Ethical Consideration of "Off-label Use" treatments

Background information

Definition

There are many definitions of off-label use. They desribe nearly all the same. Off-label use of a medicine is the use of it outside of the originally tested and strictly conditioned licensed indication [1,2,3]. The European Medicines Agency (EMA) defines it a bit more specific:

Situations where a medicinal product is intentionally used for a medical purpose not in accordance with the authorized product information. Off-label use includes use in nonauthorized paediatric age categories. Unless specifically requested, it does not include use outside the EU in an indication authorized in that territory which is not authorized in the EU.

This is from the EMA Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 2) 2013. (EMA/876333/2011 Rev 2*) (see also [1]).

When this kind of treatment is considered

This kind of treatment has many different purposes. The most important are [2]:

• dosage: often lower doses than licensed are used because the does depends on the age and weight of the patient
• age: for many medicines there is no license for children under a certain age or no license for children at all
• indication: some medicines can be used to treat childhood illnesses which are not covered by the license
• route of administration: sometimes no suitable license formulation can be found
• contraindications: aspirin, for example, contraindicates the Reye syndrome at children

Legal background

The legal discussion of off-label use aims to risks for patient safety of medicinal products used without indication or deviating from technical information which is in this case the dosage [1]. Although it’s legal for doctors to subscribe off-label drugs, it’s illegal market these drugs for off-label uses.

Drugs shall guarantee the highest possible level of safety and effectiveness, but sometimes there are no drugs or the spectrum of medicines is exhausted very fast with no improvement of the health status of the patient. Unfortunately the physician has to administer his decision, so he/she has a dilemma to solve. The regulatory drug approval and the medical malpractice law exist to protect the patients of arbitrariness. The regulations in Germany were essential after the thalodomide (in Germany also known as Contergan) scandal. In section 21 AMG [German medical law] (see also Article 6, section 1 of the EU directive 2001/83/EC) is written that legal assurance needs official authorization and approval in three different ways:

• analytically: the drug has to be tested chemically, physically and bilologically
• toxicological
• pharmacological

The latter two also have to be tested on humans. The disregard of this rule is a criminal act leading to prison (intention) or fines (negligence) defined by section 96, number 5, 97 subsection 1 AMG [1].

In Germany, every citizen has a health insurance. Either a private one or a public. The different insurances types have to pay different regarding off-label prescriptions. The private health insurance pays nearly all prescriptions because of the legitimate interest to use drugs not belonging to conventional medicine which have been proven to be beneficial for the patients. The public health insurance, on the other hand, has a more complex procedure determining if they pay or not. This depends on three conditions [1]:

• it has to be a serious disease (life-threatening or strongly affecting the quality of life)
• all therapies have to be exhausted so no other possibility is left
• reasonable expections of success based on data (of other patients)

Reasons for usage of off-label treatments

A off-label use of a therapy is necessary, if there is no other appropriate alternative on the market for treatment, which is authorized by the Marketing Authorisation(MA). Also, the benefits of applying the planned therapy should outbalance the risks of the treatment.

In addition to that, following reasons could have an effect for deciding to go for off labeled therapies:

• use medication for treatments of children, where clinical trials is often not possible
• use for a slightly altered or minor form of a symptom/disease, which has to be approved seperately usually

Benefits and risks

The following arguments point out, why it is often beneficiary to use treatments of-label:

• if approved treatments have failed, a treatment can provide some sort of innovation in clinical practice
• provides earlier access to potentially effective medication, which could not be accessible so fast with the normal procedure of regulating
• doctors can adopt new practices with newly acquired evidences from researches

Risks

• drug safety and efficacy is not fully tested
• newest medication tends to be expensive, so overall treatment costs will increase
• drug companies can use off-label use in order to avoid more complicated approval procedures to save costs, so that more and more products are note testet enough
• the try-and-use approach can dominate the evidence-based treatment by going off-label to much
• patients may not pay so much for drugs which are not proven

Examples for off-label use

Reasons for using off-label drugs according to [7] in cancer treamtent are:

• Some cancer drugs are found to work against many different kinds of tumors.
• Chemotherapy treatments often combine drugs which might include one or more drugs not approved for that disease
• Cancer treatment is always changing and improving.
• Oncologists (cancer doctors) and their patients are often faced with problems that have few approved treatment options
• Oncologists and their patients may be more willing to try off-label drugs than other medical specialties.

Another example is Ativan(Lorazepam) which is now often used as an anti-nausea drug in cancer treatment but was traditionally used to supress panic attacks. It is most commonly given under the tongue, which is also not listed on the drug label, so as well as being used off-label it is also injected off-label [7].

A recent study that investigates an off-label drug is [8]. They aim to hinder the reoccurrence of a remove glioblastoma with the use of the antibiotic DOX to turn on the high-capacity adenoviral vector (HC-Ad) encoding therapeutic Flt3L expression. DOX is usually applied to humans as an antibiotic to treat various types of infections.They tested the drug in rats to observe the expression of Flt3L and to find out if there is any toxicity occurring. The results were promising and showed that Flt3l will be expressed in human glioma at a DOX dose of 200 to 300 mg/day, which is an approved dosage by the FDA.

Another succesful application was the adding of the anti-malaria medication cloroquine to traditional therapy with vemurafenib. This helped to cure Lisa Rosendahl who suffered from glioblastoma on which chemotherapy, radiation treatmens and surgery already failed [9]. Vemurafenib showed initial sucess, however the cancer used a process known as autophagy which manages cellular recycling. Certain cell organelles encapsulate any additional, harmful material within the cell and ferry it to the cell's lysosomes to be disposed. Cloroquine inhibited the brain tumor from using autophagy and the vemurafenib worked fine. Mulcahy-Levi et al. treated 3 patients with this apporach and discussed his reults in [10].

Still using off-label drugs comes with obvious risks as discussed in the previous sections. A off-label use that went wrong was Fen-Phen [11]. Fenfluramine and Phentermine were approved for short-term use as diet aids, but showed no significant results. So in 1979, Dr. Michael Weintraub, tested if a combination of both drugs would work better. From a small study of 121 obese patitents he got promising results. Word of fen-phen spread and patients began calling doctors to demand the drugs. In 1995 Fen-Phen was withdrawn from the market by the FDA, because doctors had found out that the drugs may cause heart valve defects in as many as a third of patients.

Bibliography

1. Lenk C, Duttge G. Ethical and legal framework and regulation for off-label use: European perspective. Therapeutics and Clinical Risk Management. 2014;10:537-546. doi:10.2147/TCRM.S40232.
2. Sharon Conroy, John McIntyre, The use of unlicensed and off-label medicines in the neonate, Seminars in Fetal and Neonatal Medicine, Volume 10, Issue 2, 2005, Pages 115-122, ISSN 1744-165X, http://dx.doi.org/10.1016/j.siny.2004.11.003.
3. Stafford, Randall S. "Regulating off-label drug use—rethinking the role of the FDA." New England Journal of Medicine 358.14 (2008): 1427-1429.
4. European Commission. Stamp 6/30 Off-label use of medicinal products. March 2017. https://ec.europa.eu/health/sites/health/files/files/committee/stamp/stamp6_off_label_use_background.pdf
5. http://blogs.findlaw.com/second_circuit/2012/12/off-label-use-promotion-is-protected-free-speech.html
6. http://www.nytimes.com/2009/01/27/health/27cancer.html
7. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/off-label-drug-use.html
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003468/
9. http://www.techtimes.com/articles/193231/20170118/malaria-drug-could-be-used-to-treat-brain-cancer.htm
10. http://cancerdiscovery.aacrjournals.org/content/4/7/773.long
11. http://www.nytimes.com/1997/09/23/science/how-fen-phen-a-diet-miracle-rose-and-fell.html