Off-label drug use is the practice of prescribing pharmaceuticals for use other than what the regulatory agency has approved the drugs for.  Sometimes the “standard of care” involves off-label drug use.

Every prescription drug approved by the FDA has a “label” – the name goes back to the  days when physical labels were applied to medicine bottles. Modern labels are too long to fit on a small bottle, and many cancer drugs don’t even come in conventional containers.  But the label is a statement from the manufacturer – you can think of it as the documentation you get in the box when you buy an electronic device. The label says the intended dosage, type of administration, and the conditions the medicine is intended to treat.

Before a drug can be brought to market in the United States, it must undergo three phases of clinical trials designed to test the drug’s efficacy and safety when used as directed. Once the drug has been tested and approved by the Food and Drug Administration (FDA), the drug is given a label – a report which describes the drug’s intended use and dosage.

If a drug is used in a different way from the FDA-approved label, its use is said to be off label. The drug may be used for a different medical condition, administered by a different route or prescribed in a different dose. This practice is also called ‘non-approved’ or ‘unapproved’ use of the drug. Such off-label use is allowed on the assumption that physicians can be relied upon to use their own judgment in such matters. Exceptions to this rule are certain opioids like morphine and fentanyl, which are considered to be controlled substances and cannot be prescribed off label. (1, 2) It is perfectly legal in the United States (and in many other countries) for a physician to prescribe a drug off-label, and the practice is more common than the general public knows. Up to 20% of drugs prescribed are off-label, and in psychiatric drugs this level is estimated to reach 31%. As new drugs are often not tested for safety and efficacy in children, this figure could reach as high as 55-75% in pediatrics. Annual expenditure on off-label drugs is estimated at around $44 billion. Off-label drug use is most common in oncology, pediatrics and HIV/AIDS care. (2, 3, 4)

The pharmaceutical companies are not allowed to advertise medicines for off-label use.  However, they can distribute literature written by others about off-label use.  And pharmaceutical companies often count on off-label use; it is built into their strategy for making drugs successful in the marketplace.

Off-label prescription possibly leaves physicians open to legal actions should the patient experience an adverse reaction to the medicine.  Without FDA backing the doctor may have a harder time in court proving his or her action met the “standard of care” requirement.

But if the disease is not included on the label, does that mean the FDA is saying the drug should not be used for that disease?  No. The working system is that the FDA explicitly approves drugs for one or a few indications, but the off-label use, as common as it is, is unofficially influenced by the medical community.  Rebecca Dresser, a professor at Washington University law school, and Joel Frader, of Northwestern University, wrote in the Journal of Law Medicine and Ethics that “policy efforts are also needed to improve the quality of off-label prescribing. Federal authorities should systematically monitor patient responses to off-label uses, regularly collect and publicize information about off-label uses, and consider proposals to regulate certain off-label uses.” 

The Omnibus Reconciliation Act of 1993 directed that Medicare cover off-label use of cancer drugs that are listed in the medical industry’s drug compendia.  If peer-reviewed articles in certain academic journals support use of a medicine, Medicare pays for them, too.

Who puts new drugs in the compendia?  The drug companies are involved in that, too, so you might think the compendia are a back-door way to getting non-approved drugs approved.  But the compendia require independent review, too.  It is not just a system where drug sponsors pay for inclusion.  The major compendia used in the US are:

Compendia: American Hospital Formulary Service Drug Information (AHFS DI), United States Pharmacopoeia Drug Information (USP DI) .  (A now-defunct compendium was American Medical Association Drug Evaluations)  

Both the American Medical Association and  the American Academy of Pediatrics (AAP) Committee on Drugs endorse off-label prescribing where it is supported by science and considered judgment.  However, doctors know prescribing medicine off-label can open them up to malpractice liability if the prescription does not meet the accepted standard of care.

Off-label drugs and cancer

Off label drug use is particularly common in cancer treatment, where this practice could reach 50% of all patients who receive chemotherapy. (5) This is due to the fact that cancer drugs are not generally approved for use in all types of cancers, but tend to be tested in patients for use against a certain stage of a specific cancer. (6)

Reasons for off-label drug use in cancer patients include:

• the fact that some cancer drugs can be effective against many different types of tumors;
• there are few approved chemotherapy drugs
• chemotherapy treatments often consist of combinations of drugs, some of which may not be approved for that particular type of cancer. (1)

Sometimes the “standard of care” involves off-label drug use.  Besides oncology, where between 50 and 75% of drug use is off-label, pediatrics and geriatrics rely heavily on off-label use.  Your cancer doctor has almost certainly prescribed chemotherapy off-label before.

Off-label prescribing opens the doctor up to malpractice liability to some extent (they don’t have the FDA backing them up) but it is also true that in oncology off-label used is part of “accepted standards of care.”  The American Medical Association has stated off-label use is a good idea when it is “based on sound scientific evidence.”

A 1997 study involving 200 oncologists reported that 3 out of 5 of them had prescribed a chemotherapy drug off label. (6) An investigation of the prescribing practices of the monoclonal antibody rituximab revealed that 75% of the prescriptions were off label. (1)

The Journal of Clinical Oncology cited a study carried out in a military treatment facility designed to quantify the off-label use of chemotherapeutic drugs. The study revealed that almost half the doses of chemotherapeutic drugs were prescribed off label. (7)

Using the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, a study was carried out of 2,082 women over 65 with breast cancer. It was found that, of the 36 chemotherapeutic agents used to treat these patients, only 22% were FDA-approved for use in breast cancer. (8)

A potential problem with this practice is that prescribing a drug off label may cause the patient’s medical insurer to deny coverage on the grounds that the drug is “experimental” or “investigational”. In 1993, however, federal legislation was passed that required insurance companies to cover therapeutic drugs that were appropriate for cancer. The law includes coverage of off-label uses of drugs if these uses have been the subject of articles in drug reference books or medical journals, or if they have been subjected to medical research studies. If the medical insurer tries to refuse coverage, copies of peer-reviewed journal articles can be forwarded to back up the patient’s claim. (2)

Concerns about Off-Label Use

For a drug to be on-label, someone (usually the patent owner) has paid for expensive research to prove the drug is safe and effective for a specific disease and type of patient.  When the drugs are used for other diseases and types of patients, the risk-benefit ratio could be different. The medical establishment judges off-label use acceptable, however, if the patient’s doctor thinks it advisable and insurance companies will pay for these uses if there is some evidence to support this use.

The government even allows pharmaceutical companies to indirectly promote off-label use.  While the companies can’t strictly advertise that the medicines can be used for indications off-label, they are permitted to distribute articles from peer-reviewed journals and reference books that discuss off-label uses.

Further, government programs Medicare and Medicaid as well as private insurers cover the cost of many off-label cancer treatments, especially if there is evidence and support listed in industry compendia.

More on this.

References

(1) Gillick, M. Controlling Off-Label Medication Use. Annals of Internal Medicine. March 3, 2009 vol. 150 no. 5 344-347. Retrieved September 21, 2010. http://www.annals.org/content/150/5/344.full

(2) American Cancer Society. What is off label drug use? Retrieved September 21, 2010.
http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Chemotherapy/off-label-drug-use

(3) Wikipedia. Off-label use. Retrieved September 21, 2010. http://en.wikipedia.org/wiki/Off-label_use

(4) Sanghavi D. Cooking the Books – The statistical games behind “off-label” prescription drug use. Retrieved September 21, 2010. http://www.slate.com/id/2239360/

(5) Casali P G. The off-label use of drugs in oncology: a position paper by the European Society for Medical Oncology (ESMO). Annals of Oncology Volume 18, Issue 12 Pp. 1923-1925. Retrieved September 21, 2010.
http://annonc.oxfordjournals.org/content/18/12/1923.full

(6) National Cancer Institute. Q&A: Off-label Drugs. Retrieved September 21, 2010.
http://www.cancer.gov/clinicaltrials/education/approval-process-for-cancer-drugs/page5

(7) Powers J F et al. Off-label chemotherapy use in a military treatment facility. J Clin Oncol 27:15s, 2009 (suppl; abstr 6631) Retrieved September 22, 2010
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=32176

(8) How Common Is Use of Off-Label Drugs in Breast Cancer? M D Anderson Cancer Center. July 2009. Retrieved September 22, 2010. http://www.mdanderson.org/newsroom/cancer-newsline/past-episodes/how-common-is-use-of-off-label-drugs-in-breast-cancer-.html