Group1: Ethical II - Treatment (off label use)

Definition of off-label use

Off-label drug use has many different definitions depending on the country and the author giving the definition. In most cases off-label drug use is the use of an approved product in a scenario that was not included in the product information. Such a scenario includes different indications, different patient age range-group, different dosage or a different route of administration. [1]

The European Medicines Agency (EMA) defines off-label drug use as follows: Intentional use of medical product for medical use not in accordance with authorized product information. Included in this definition is the use in non-authorized paediatric treatment. Also presumed by the definition is that the off-label use is done intentionally in EU countries and implicates the product information relevant for usage in the European Union. [2]

Off-label drug use is very common in paediatrics: about 90 % of drugs prescribed to children are not approved for that use. In adults about 40 % of prescribed drugs are not used for the approved purpose. This is most commonly done in cases where patients have rare diseases because there are no clinical trials to test drugs specifically for such diseases. [1]

Every newly available drug is studied in detailed by doctors to evaluate the potential off-label use for the doctor’s patients. This is very difficult since the doctor takes high risks when administrating drugs for the first time in a non-approved scenario. Such a procedure demands a lot of courage from the physician since the off-label use of drugs is not always successful. [1]

Legal frame for off-label drug use in the EU and Germany

In countries that are part of the European Union, the approval for drugs is depending on national drug laws. These regulations are derived from directives developed by the EU. Implementing strict regulatory laws on drug approval leads to too much off-label drug use and elevates the risks of complications during treatment. A perfect regulatory system consists of an approval procedure that allows all important applications of a drug to be approved for treatment. In Germany, the first drug laws were implemented in 1961 after a medical scandal regarding the medicine thalidomid. In 1976 these laws were extended to include mandatory authorization for the usage of drugs. This means that before 1976, there existed no off-label use since there were no approved and disapproved drugs on the market. [2]

Goal of recent EU regulations is to specifically authorize drugs for the different respective treatments and minimise off-label use. In addition, through those regulations, adequate documentation can be achieved by using optimized forms and formulations. These regulations are not aimed at restricting pharmaceutical companies, but to give them incentives to steer them in the wanted direction. If a drug is approved for a majority of treatments, including the common off-label treatments, the EU grants a six-month extension to the Supplementary Protection Certificate and a two-year market exclusivity under the EU’s Orphan Regulations. Those measures strengthen pharma companies by securing their patents and intellectual property, but they don’t take into account the elevated costs and workload needed to extend the necessary studies, especially for medicine for children and teenagers. Mainly drugs for children and teenagers are in the focus, since they are mainly prescribed off-label, and clinical trials are uncommon for this kind of drug.

A main legal consideration in off-label drug use is the patient’s safety and the risk a doctor is allowed to take. Many doctors are in a dilemma because on the one hand they have a duty to cure a patient but on the other hand they risk legal consequences when the non-approved treatment is damaging to the patient’s health.

In Germany the early legislation allowed off-label drug use only in cases where patients had a life-threatening diseases and no other officially authorized drug is available. In recent years, this legislation was altered to be more patient-friendly and only an urgent necessity is required for the doctor to prescribe off-label drugs for treatment. This change also had consequences for health insurance and insurance coverage of off-label treatment. At the moment, a proof of efficacy for the chosen treatment and the above mentioned urgent necessity is required for a reimbursement by public health insurances.

Other European countries, like Switzerland, have similar or even more relaxed regulations concerning off-label drug use. [2]

FDA regulations for off-label drug use

The United States Food and Drug Administration, short FDA, is responsible for approving drugs for medical use and has started to regulate off-label drug use in the year 1938. Regulations try to balance the interest of pharma companies to sell their product by influencing doctors and to let the doctor judge the situation neutrally and make the best decision for the patient’s health.

This lead to the rule that doctors can prescribe off-label drugs to patients, but pharma companies can’t promote the off-label use of their products. But they can give the doctors access to scientific articles about the use of their drugs in a non-approved treatment. Only independent third-party sources have the right to promote off-label usage of drugs in the United States. [3]

Reasons for off label use

There are multiple scenarios where a drug might be administered outside the specification of the product information. First of all, as mentioned above a large group of the population is less represented in clinical trials. This group includes newborns, children, pregnant or lactating women, but also the elderly and people with pre-existing conditions like liver or kidney disorders. Since these people cannot be left untreated, the appropriate medication needs the be prescribed off-label. Another reason can be the unavailability of a safe, effective and licensed therapeutic option. This can be the case in illnesses with a low prevalence in the population or have are heterogeneous, like cancer or in terminally ill patients, that have exhausted all other treatment options. The evidence, that a medication can be safely and effectively used to treat a condition that it is not intended for, might also indicate an off-label use. This practice is often referred to as evidence-based medicine (EBM) [4][5].

Prevalence of off-label use

Some fields of medicine are especially prone to off-label use of drugs. Here are some of the most important.

• Paediatrics (78% if hospitalized children receive at least one off label medication)
• Psychiatry
• Oncology
• Intensive care

Risks of off-label use

The prescription of drugs to people outside the intended audience implies some risks, that should not be left unnoticed [6][7].

• The risk of suffering from adverse drug reactions during off label use of drugs is higher compared to on-label use, especially if the off-label use is lacking strong scientific evidence, which is the case in about 4/5 of the cases according to a Canadian study. (See Figure below)
• Off label use is lacking recommendations for usage like safe dose ranges, contraindications, preffered way of administration and other guidelines, that help the doctor to optimize the treatment.
• The interaction of the off-label medication with other drugs is not well studies for the new use. Often patients are prescribed more than one drug and the doctor might not be updated on all changes since this information might change rapidly. A high number of administered medications has been associated with increased side effects.
• Adverse reactions to the drugs might be hidden by comorbidities, especially in very ill patients who often recieve off-label drugs.
• Off-label use is potentially harmful.
• Sometimes drugs are used off-label without reasonable evidence, that the medication is actually helping, or continued despite newer findings (e.g. when the doctor does not read up on recent developements).
• Drugs that are used to treat a condition might actually induce a more severe illness in the patient.
• The insurance might not pay for the drug, which would induce an additional financial burden for the patient.

Benefits of off label use

Off-label prescription of drugs has been a habit for a long time now and obviously there are benefits that provide good reasons to continue this practice [7][8][9]

• Off-label use can be the only option for patients to receive any kind of medication. This can be the case, when there is not treatment to begin with, but also when all other treatment options have failed to improve the condition.
• Sometimes, the drug cannot be tested on all potential patients.
• In oncology, off label use is necessary because every case needs to be considered and treated individually.
• Some trials might not be pursued by the pharmaceutical industry, because they do not promise enough financial reward.
• A gold standard treatment is often not available, especially in children and neonates.
• An expert opinion might be available that can be used as evidence for the off-label use
• In any case, the treatment option which will be chosen must be in the patients best interest, and evidence not the label must be the driving factor in the choice of medication.

According to cancer.org, clinical trials are done in order to prove that the drug

• Successfully treats a specific medical condition
• Works the way it is expected
• Safe to use as instructed

When FDA is satisfied with the drug and it does follow the steps above, the drug is labeled. The Labeling is a specific report with every detail of information regarding the drug. However, the legislation as explained previously, allows sometimes some drugs to be used ‘off-label’ because of several reasons. One being that filing new reports and applying for FDA approval might be lengthy and costly. For cancers in general, and for brain cancers as well, it is considered an ‘off-label’ usage of a drug in case [9]:

• Used for different type of cancer (different stage of cancer)
• Given in a different way (different route)
• Given a different dose

Especially generic medicines that are very well spread in the market, are the ones that are proven to be good in off-label use for brain cancers, and cancers in general. Furthermore, during chemotherapy there are used a cocktail of different medications at the same time, and the combination usually includes drugs that are off-label, since they are proven to perform very well against different kind of tumors.

A very common case in off-label use for cancer treatment is treating certain type of pains with Tricyclic antidepressant. This drug is approved by the FDA for usage in clinical depression. However, this drug is very rarely used for its initial purpose since many other antidepressant drugs showed to perform better [9].

Bevacizumab is another generic name for the drug which is used in malignant brain tumor treatments (Glioblastoma) as an off-label drug. In the US, the drug is known under the name ‘Avastin’ and it is FDA approved for colorectal and certain type of lung cancer. The off-label usage of the drug helps patients to increase the time of regrowth for recurrent glioblastomas. According to the study, 36% of the patients who received bevacizumab alone, did not show any growth in the tumor mass for at least six months. Scientists argue upon the successfulness of the drug usage in patients depends on the width of blood vessels in brain-tumors. The ones that have thinner blood vessels are supposed to have a higher success rate compared to the ones with thicker blood vessels. Nevertheless, the usage of the drug is not still standard. Scientists are trying different methods on giving the drug, as alone, in combination with chemotherapy and/or radiotherapy [10][11].

Avastin Bevacizumab [12]

Another case is the usage of Lorazepam (Ativan), which is an anti-anxiety drug used for anti-nausea in cancer treatment. Furthermore, the drug is most commonly given under the tongue, which is not prescribed as such in the label report. Thus, this drug is “given for off-label use in an off-label route” according to cancer.org [9].

Interestingly enough, a malaria drug used off-label for severe Glioblastoma, has shown to be successful in the case of Lisa Rosendahl. After identifying the tumor mass, and many trials of treatment, radiotherapy, and even surgery, an off-label drug under the name of ‘Chloroquine’, which is primarily used for Malaria, has shown very good effects against the tumor. The success behind is the capabilities of Chloroquine in cell autophagy. Initially the patient used Vemurafenib for cell autophagy, however the results were disappointing and not working accordingly, thus, because of these capabilities ‘chloroquine’ has been used as a replacement and showed very good results [13].

Malaria Drug used to treat Brain Cancer [14]