Use of drugs in patient populations for purposes which are not approved by the regulatory authorities is termed ‘off-label’ use. As the regulatory authorities do not have specific power over doctors’ prescribing habits (provided that the doctor assumes the medical risk), it is a common practice to prescribe drugs for purposes which have not been authorised by the regulators. While it is legal for doctors to prescribe off-label drugs, it is illegal for companies to market the use of these drugs.
The regulatory authorities (EMA/FDA etc), before allowing the marketing of a drug for its approved uses, review data from pre-clinical and clinical trials for safety and efficacy of the drug. On the other hand, off-label uses of a drug do not undergo tests and review as per the standards required by the regulatory authorities and therefore cannot be guaranteed for safety and efficacy. Therefore, promoting off-label uses of a drug is deemed illegal for pharmaceutical companies as patients are exposed to possible adverse effects and the efficacy of the drug is unproven.
The marketing authorisation process of the regulatory authorities has stringent parameters according to which drugs need to be tested. During this process, the drugs are given a ‘label’, which provides information regarding the use of the drug, i.e. exact diseases and dosage (Kesselheim, Mello, Studdert, 2011). Often, the reasons cited for pharmaceutical companies to engage in off-label marketing practices are to increase the sales revenue of the drug or to minimise competition from generic drugs. In a US study, Kesselheim, Mello and Studdert suggested that there are three goals for the off-label marketing strategies of the companies which are not mutually exclusive. The most common goal was to expand the use of a drug to treat unapproved diseases (85% of the cases). The others were to alter (usually increase) the dosage of a drug or to expand the use of a drug in unapproved patient groups, such as children.
According to Gazarian et al. 2006, approximately 40% of the drugs prescribed to adult patients and 90% of the drugs prescribed to pediatric patients are off-label. A 1998 article published in the British Medical Journal, suggested that doctors in the US and UK have shown quite some interest in using off-label drugs for pediatric patients. Off-label drugs used in these cases are usually established drugs, like morphine and paracetamol. They are often used in violation of the terms of product license, generally giving higher dosages than recommended. A number of cancer patients are also put on off-label medication as many of the cancer drugs have multiple uses. Radley, Finkelstein and Stafford conducted a study in 2001 which took into account 160 commonly prescribed drugs in the US. Their study revealed that, of 150 million off-label prescriptions that were written for the drugs that year, 73% had limited or no scientific support. This increased concerns for the safety of the patients being prescribed these medications.
In recent years, it has come to light that many of the big pharmaceutical companies have been fined for promoting off-label drugs. Bloomberg released an article in 2009 discussing Pfizer’s billion dollar fines for off-label drug promotion. The company had already paid a hefty sum of US $430 million in the form of fines for promoting unapproved uses of an epilepsy drug, Neurotin, in 2004. Again, in 2009, Pfizer was asked to pay a huge amount to settle cases regarding the promotion of off-label uses of Bextra. The Financial Times reported the settlement amount to be US $2.3 billion, which was the largest criminal fine ever paid in US history. Bextra had been approved for pain relief only in cases of menstrual pain and arthritis, but according to Bloomberg, the company executives at Pfizer were pushing salespeople to promote Bextra as a general analgesic. Among other companies, Bristol Myers Squib Co. and Eli Lilly Co. have also paid large amounts in fines for off-label marketing.
Cases involving off-label promotions by drug manufacturers continue to make the news, despite the monetary penalties and the safety concerns about the patients. Although illegal, off-label promotion seems to be a profitable business strategy. The annual sales figures that are achieved by the companies with this strategy seem to dwarf the fines they have to pay for using it. This has become a serious problem for the regulatory authorities and the people who are being treated with these drugs. In future blogs, we will look at the measures that are being taken to address this problem from a regulatory perspective.
Craft, GS, Jr 2008, ‘Promoting Off Label in Pursuit of Profit: An Examination of Fraudulent Business Model’, Houston Journal of Health Law & Policy, vol. 8, pp. 103-131, retrieved on 15th July 2011, http://www.law.uh.edu/hjhlp/Issues/Vol_81/Craft.pdf
Evans, D 2009, ‘Pfizer Broke the Law by Promoting Drugs for Unapproved Uses’, Bloomberg, 9 November, retrieved on 15th July 2011, http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a4yV1nYxCGoA
Fugh-Berman A, Melnick D 2008, ‘Off-Label Promotion, On-Target Sales’, PLoS Medicine, vol 5, no 10, retrieved on 15th July 2011, http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050210
Gazarian, M, Kelly, M, McPhee, JR, Graudins, LV, Ward, RL, Campbell, TJ 2006, ‘Off-label use of medicines: consensus recommendations for evaluating appropriateness’, The Medical Journal of Australia, vol 185, no 10, pp. 544-548, retrieved on 15th July 2011, http://www.mja.com.au/public/issues/185_10_201106/gaz10250_fm.html#0_CHDIHHCF
Horen, B, Montastruc, JL, Lapeyre-mestre, M 2002, ‘Adverse drug reactions and off-label drug use in paediatric outpatients’, Br J Clin Pharmacol, vol 54, no 6, pp. 665-670, retrieved on 15th July 2011, PubMed Central Database.
Jack, A 2009, ‘Pfizer to pay a record fine for off label promotion practice’, Financial Times, 28 January, retrieved on 15th July 2011, http://www.ft.com/intl/cms/s/0/d58caf5e-ecdc-11dd-a534-0000779fd2ac.html#axzz1S2QBn7OM
Kesselheim AS, Mello MM, Studdert DM, 2011, ‘Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints’, PLoS Medicine, vol 8, no. 4, retrieved on 15th July 2011, http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000431
Radley, DC, Finkelstein, SN, Stafford, RS, 2006, ‘Off-label Prescribing Among Office-Based Physicians’, Archives of Internal Medicine, vol 166, no. 9, retrieved on 15th July 2011, http://archinte.ama-assn.org/cgi/content/full/166/9/1021
Turner, S, Longworth A, Nunn, AJ, Choonara, I 1998, ‘Unlicensed and off label drug use in paediatric wards: prospective study’, British Medical Journal, vol 316, pp. 343-435, retrieved on 15th July 2011, http://www.bmj.com/content/316/7128/343.full.pdf
‘Medicine Drugs’ uploaded to Wikimedia Commons on 22 December 2009 by Mizunoryu