-label prescription if the initial treatment shows no success or presents intolerable undesired effects.
  • medical practice not being subject to the regulation of medicines in the EU, an extensive off-label use could undercut the public expectation that there has been a proper evaluation of a product’s safety and efficacy.[1]
  • the lack of scientific knowledge associated with off-label use and the consequent likelihood that a noteworthy share of the population could receive treatments for which there are no data regarding safety and efficacy, putting their health and lives at risk.
  • off-label practices could pose a threat to public health in general because extensive uncontrolled use conflicts with any centralised approval system based on the conditioning of the marketing of a product to scientifically valid and statistically significant evidence indicating that its potential benefits are likely to outweigh its potential risks.[2]
  • economic implications need to be considered. Off-label use might arguably be associated with an increase in healthcare costs.[3] This might arise either when a more expensive off-label medicine is employed and reimbursed in favour over a cheaper on-label product or when an insurer refuses to cover the off-label treatment costs, and as a result, the out-of-pocket expenses of patients are enhanced.[4]


[1] Off-Label Use of Drugs and Medical Devices: A Review of Policy Implications, RS Stafford 2012, 91 Clinical Pharmacology and Therapeutics 920.

[2] Supra note 16

[3] RA Tabora, “Litigation Aspects of Off-Label Use: Quality of Care, Generally Accepted Medical Practices & Emergence of Cost Containment” (2009) 19(3) Albany Law Journal of Science & Technology 619; D Kwok, “Controlling Excessive Off-Label Medicare Drug Costs through the False Claims Act” (2017) 27 Health Matrix 185.

[4] D Holley, “Balancing on the Edge: The Implications and Acceptability of Off-Label Drug Use” (2009) 19 Albany Law Journal of Science & Technology 633; T Lemmens and S Gibson, “Decreasing the Data Deficit: Improving Post- Market Surveillance in Pharmaceutical Regulation” (2014) 59 McGill Law Journal 943.

5. Off-label use across specific patient groups

Off-label use happens in all patient groups, but it is more common among certain patient populations. According to the ´Study on off-label use of medicinal products in the European Union´, such uses are particularly widespread in paediatrics—where children are often excluded from clinical trials—and in the area of rare diseases. Most studies reported in literature on off-label use in adults focus on specific therapeutic areas, such as oncology including haematology, psychiatry, or on rheumatology. The most frequently mentioned therapeutic area was oncology, including haematology. Pregnant women and the elderly are also groups of concern.

Rare diseases as a group are unique insofar as for many rare diseases there is no approved medicine, leaving off-label use as the only treatment. A 2012 survey in France among rare disease centres (92 out of 131 centres participated) identified 480 off-label practises corresponding to 82 rare diseases. In a survey, ‘EURORDIS Rare Diseases Europe’ estimated that 23% of the participating patients with rare diseases benefit from an off-label use product (120 out of 524 responses). In Hungary, 2% of the authorised off-label cases concern rare diseases.

The HMA states that particularly in paediatrics, the term “off-label use” mainly implies the absence of safety information, age-appropriate formulations, strengths and dosing recommendations for the physician and in consequence for the patient.

In the following two examples for off-label use in specific patient groups, paediatrics and oncology, are given.

5.1. Paediatric population

Specifically, paediatric prescriptions are frequently off-label as many medicines were not tested for use in children and not authorised for use in children. There is however broad consensus that children deserve access to medicines that have been specifically developed and researched for their use in young patients.

Regulation (EC) No 1901/2006/EC, the Paediatric Regulation (see also lesson 2, section 3.3 Paediatric medicines), came into force in the European Union (EU) on 26 January 2007. It was seen as a response to the absence of sufficient numbers of suitable, authorised medicines for children. The regulation was adopted to “ensure that medicines are regularly researched, developed and authorised to meet the therapeutic needs of children”. Its objectives were to:

  • facilitate the development and availability of medicines for children aged 0 to17 years of age;
  • ensure that medicines for the treatment of children are subject to ethical research of high quality and are appropriately authorised for use in the paediatric population;
  • improve the available information on the use of medicines in various paediatric populations.
  • achieve this without unnecessary trials in children or delaying the authorisation of medicines for adults

It applies to both, “nationally” (MRP, DCP, national) as well as to centrally authorised medicines.

In their Report on the survey of all paediatric uses of medicinal products in Europe 2010, three years after the coming into force of the paediatric regulation, the EMA summarised their findings on off-label use in the paediatric population: “Prescriptions of off-label and unauthorised medicines for children is widespread throughout the European Union (between 45-60% of the total number of prescriptions from this survey, confirming the results from previous publications). Both hospitalised children and out-patients are frequently treated with medicines used outside the terms of their marketing authorisation”.

A 2017 EC-commissioned study on off-label use of medicines in the EU (‘Study on off-label use of medicinal products in the European Union’) suggested that in children 0-18 years of age the prevalence of off-label use was still widespread, in hospital settings with a mean of  33,8 ± 15,5 SD and outpatient settings with a mean of  40,8 ± 28,1 SD. The authors concluded that, so far, the introduction of the Paediatric Regulation did not seem to have led to a lower prevalence of off-label use[1]

The most common examples for off-label use in children are medicines prescribed:

  • at a different dose or frequency, (many medicines used in children were prescribed and administered based on physicians’ own experience rather than on the results of clinical research)
  • in a different formulation or an alternative route of administration (absence of suitable formulations and routes of administration; paediatricians had to adapt the dosage and form of medicines authorised for adults, for example, by using only a portion of a tablet for adults after dissolving)
  • in this age group for which it had not been authorised
  • for a different indication than that which was authorised

This carries the risk of either lack of efficacy or poses safety problems in children, the latter perhaps of lesser concern in adults but possibly important and serious in children.

A single prescription can be categorised as off-label use in several different categories, of which the most common are shown in Table 3. In earlier studies, a medicine’s use was classified as off-label if the dose, dosing frequency, or the age/weight of the patient was not in agreement with the particulars in the SmPC. In more recent studies, the most prominent reasons for off-label use were a total lack of information in the SmPC about paediatric use of the medicine and the use of a non-approved dose in relation to age or weight.

Table 3. Off-label categories in Paediatrics.

Off-label category

Description

Age

Medicine not recommended in the SmPC below a certain age.

Weight

Medicine not recommended in the SmPC for children below a certain weight.

Absence of paediatric information

No mention at all in the SmPC regarding paediatric use.

Lack of paediatric clinical data

Stated lack of evidence of efficacy and safety in paediatric patients in the SmPC.

Contraindication

Statement in the SmPC that the medicine is contraindicated in children.

Indication

Medicine prescribed for indications outside of those listed in the SmPC.

Route of administration

Medicine administered by a route not described in the SmPC.


[1] 32 studies on off-label use (including data from 16 EU Member States) in various paediatric populations in the hospital setting showed a range of 13-69% of the investigated prescriptions being off-label. In 40 studies (including data from 12 Member States) in the outpatient setting, a wider range of 2-100% was found.

 

5.2. Oncology (cancer)

The off-label situation is more extensive in oncology than in other therapeutic fields. Across almost all cancer types, many products are already commonly used off-label. Because oncology remains a therapeutic area of high unmet need, prescribers and patients are often willing to accept the use of medicines in circumstances in which their efficacy and safety profiles have not yet been clearly established. A systematic review of the literature showed that off-label use of oncology medicines was in the range of 18% to 41% for hospitalised patients and of 7% to 50% for patients treated ambulatory. In total, 13% to 71% of adult patients with cancer received at least one off-label chemotherapy during their treatment. This was more likely to happen in patients who had exhausted all standard lines of treatment. The main off-label uses were in an unauthorised indication for a specific tumour and in an unauthorised line of treatment (Saiyed, Ong and Chew, 2017 [1]).

The principal reason is the large number of different types of cancer. In fact, each cancer medicine may be useful in several different types of cancer. In practice, many widely used anti-cancer medicines are not authorised for all indications in  which they can be effectively employed.

In a 2021 policy brief titled ‘ Repurposing of medicines in oncology – the underrated champion of sustainable innovation’ [2] the World Health Organisation (WHO) describes an initiative for Non-commercial repurposing[3] of off-patent medicines for cancer treatment which should have the potential of addressing currently unmet needs in a cost-effective way, especially in areas that are not attractive for the industry, such as rare cancers.


[1] Saiyed, M., P. Ong and L. Chew (2017), “Off-label drug use in oncology: a systematic review of literature”, Journal of Clinical Pharmacy and Therapeutics, Vol. 42/3, pp. 251-258, http://dx.doi.org/10.1111/jcpt.12507.

[2] Repurposing of medicines – the underrated champion of sustainable innovation. Copenhagen: WHO Regional Office for Europe; 2021. Licence: CC BY-NC-SA 3.0 IGO.

[3] Repurposing is a strategy to identify new uses for approved or investigational medicines outside the scope of their original medical indication.

6. Responsibilities of the prescribing doctor

By prescribing a medicine off-label, doctors have to take a special responsibility because they are prescribing something which the regulatory authority has not stated is safe and efficacious for use beyond the situations covered by the MA.

Even when the treatment was successful and, in comparison with other possible treatments, in the best interest of the patient, the doctor could be accused that their decision to use a medicine off-label was not in line with best practice and, depending on the health system, the treatment may not be reimbursed.

6.1. Doctor-patient discussion in off-label use

Legal and ethical principles require doctors to inform patients about risks of medical treatments. While off-label prescriptions are common and sometimes necessary, they also present significant risks. Given that off-label prescribing of medicines may expose patients to unnecessary risks, it is ethically required for doctors to disclose off-label prescribing to patients and seek their consent to the off-label use.

This includes discussing with the patient/parents/carer the reason for using the medicine, possible alternative therapies (in case there are any) and potential side effects.

Items to discuss could be:

  • Whether the medicine is approved for treatment of the particular condition or would be used off-label.
  • Whether there is an approved alternative.
  • Whether the off-label treatment has advantages compared to approved alternatives.
  • Whether credible research supports the off-label use.
  • Whether using the medicine off-label could carry additional risks.

Additional information about any uncertainties associated with the use off-label should be given. Patients should ask for additional information to address specific concerns.

Documentation of the consent process is recommended and, in some cases, obtaining written consent may be appropriate.

The informed consent should be expanded to require disclosure of off-label prescribing where the medicine has not been proven safe and effective for the specific condition, especially where scientific evidence is inadequate and risks are substantial or unknown.

Requiring disclosure protects patient autonomy and educates patients about alternatives and risks, leading to improved healthcare decisions.

7. Pharmacovigilance and off-label use

Directive 2001/83/EC requires the marketing authorisation holder (MAH) to report to the competent authorities ‘any other new information which might influence the evaluation of the benefits and risks of the medicinal product concerned’, including ‘data on the use of the medicinal product where such use is outside the terms of the MA’. So, if important safety information relating to ‘off-label’ use becomes available, this should be implemented in the SmPC. Further guidance is given by the European Medicines Agency (EMA) guideline on Good Pharmacovigilance Practices (GVP) and in an EMA Q&A presentation on Off-Label Use (January 2015).

With the popularity of social media and direct interaction across patient communities, patient organisations can play an instrumental role in extending and deepening the reach and effectiveness of pharmacovigilance. This is especially important in case of off-label use. Pharmaceutical companies are increasingly monitoring social media, and establishing formal interactions with patient organisations to follow up on the lifecycle of their products in other forms than Phase IV or post-marketing studies/trials. This also entails an increased level of responsibility on the side t of patient organisations so that they can keep this process under control, and observe safety and legal constraints. Promoting off-label use must be avoided, and pharmacovigilance on the side of the patient community is key for the future of any product, and the health and safety of patients.

8. Further reading

9. References

1. Study on off-label use of medicinal products in the European Union, NIVEL, Dutch National Institute for Public Health and the Environment, and the European Public Health Alliance, 2017.

2. Declaration on Good Off-Label Use Practice ‘Promoting Good Practice for the off-label use of medicines’, European Brain Council et al., 2021

3. New Early Access and Off-Label Use Rules in France, Léna Beley et al., July 6, 2021, Posted in Compassionate Use, European Union, Healthcare system, Medicinal Products, Pharmaceutical companies

4. Ciênc. saúde coletiva 25 (9) Sept 2020 https://www.scielo.br/j/csc/a/GQwLcBQZmGYp7mK3V6r7tFt/?lang=en&format=pdf

5. ADDRESSING CHALLENGES IN ACCESS TO ONCOLOGY MEDICINES © OECD 2020
https://www.oecd.org/health/health-systems/Addressing-Challenges-in-Access-to-Oncology-Medicines-Analytical-Report.pdf