Introduction
Off-label drug use is the prescribing of available and marketed medication for a disease or symptom which it has not received approval for (Wittich, et al., 2012). It may also refer to the use of a drug in a section of the patient population for which it hasn’t been approved (as is often the case in paediatrics) or the use of a drug in a dosage form for which it has not been approved. In the vast majority of countries, the local regulator (such as the European Medicines Agency in Europe, the FDA in the USA and the Pharmaceuticals and Medical Devices Agency in Japan, etc.) approves medications that have been shown to be safe through clinical trials for specific diseases or symptoms but beyond this doesn’t limit how doctors prescribe drugs that are on the market thus creating the opportunity for off-label use. Off-label use is widespread in medicine but is more common in areas where the patient population is not likely to be included in clinical trials. The stand-out examples being children, pregnant women and psychiatric patients. Off-label drug use does not apply to drugs used for research in clinical trials, these have to meet strict safety tests in animals before they can be approved for use as part of a study.
Why go off-label?
There are a number of reasons why off-label drugs might be used, a few of the common ones are:
- A medication may not have been trialled on a specific patient population (e.g. children) and therefore isn’t approved for use on that group.
- A life-threatening or terminal medical condition might cause the doctor to try any logical treatment as a “drug of last resort”.
- The drug belongs to a class of medications and even if one member of the class is not approved for a specific disease or symptom but another is, then it is likely that the drug will have the same effects (see Bevacizumab below).
- The pathologic and physiological conditions of two diseases are similar, doctors may use a medication approved for one of these to treat the other. For example, anxiety medication is often also used to treat post-traumatic stress disorder.
Where are off-label drugs used?
As mentioned above, off-label use is widespread, but particularly in psychiatry (Alexander, et al., 2011). Of the top 5 off-label drug uses (in the US) the most common class of drugs are those to treat psychiatric conditions which are prescribed off-label for other psychiatric conditions (Ipaktchian, 2008). For example, Quetiapine and Risperidone, both Schizophrenia drugs used off-label for Bipolar disorder as is the depression drug Escitalopram. The only two non-psychiatric drugs in the top 5 are Warfarin, a blood thinner used off-label in heart disease and Montelukast an asthma drug that is used to treat the related condition of COPD.
Off-label use is becoming even more common today with the global sharing of medical information (Wittich, et al., 2012), whilst regulators do share drug safety information to some extent, it is possible for a drug to be approved for one use in one country and not approved for that use in another (but still marketed there for another condition). In such cases it makes sense that doctors are able to prescribe the drug to treat the condition it is approved for in the other country.
Off-label to ‘on’-label?
It is possible for off-label drug use to become sufficiently widespread that it becomes part of the clinical routine, in some cases even supplanting the existing approved treatment. An example of this is tricyclic antidepressants, no longer a first-line drug for depression due to their side effects (and the introduction of MOAIs and SSRIs which classes of antidepressant with fewer side effects), they are now used as the first-line treatment for neuropathic pain (Wittich, et al., 2012).
However, off-label uses are hardly every “converted” to on-label uses because it requires replicating the entire drug approval process, clinical trials and all, which is a time-consuming and costly process. And this would have to be done for each new disease or symptom that the drug would target. In addition, many off-label uses are discovered long after the drug is first marketed, by which point they have become “generics” and no longer make money for their original creator since the associated patents have expired. There is therefore no incentive to invest money in approving these drugs for new conditions when they can’t be used to make money back for the company conducting the trials.
Legal Background
USA
The practice, called "off-label" prescribing, is entirely legal and very common in the United states. More than one in five outpatient prescriptions written in the U.S. are for off-label therapies. Every prescription drug marketed in the U.S. carries an individual, FDA-approved label. This label is a written report that provides detailed instructions regarding the approved uses and doses, which are based on the results of clinical studies that the drug maker submitted to the FDA.(Miller et.al)
In the United States, the law permits a physician or other healthcare practitioner to prescribe an approved medication for other uses than their specific FDA-approved indications. Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal FDA approval. Marketing information for the drug will list one or more indications, that is, illnesses or medical conditions for which the drug has been shown to be both safe and effective.
However, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective, and are not limited to official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is often extensive medical literature to support the off-label use. The FDA does not have the legal authority to regulate the practice of the medicine, and the physician may prescribe a drug off-label.
(Edgmont. et.al) mentioned that the goal for a physician to document to support adequate continuing care for the patient. Adequate treatment record documentation supports patient care and serves numerous other purposes, including providing the base for a defense in the event of a lawsuit or board complaint. If the documentation supports patient care, it likely will fulfill the purpose of providing a defense.
To adequately support patient care, physicians treatment record documentation should be such that other clinicians can read your notes and be able to understand what he did in the course of treatment and why he did it.
The biggest problem is getting insurance plans to pay (reimburse) for off-label drug use. Many insurance companies will not pay for an expensive drug that’s used in a way that’s not listed in the approved drug label. They do this on the grounds that its use is “experimental” or “investigational.” (The American Cancer Society medical and editorial content team.et.al)
In cancer treatment, these issues have been largely addressed through 1993 federal legislation that requires insurance to cover medically appropriate cancer therapies. This law includes off-label uses if the treatment has been tested in careful research studies and written up in well-respected drug reference books or medical journals. In 2008, Medicare rules were changed to cover more off-label uses of cancer treatment drugs.
UK
Off-label prescribing is legal in the UK and widely used, particularly in paediatric medicine. However, doctors are required to meet the following conditions if they choose to prescribe a medicine for use outside the terms of its licence:
- Be satisfied that it would better serve the patient's needs than an appropriately licensed alternative
- Be satisfied that there is a sufficient evidence base and/or experience of using the medicine to demonstrate its safety and efficacy. The manufacturer's information may be of limited help in which case the necessary information must be sought from other sources
- Take responsibility for prescribing the medicine and for overseeing the patient's care, monitoring and any follow up treatment, or arrange for another doctor to do so.
- Make a clear, accurate and legible record of all medicines prescribed and, where you are not following common practice, your reasons for prescribing the medicine.
(General Medical Council, 2013)
In addition, an approval for funding must be sought from the local healthcare funding organisation in order to fund the patients’ treatment. Since currently funding is only provided to cover the cost of medicines for their approved use and section of the patient population as determined by NICE, The National Institute for Health and Care Excellence.
Benefits and Risks
Benefits :
Off label prescribing can be helpful at times when there are no other options left to try out for the patient. This might happen in cases of rare disease or cancer. Chemotherapy drugs approved for one type of cancer can be used to target may different types of tumors. Off label use of these chemotherapy drugs might help in the treatment. Combination of off label and approved drugs are often part of the treatment. Some examples of off-label include Beta-blockers. Beta-blockers are approved by FDA for the treatment of high blood pressure but they are widely recognized by cardiologists as a standard of care for patients with heart failure.
G. Caleb Alexander, MD, MS, Assistant Professor of Medicine at the University of Chicago Medical Center talks about the advantages of using off-label drugs. Below we summarize them,
- Allows for clinical innovation, especially for patients who do not respond to standard treatments : There are scenarios when the patient do not respond to the standard treatments. The doctors at this point can use their innovative thinking and create a treatment that uses a combination of off-label and standard drugs.
- May be only available option for uncommon conditions or for patient populations that have not been studied : As mentioned above, there might be situations when the patient has exhausted all the treatment options in cases of rare types of cancer. Also there might be cases when the drugs are not tested on the population group that the patient belongs to (e.g : infant). In these cases off-label drugs are the only option to move forward.
- Allows physicians to anticipate growing evidence of efficacy prior to formal evaluation.
- Increases return on investment for pharmaceutical firms : The approval process for a drug for a specific disease is a costly and time consuming process. Although the drugs might help in targeting other diseases, they are not usually sent for approval due to the costs involved. Using these drugs for other diseases (off label use) increases the return on investments by reducing the approval cost.
Risks :
Doctors emphasize that off-label prescribing has its place in medical practice. The doctors, despite of the advantages involved also admit that the use of off-label drugs increases the risk of lawsuits if the patient has some side effects from the use of the drug. On of the best example that shows the risks involved in the use of off-label drugs is Fen-Phen. The FDA approved medications fenfluramine hydrochloride and phentermine hydrocholoride as individual, short-term treatments for obesity. But doctors eventually began prescribing the two drugs together after an article describing the cocktail's dramatic weight loss effects appeared in a medical journal and numerous mainstream publications. This cocktail had devastating results which involved severe, and potentially deadly, heart valve damage. These side effects led to a removing Fen-Phen off the market.
Although some off-label therapies can be beneficial and even lifesaving for some patients, in most cases, there is little or no scientific evidence to prove they work. In a recent commentary in the Archives of Internal Medicine, three scientists from the National Institutes of Health (NIH) Clinical Center's department of bioethics say that "off-label use has been identified as one aspect of problematic drug prescribing," in part because of inadequate data regarding drug safety and effectiveness for the off-label use.
G. Caleb Alexander, MD, MS, Assistant Professor of Medicine at the University of Chicago Medical Center talks about the disadvantages of using off-label drugs. Below we summarize them,
- May diminish public expectation that drugs will be evaluated for safety and efficacy before use
- Blunts industry incentives to perform studies required for FDA label changes : FDA label changes takes a lot of time and money. If a drug gets approval by the community of the doctors, there is no need for the FDA approvals for label change. This offloads the legal risks from the Pharma industry and blunts the incentives to get it approved.
- Drugs used off label may have unrecognized safety and efficacy problems : An approval process involves testing the drug on a sample cases that represent the population. This gives a efficacy profile of a drug on the population. Off-label drugs lack this profile and it then is the task of researchers or the doctors to gauge the efficacy of the drug by involving them in the treatments.
- Promotes use of drugs in populations (e.g., children, the elderly) for which they have not been tested : As mentioned in the benefits, this might also be a risk as use of off-label drug might result in side effects which might be life threatening.
Examples
Fentanyl
Off-label use is not always a positive thing. In some cases, it has led to the death of a patient. Such an example is Fentanyl, a powerful painkiller. A particular formulation of fentanyl is branded as Subsys in the US and approved for treating cancer patients who are opioid tolerant and who experiments intense flares of pain. As an opiate, it is a particularly dangerous drug, like other opiates Heroin and Morphine (and being 50 to 100 times more potent that the latter) it is addictive and can easily lead to overdose. In one case in the US a woman was found dead from an overdose after being prescribed fentanyl off-label for back and neck pain (Armstrong, 2016).
There are perhaps other factors at play in this instance in addition to the “off-label” prescribing. Such as the patient being given 30-day supplies of the drug at a time (in other countries opiate use is more strictly controlled and only small quantities are dispensed to patients at a time) and the fact that pharmaceutical companies in the US directly market to patients, and when they do so often include off-label uses of the drug despite this being illegal (Wikipedia has a large list of cases where this has happened). Another drug, canagliflozin (branded Invokana), is approved as a diabetes drug yet the manufacturer touts its weight-loss effects on the drugs website (Levin Papantonio, n.d.). This is dangerous since patients taking Invokana are nearly seven times more likely to suffer a heart attack or stroke.
Fentanyl a powerful opiod painkiller that is perscribed off-label for pain releif despite only being authorised for use in cancer patients who are opiod tolerant. (Source: Huffington Post)
Nevertheless, this highlights one of the main problems with permitting “off-label” use. Where “off-label” use is permitted the responsibility is passed from the regulator to the doctor. Whilst the regulations surrounding off-label prescribing in most countries require that the doctor be satisfied that the drug will be more effective than a currently licenced alternative it is obviously difficult for doctors to keep abreast of the wealth of studies and research surrounding any particular drug and evaluate its suitability. This can lead to doctors being swayed to prescribe off-label based on the patients wishes or anecdotal evidence from other doctors rather than their own understanding of the evidence. Ultimately this means that sometimes inappropriate drugs are given to patients for is a bad thing. This is even worse in systems where the patients and doctors’ interests are not well aligned, e.g. when doctors can be payed kickbacks by pharmaceutical companies for prescribing their drug. As we can see from the fentanyl case, this can have devastating consequences.
Toxoplasma gondii - a protozoa which causes the disease known as Toxoplasmosis (Source: Centers for Disease Control).
Drug Repurposing
One of the areas where off-label use can be extremely useful is in overcoming drug discovery challenges. As we know, drug discovery is both time consuming and expensive. By repurposing drugs which have been shown to be safe for other conditions to threat new ones we can potentially save both time and money. Off-label use can also benefit sufferers of little known diseases, or diseases for which there is not a large market and so which gain little interest from pharmaceutical companies who are driven by the need to make profits. This is unsurprising, it is estimated to cost $US800 million and 1–2 decades to discover and develop a new drug, and so can’t be done without a potential return on that investment.
An example of often overlooked conditions that can benefit from off-label drug use (or “drug repurposing”) are the parasitic diseases such as malaria, trypanosomiasis, leishmaniasis, toxoplasmosis, and cryptosporidiosis. This is particularly important because these parasites often quickly become resistant to new drugs, rapidly rendering them useless (and further decreasing the incentive to develop them in the first place).
Here we briefly outline a number of drugs which have been repurposed for use in treating human parasitic protozoan diseases, adapted from Andrews, et al. (2014).
- A number of broad spectrum antibiotics like Doxycycline have been shown to be effective against the liver stages of the malaria parasite.
- A group of drugs known as the sulphonamide group is used to treat a range of diseases including kidney disease, glaucoma, epilepsy and obesity and have been repurposed to treat T. gondii and P. falciparum parasitic infections.
- Eflornithine, a drug that was identified as an anti-tumour agent and then discarded due to adverse side effects in clinical studies has been used to treat African sleeping sickness.
- Amphotericin B deoxycholate is authorised for use against fungal infections but was later used in India to treat visceral leishmaniasis.
Conversely, a number of drugs have been approved for treating protozoan infections but then repurposed for other diseases. Quinine for example, an antimalarial drug is now used along with members of the same family to treat lupus, arthritis and leg cramps (Andrews, et al., 2014).
We live in a world where we are rapidly running out of drugs, particularly antibiotics (Allan, 2014) and potential drugs are being lost due to deforestation (McGrath, 1999). Moreover, the drugs we do have often go through periods of shortages. Everything from cancer drugs, anaesthetics, pain control to cardiac medicine and psychiatric drugs have either been unavailable or in short supply at one time or another (Eban, 2017). Off-label use of one of the may drugs we already have could provide a solution to these problems and more.
Off-label drug use represents a wide pool from which to draw new and alternative treatments. In addition to the drugs that are already in use there is also the compounds which have been abandoned by the pharmaceutical companies. A study by Huang, et al. (2011) estimated that there are around 8969 compounds available for repurposing. Unfortunately, there is a difficulty in accessing these compounds, usually due to issues involving intellectual property. Then there is the issue of funding, making sure that off-label use is safe and transitioning to on-label use is expensive (it’s why the drug companies don’t do it), with some studies resorting to crowd funding in order to investigate the safety of some drugs for off-label use (Geddes, 2016). An alternative approach might be to repurpose medicines used on animals for humans, particularly in diseases where there are similarities (e.g. many of human and animal infecting protozoa are genetically similar) (Andrews, et al., 2014). Of course, as discussed in the animal testing section, these similarities only go so far, and this approach should be taken with caution.
Bevacizumab (Avastin)
Bevacizumab (branded Avastin) is a drug approved for cancer treatment as an anti-angiogenic, that is it prevents blood vessel formation but inhibiting a growth factor called VEGF or vascular endothelial growth factor A. Ranibizumab (branded Lucentis), as the name might suggest, is a related drug derived from the same parent mouse-antibody. Consequently, it has the same effectiveness and similar side effects to Bevacizumab. The difference is that Ranibizumab is only approved to treat age-related macular degeneration (ARD), a common form of age-related vision loss. But that’s not the important difference, the other main difference is price, Bevacizumab is about 12 times cheaper than Ranibizumab (because it is supplied in larger doses for cancer treatment than needed to treat AMD) (Torjesen, 2012). This would suggest that a cheaper way to treat AMD would be to use Bevacizumab off-label. Particularly since a review has found that Bevacizumab is just as safe for use as an AMD treatment (Moja, et al., 2014).
And therein, lies the controversy. Drugs giant Roche is the licence holder for both Bevacizumab and Ranibizumab and is fighting tooth-and-nail to prevent Bevacizumab being used in place of Ranibizumab as it would eat into its profits. If the licences for both drugs were held by different companies we would probably see one apply for the label-use to be expanded to include AMD, but since Roche develops both drugs it has no incentive to expand the labelled use of Bevacizumab as it would directly reduce its sales of Ranibizumab.
Avastin proposed mechanism of action (Source: Genentech)
In the UK where the healthcare system is under severe financial strain, the drugs company has taken legal action to prevent funding of prescriptions of Bevacizumab for AMD and has used its influence with patient groups to discourage patients from taking Bevacizumab. Since there is no real benefit to the individual for choosing the cheaper drug (they don’t pay either way) it is difficult to convince patients use Bevacizumab off-label. As it currently stands the regulatory body for doctors in the UK favours licensed drugs over unlicensed. Although it is not unlawful for doctors to prescribe unlicensed drugs this doctors at a risk of being investigated (and so potentially having their licence to practice revoked) if they prescribe unlicensed medicines (Lock, 2014).
Elsewhere we have pointed out how off-label prescribing by doctors without sufficient data (e.g. Thalidomide) or without the patient’s best interests at heart (e.g. fentanyl) can lead to unacceptable consequences. One potential solution to this is to limit or take away the power away from doctors to prescribe off-label. We think however that the Bevacizumab/Ranibizumab story shows that even regulators do not necessarily have the best interests of the patient or society at heart and in some cases, have their hands tied by regulation which hampers medical innovation. This would suggest that there is a need to doctors to have the freedom to prescribe off-label in order to facilitate sensible drug use. Of course there should a balance, doctors should not be given carte blanche to prescribe drugs however they wish but neither should they be prevented from doing so where there is a sound case for using a better alternative.
Thalydomide was initially prescribed off-label (Source: Getty Images).
Thalidomide
You might expect Thalidomide to be the poster-child for the negatives of off-label use. It was, after all, it’s use off-label as a morning sickness treatment started by Australian obstetrician Dr William McBride that lead to hundreds of children being born with severe birth defects (Fintel, et al., 2009). Thalidomide was later shown in interfere with babies’ normal development and cause phocomelia, that is shortened, flipper like or even absent limbs.
However, Thalidomide is today approved for the treatment of some conditions. The first being leprosy and the second being as a chemotherapy agent for patients with Multiple myeloma, a cancer that forms in white blood cells (Schaffer, 2011). The reason Thalidomide was explored as a anti-cancer drug is that it was thought that it inhibited the development of blood vessels (angiogenesis) which tumours need to grow and this is how it prevented the development of normal limbs (Zimmer, 2010). Thalidomide was originally prescribed off-label for these conditions as well. Thalidomide is now a template for a whole class of drugs (e.g. lenalidomide, pomalidomide, apremilast) with a wide range of applications including lymphoma, luekemia, anemia, systemic sclerosis, psoriasis and arthritis. There are also investigations into its use in dermatology (Chen, et al., 2010) and as an immune booster for the elderly (Huang, et al., 2011).
If the Thalidomide story tells us anything it is that off-label drug use can do both harm and good, and shows the need for proper risk assessment when using drugs off-label. Using any drug off-label for morning sickness, when there are many non-drug treatments, and approved drugs (antiemetics) was probably not a good use of off-label prescribing. Indeed, it runs contrary to the idea that doctors should only prescribe off-label when they are convinced that the off-label treatment is more suitable than the alternatives. In this case, we would say the risk of prescribing Thalidomide was very high, whereas its first use as a “drug of last resort” for a severely ill leprosy patient who had little chance of getting better had a much lower risk of harm.
Without off-label prescribing it is unlikely that Thalidomide would have had experience the comeback it has today and is an important reminder that new uses can be found for old drugs even if they have been previously consigned to the dustbin of time (Sirven, 2010). But, it is also a cautionary tale that we should properly weigh up the risks and rewards whenever we make use of drugs off-label.
Doxycycline
Doxycycline is a widely used antibiotic and is used to treat a range of bacterial infections as well as Lyme disease, cholera, syphilis and together with quinine for malaria (FDA, 2012). However there has been research to assess the use of Doxycycline “off-label” to induce therapeutic transgene expression in treating Gliomas (VanderVeen, et al., 2013). Tumour recurrence is very common in patients with Glioblastoma’s due to the fact that the tumours are likely to mutate and undergo genetic rearrangements. The therapy proposed by VanderVeen, et al. (2013) is to inject an adenoviral vector (a section of virus DNA which is used to carry genetic material into cells, in the same way as the Adenoviruses would when infecting cells) which codes for the expression of Flt3L or “FMS-like tyrosine kinase 3 ligand” into the tumour bed after tumour resection in order to prevent tumour recurrence.
Flt4L is a small molecule that increases the number of immune cells in the surrounding area. It is thought that this may help the kill cancer cells (Shortman & Naik, 2007). To prevent the Flt3L from being produce by the cell all the time after the DNA is delivered, the Flt3L gene is linked to a tetracycline-controlled transcriptional activation system. This is a system by which gene expression by cells is controlled by the presence or absence of the antibiotic tetracycline, of which doxycycline is a derivative (Gossen & Bujard, 1992). Consequently, in order for the therapy to work, doxycycline would have to be given to patients off-label in order to activate Flt3L gene expression. The use of Doxycycline as a regulator for Flt3L expression is a safety feature of the treatment as it allows expression to be turned “on” and “off” gene expression upon the addition or withdrawal of doxycycline.
VanderVeen, et al. (2013) show that expression of Flt3L in the rat brain can be triggered by doses currently approved as safe for treating humans with bacterial infections and so the off-label usage is also safe.
Doxycycline (Source: Wikipedia)
Mebendazole & Co.
Recently a number of clinical trials have started (e.g. the METRICS Study) to investigate the effectiveness of common drugs (i.e., those widely used for other conditions and available on prescription or over the counter) on cancer. The idea is that since the drugs are well understood and have low levels of side effects they provide a good way to supplement existing cancer treatment regimens. They can also be taken at home without supervision from medical staff. Outside of clinical trials these drugs are also discussed by patients online who anecdotally report improvements with a certain drugs. Doctors may or may not prescribe these drugs to patients, depending on how liability is decided where they are and their willingness to try experimental treatments.
A few of the commonly used drugs are given below with the rationale (Wood, 2015):
Drug | Rationale |
Metformin | A diabetic drug used to reduce blood sugar. The idea is that since cancer cells require large amounts of sugar they will be deprived of this if the levels in the blood are reduced and so grow more slowly. |
Statins | Statins reduce cholesterol. The idea is that since cholesterol is used in the formation of cell walls, by reducing the amount of cholesterol available in the body tumour cells will be less likely to form. |
Mebendazole | A worming tablet. There is evidence that this drug may inhibit cell growth. |
Cimetidine | An antacid that inhibits cell adhesion and reduces tumour angiogenesis (growth of blood vessels to the tumour). |
Itraconazole | An anti-fungal drug that is thought to prevent angiogenesis (blood vessel growth). |
Isotretinoin | An acne drug, it is occasionally used to treat skin and neurological cancers and prevent the resurgence of brain tumours. |
The use of some of these drugs is backed by research. For example, Hirsch, et al. (2009) show that Metformin blocks tumour growth and prolongs remission. Others are used on an anecdotal basis, and a few studies have suggested that some may even be ineffective. Isotretinoin has been shown in some studies to not statistically significantly reduce the rate of second primary tumours (Khuri, et al., 2006).
For this reason, it is important that clinical trials are still carried out on these drugs, despite their “off-label” use. Evidence backed research is what ensures that treatments are effective and safe. It is also important for funding, at the moment “off-label” use of drugs does not automatically get covered by insurance or health care systems in most countries on the basis that it would be wasteful to spend money on treatments that haven’t work. This is however something of a “catch-22” in that there is no real incentive to show that these drugs work as anti-cancer drugs. Since most of them are old, they are no longer covered by patents and so cannot make any money for the pharmaceutical industry even if they spent the money on clinical trials.
Mebendazole (Source: Drugs.com)