What Is an “Off Label” Cancer Drug?
All prescription drugs have been approved for use by a corresponding authority( f.e int the U.S. it is a Food and Drug Administration (FDA)). After a drug is approved, it sometimes is used for different purposes or in different populations. That is “off label” use of a drug.
Even though most of people think that this is illegal, off-label use is generally legal unless it violates ethical guidelines or safety regulations. The ability to prescribe drugs for uses beyond the officially approved indications is commonly used to good effect by healthcare providers.
Two main types of off label use occur:
- a drug is used to treat the approved disease, but used in a manner different than stated in the FDA approval.
For instance, use of the antidepressant Zoloft is off label in children (Zoloft is FDA approved for adults only); taking a drug in a larger dose or on a different schedule than that approved by the FDA is also off label.
- a drug is used to treat a condition or disease different than that for which the drug was originally approved.
Cancer drugs are often used off label to treat metastatic patients who have exhausted traditional treatment options, but only if evidence indicates the drug might be effective against the patient’s particular cancer situation. For example, crizotinib (Xalkori) was approved by the FDA only for non small cell lung cancer (NSCLC) patients whose tumors tested positive for the ALK translocation (a type of mutation in a specific gene called ALK). In addition, the approval stated the patient’s ALK-positive (ALK+) status had to be determined by a specific molecular test. Prescribing Xalkori for patients who test ALK+ using a different type of test (genomic profiling) is an off label use, because the patients weren’t tested with the specific test named in the FDA approval. This is not a big deal, because research indicates both tests identify ALK+ tissue with high accuracy. [1]
Xalkori is also legally prescribed for a different disease: ROS1+ lung cancer in patients. ROS1 is a different tumor mutation than ALK, but has a similar structure–technically, ROS1+ NSCLC is a different disease than ALK+ NSCLC. This is an off-label use, because Xalkori has not been approved for treating ROS1+ lung cancer. Xalkori for ROS1+ lung cancer has been in clinical trials for over two years, with a goal of someday obtaining FDA approval (this is the clinical trial in which I am enrolled). Strong evidence from this clinical trial indicates Xalkori has a high response rate in ROS1+ lung cancer patients, so oncologists are now prescribing Xalkori for this use even though it’s not approved by the FDA for that purpose. [1]
According to statistics, in 2005 the National Comprehensive Cancer Network estimated that 50% to 75% of drug or biologic therapy used to treat cancer in the United States was off label.[6] The reasons are multifactorial. There is a spectrum of cancer types that may have shared biology and sensitivity to therapeutic agents and yet are different diseases in terms of the drug approval mechanism. FDA approval requires a lengthy and expensive process, even for a single-disease indication. Once a drug is off patent, there is little enthusiasm in pharmaceutical circles to invest the resources to expand the labeled indications for an agent. [7], [8]
Even a drug that’s approved to treat a particular cancer can be used to treat that cancer in off-label ways. Examples are when a drug normally approved for first line treatment is used for maintenance, or when the dosing interval differs from the schedule called out in the FDA approval. A boy who has metastatic lung cancer could not tolerate the standard combination chemotherapy for lung cancer because he couldn’t have a platinum drug. He wanted to have Gemzar, a relatively well-tolerated chemo, off label as a single agent (Gemzar’s FDA approval says it must be used with a platinum drug). After consulting several different oncologists, all of whom wanted to put him on hospice, he found an oncologist willing to give him Gemzar off label as a single agent. He was stable on Gemzar for over two years. [1]
Statistics
Data from scientific literature reveal that the prevalence of off-label use in the EU within the pediatric population is generally high, covers a broad range of therapeutic areas and is common practice for many prescribes in both the hospital and the outpatient settings. Thirty-two studies which took place in various pediatric populations within a hospital setting (covering data from 16 EU Member States) showed that a range of 13-69% of the prescriptions investigated was off-label. In forty studies in the outpatient setting (covering data from 12 Member States) there was a range of 2-100%. A similar pattern was observed for the adult population. Twenty three studies in various adult populations in an inpatient setting (covering data from six Member States) showed that a range of 7-95% of the prescriptions investigated being off-label. In 13 studies in the outpatient setting (covering data from six Member States) a range of 6-72% was found. Variation in off-label prevalence is not only observed between but also within countries, depending for example on the methodology used and the population studied. A comparison of prevalence figures between the various EU Member States is therefore not possible, but it is apparent that the majority of, if not all, EU Member States are faced with off-label use of medicinal products to some extent. [9]
Health Insurance Coverage of Off-Label Drugs in Cancer Treatment
Medicare and many insurance companies pay for off-label drugs for cancer treatment, as long as the off-label uses are listed in an approved compendium. A compendium is a collection of drug summaries put together by experts who have reviewed data about the drug’s use in patients. Reimbursement is one of the biggest drawbacks when it comes to off-label drugs. Most of insurance companies do NOT cover off-label drugs with the reason of "experimental" use. The law in US changed in 2008, so health insurance would cover most of off-label drugs especially the cancer ones but still the law is complex.
Health Insurance Coverage of Off-Label Drugs(Germany)
In the context of the German public health care insurance:
- There has to be serious disease, which is life-threatening or strongly affects the patient’s health-related quality of life.
- There exists no other possible therapy, and there must be a “reasonable expectation”, based on the available data, that the product in question is the key to successful treatment.
- This “reasonable expectation” is only given when either the extension of the authorization has already been applied for and the results of a controlled Phase III clinical trial demonstrate clinically relevant efficacy, or if there are findings which were recovered and published out of the authorization process, leading to a professional consensus on the likelihood of benefit with acceptable risks.
Children and Off -label drugs
Did you know that the licensing process itself was introduced to US and Europian countries as a response to drug-related fatal tragedies that occurrred in newborn babies, infants and children?
The drugs given to all of those infants at that time were:
- chloramphenicol-induced gray baby syndrome
- thalidomide- induced phocomelia and deaths
- diethylene glycol poisoning
Much of pediatric practice, particularly in hospitals and by specialists, has involved the off-label use of medications and educated guesses about doses, safety, and effectiveness.[3] Pediatric treatments often rely completely on off label use as clinical studies cost $30,000 per child and pose special informed consent obstacles. Federal regulations require institutional review boards to hold pediatric studies to a higher standard; as a result, they reject some studies that might have been approved in adults.This leads to the current situation, where although no drug can be approved without first undergoing extensive tests in adults, drugs taken by children are approved frequently without any pediatric testing.[4] Over 80% of all drugs prescribed for children carry orphaning clauses (disclaimers with respect to pediatric use that FDA requires because of the paucity of clinical studies involving children) in their package labels. [5], [2]
Pros & Cons
Pros and cons of using off-label drugs for a cancer treatment
"+"
- Enhance medical understanding of which treatments work against various forms of cancer.
- agency has been too slow to recognize promising new off-label treatments → no need to wait
- Many cancer drugs are effective against more than one type of cancer.
- Allows for clinical innovation, especially for patients who do not respond to standard treatments
- Off label use of drugs gives evidence for their effect (physicians can know if they need to use a specific drug again or no)
- Increases return on investment for pharmaceutical firms.
"-"
- It has not been shown to be effective against a certain cancer. → May be just a waste of money and needlessly expose patients to the side effects of drugs that may not help them.
- The possible risks of giving the drug outweigh the possible benefits.
- Raise the possibility of conflicts of interest, because the rules rely on reference guides that in some cases are linked to drug makers
- Not all off label drugs are covered by insurance companies which is a big problem since all these drugs especially cancer cost a lot.
- Approving an off-label drug it takes a lot of time and huge costs so most of them take years to approve.
Is it ethical to use it?
Coverage of drugs for cancer treatments not approved by the Food and Drug Administration. → overly expansive coverage may encourages doctors to use patients as guinea pigs for unproved therapies.
Due to their astronomical pricing, covering recent anticancer agents in their labeled indication is a major concern in most health systems. So, off-label prescribing adds reimbursement difficulties. Covering of off-label use depends on the country, the level of clinical evidence. [10]
Is it ethical to promote it?
Promotional materials should be limited to the indications for use for which the device has been approved by the FDA. It is generally not acceptable to discuss or describe any off-label uses of the device in documents or advertising and promotional materials distributed by company ( e.g., press releases, videos, descriptions or pictures of procedures developed by the company).
The following are settlements reached against pharmaceutical companies to resolve allegations of off-label promotion of drugs. Under the Federal Food, Drug, and Cosmetic Act, it is illegal for pharmaceutical companies to promote their products for uses not approved by the Food and Drug Administration (FDA), and corporations that market drugs for off-label indications may be subject to civil liability under the False Claims Act as well as criminal penalties.
Unfortunately we could not find a good statistic information for that usage.
Real life examples
We wanted to have some real life examples from people who had experience with use of off- label drug so we decided to post a question on an question-and-answer site (Quora) regarding this topic and we got some pretty interesting answers. We are putting the answers down below, unedited and uncut. Although the examples are not related to cancer problems, the answers are still very relevant. Basically, the people who responded, explain about their disease and the medication (which were off-label) their doctors gave them. We won't show their names for privacy reasons.
Answer no.1:
Clarification: Ssri, snri, maoi and tricyclic are all antidepressants or also called depression drugs. Ssri is a newer type of antidepressant and its full name is selective serotonin reuptake inhibitors (SSRIs). The SSRIs include drugs such as Prozac, Zoloft, and Paxil. This medication act on a chemical in the brain called serotonin. Serotonin helps regulate mood, but it also plays a role in digestion, pain, sleep, mental clarity, and other bodily functions. Obviously it has also a lot of side effects. The other ones, Maoi (monoamine oxidase inhibitors) and tricyclic are older classes of antidepressants. Their side effects are more severe than those of the newer antidepressants, so they are only prescribed as a last resort after other treatments and medications have failed. [13]
PTSD (posttraumatic stress disorder) is a mental health problem that some people develop after experiencing or witnessing a life-threatening event, like combat, a natural disaster, a car accident, or sexual assault. [14]
Answer no.2:
Ps: This time the answer is pretty long but it is very interesting. The person who replied did not wrote only its experience but also its opinion about this kind of drugs.
"I have been on countless medications over the years and most of them have been for “off label” use. As someone with fibromyalgia, I can tell you that there are only 3 or 4 medications that are FDA approved to treat fibromyalgia and they weren't even approved for that until a few years ago. Before that, a couple of them were intended to treat other medical conditions and later started being prescribed for fibromyalgia as an “off label” use. These medications can be quite expensive and don't work for everyone(myself included), so doctors still use other medications that aren't labeled FDA approved for fibromyalgia to treat it. I have found Neurontin (generic name, gabapentin) to be 100% vital to keeping me as functional as possible… it doesn't take all the pain away, but without it, I'd be in a wheelchair all the time(with it, I can walk with a cane and only need the wheelchair on extreme pain days). Neurontin is an anti-seizure medication. Also, I have suffered from atypical migraines for about 22 years. I have taken numerous medications to try to treat it over the years. I tried the medications FDA approved to treat them and quickly learned that they not only don't work for me, but many of them make me sicker. Because of this, my neurologists tried many other medications and most of them were labeled to treat other conditions(most were anti-seizure medications). I have noticed over the years, that many drugs prescribed for depression and other psychological conditions were designed to be anti-seizure medications that can work quite effectively for psych symptoms. So many of the medications you will see out there were once designed for a different purpose than what they are used for now. For example, Viagra was designed to be a heart medication initially, Vistaril is an antihistamine that is also used to treat anxiety(quite effectively for some people), Benedryl is an antihistamine that is the active ingredient in most of the over-the-counter sleep aids to induce drowsiness, there is a blood pressure medicine I'm currently taking that the doctor said could prevent further kidney damage and possibly reverse the damage. I do have as a result ofy Diabetes, the list could go on and on. A lot of people don't realize that the medications they are taking were initially designed for a different purpose and then later discovered the variety of conditions they could treat. Health insurance companies discourage the use of medications for “off label” use and sometimes won't cover their cost if prescribed to a patient. Infortunately for the patients of these insurance companies, the simple truth is that sometimes drugs used for “off label” purposes just work better for some conditions in some patients. You shouldn't be afraid to try something that could potentially help you just because it wasn't created for that condition initially. Remember medicine is a science that is always learning new things. If we kept the mindset that we had no need to find new ways to treat medical conditions or new ways to fully realize the potential of current treatments, things like Lobotomies(yes, I'm aware this still happens sometimes but not nearly as often as it used to), heroin, mercury, and doctors treating women's “hysteria” by manually stimulating them to orgasm would still be common practices. Accepting new ways to treat medical conditions is vital to improve people's health and well-being."
Clarification: Fibromyalgia, also called fibromyalgia syndrome (FMS), is a long-term condition that causes pain all over the body. As well as widespread pain, people with fibromyalgia may also have increased sensitivity to pain, fatigue (extreme tiredness), muscle stiffness, difficulty sleeping, problems with mental processes (known as "fibro-fog") – such as problems with memory and concentration, headaches, irritable bowel syndrome (IBS)– a digestive condition that causes stomach pain and bloating [15]
References:
[1] https://grayconnections.net/2014/02/20/what-is-an-off-label-cancer-drug/
[2] Off-Label Use of Prescription Drugs should be Regulated by the FDA (2003 Third Year Paper) http://nrs.harvard.edu/urn-3:HUL.InstRepos:8852151
[3] Robert Steinbrook, Testing Medications in Children, 347 N. Eng. J. Med. 1462 (2002).
[4] Althea Gregory, Denying Protection to Those Most in Need: FDA’s Unconstitutional Treatment of Children, 8 Alb. L.J. Sci. & Tech. 122 (1997).
[5] Robert Levine, Ethics And Regulation Of Clinical Research 241 (2d ed. 1986).
[6] Soares M: “Off-label” indications for oncology drug use and drug compendia: History and current status. J Oncol Pract 1:102-105, 2005
[7] Casali PG, Executive Committee of ESMO: The off-label use of drugs in oncology: A position paper by the European Society of Medical Oncology (ESMO). Ann Oncol 18:1923-1925, 2007
[8] David G. Pfister, Off-Label Use of Oncology Drugs: The Need for More Data and Then Some, Journal of Clinical Oncology, New York, NY, 2012
[9] Marjolein Weda, Joëlle Hoebert et al. Study on off-label use of medicinal products in the European Union, European Union, 2017
[10] Levêque D. Off-label use of targeted therapies in oncology. World Journal of Clinical Oncology. 2016;7(2):253-257. doi:10.5306/wjco.v7.i2.253.
[11] https://en.wikipedia.org/wiki/List_of_off-label_promotion_pharmaceutical_settlements
http://www.webmd.com/a-to-z-guides/features/off-label-drug-use-what-you-need-to-know#4
13 https://www.helpguide.org/articles/depression/antidepressant-medication.htm
14 https://www.ptsd.va.gov/public/PTSD-overview/basics/what-is-ptsd.asp
15 http://www.nhs.uk/Conditions/Fibromyalgia/Pages/Introduction.aspx
16 https://www.managedcaremag.com/archives/2009/5/when-should-insurers-cover-label-drug-usage