3. Off-label use

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.