As we recently discussed, a number pharmaceutical companies have been fined for promoting off-label uses of their drugs. These practices are difficult to control and the monetary penalties seem to have had little effect on manufacturers, as the number of off-label breaches being reported continues to grow.
In the world of contemporary medicine, off-label prescribing plays a fundamental role in providing the best available standard of care for several health problems. In some areas of practice, including oncology, pediatrics and obstetrics, off-label prescribing provides some of the best known interventions for patients. Yet, off-label prescriptions can also threaten the safety of the patients if they are not supported by legitimate scientific evidence. Hence, promoting such uses of drugs is not encouraged by the regulatory authorities with a view to safeguard the health of patients (a key regulatory role).
It is imperative, when discussing the issue of off-label marketing, that we take into account the regulators’ perspective and consider the measures taken to control the phenomenon of off-label marketing and to work with the industry to expand ‘on-label’ uses for specific drugs.
The Food and Drug Administration (FDA) and other regulatory authorities around the world have laid a framework to govern the promotional activities of the pharmaceutical companies. Recently, new guidelines were finalised for the dissemination of information on unapproved uses of drugs by the FDA in the US. This document, called the ‘Good Reprint Practices’, is designed to provide an outline for drug makers to engage in legitimate off-label marketing. As per the guidelines, journal articles or other reference material drawn on to support the off-label use of a drug must be published by an organisation whose editorial panel consists of independent, unbiased experts. These reference articles are able to be distributed to healthcare professionals, medical or health organisations, drug formulary committees and hospitals. Similar rules apply for companies in the European Union under the Community code Directive 2001/83/EC.
The guidelines have not brought about any significant decline in the number of illegal marketing cases and drug manufacturers continue to go against the law in search of greater financial benefits. The number of off-label prescriptions, especially for pediatric patients, provides some drug manufacturers with an impetus to market unapproved uses of drugs more aggressively. In 2006, Gazarian et al. revealed that 90% of the drugs prescribed to children are off-label, which indicates the commonality and legality of the issue and also raises the question as to why so many drugs are prescribed off-label for children. An article by pediatrician Alexander Cvetkovich-Muntañola, in the February issue of Foresight, suggested that the limited number of drugs tested in children often forces pediatricians to resort to off-label use.
According to a 2009 FDA report, there are a variety of reasons for the limited number of drugs tested in children. The most important being the perception amongst pharmaceutical companies that the pediatrics market will not be able to provide good returns on their investments. It is also much more difficult to conduct clinical studies in children as there are additional factors which need to be taken into consideration which are unnecessary in the study of adult patients (i.e. the need for a child-friendly study environment and administration techniques, age appropriate equipment and the employment of pediatric specialists). Ethical issues and recruitment difficulties compound these problems.
For these reasons, the studies are not only difficult, but also expensive. Large investment risk for potential minimal return is not a sound business strategy in an increasingly competitive pharmaceutical landscape. This lack of commercial incentive is another factor contributing to the small number of drugs approved for children.
In an attempt to combat these issues, regulatory authorities have begun providing incentives to the pharmaceutical industry to encourage pediatric studies and registration. Under the Best Pharmaceuticals for Children Act (BPCA) and the Pediatrics Research Equity Act (PREA), which were issued in 2002 and 2003, respectively, pharmaceutical companies in the US are eligible for an additional six months of market exclusivity for a drug if they conduct studies in children as per FDA guidelines. The corresponding European authority, the EMA (European Medicines Agency), have made similar provisions for pediatric drugs in Europe. To ensure that the studies done on pediatric drugs are legitimate, the EMA has introduced a new development plan, called the Paediatric Investigation Plan (PIP), which verifies the relevance of the data obtained from studies conducted in children before a drug can be authorised for use in this group.
The success of these incentives indicates that the introduction of new, similar programs may encourage more valid research by pharmaceutical companies. This will not only help bring more drugs to market but also increase the on-label uses of existing drugs. If conducted legitimately, off-label marketing is capable of opening up new areas of research to benefit multiple patient groups.
References
Cvetkovich-Muntañola, A 2011, ‘Pediatric Clinical Trials: One Size Doesn’t Fit All’, Foresight, vol. 4, no. 2, retrieved 15 August 2011, <http://www.incresearch.com/Resource/Foresight/Foresight_201102-V4-Issue2.pdf>.
Covington & Burling LLP 2009, Food & Drug E-ALERT: FDA Issues Final Guidance on “Good Reprint Practices”, Covington & Burling LLP, retrieved 20 August 2011, <http://www.cov.com/files/Publication/3d62ff1e-19f0-4636-9363-d3c5b5e7e996/Presentation/PublicationAttachment/5126d07c-225b-46b7-81b7-de3ca1e60924/FDA%20Issues%20Final%20Guidance%20on%20%E2%80%9CGood%20Reprint%20Practices%E2%80%9D.pdf>.
Drakulich, A 2008, ‘FDA to Allow Off-Label Information, Draft Guidance May Be Too Soon, Too Simple’, retrieved 15 August 2011, <http://pharmtech.findpharma.com/pharmtech/article/articleDetail.jsp?id=492953>.
European Medicines Agency n.d., ‘Paediatric investigation plans, waivers and modifications’, European Medicines Agency, retrieved 15 August 2011, <http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000293.jsp&jsenabled=true>.
European Medicines Agency n.d., Directive 2001/83/EC of the European Parliament and of the council of 6 November 2001 on the Community Code relating to medicinal products for human use, European Medicines Agency, retrieved 15 August 2011, <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf>.
Food and Drug Administration 2011, ‘Drug Research and Children’, retrieved 15 August 2011, <http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143565.htm>.
Food and Drug Administration 2009, ‘Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices’, retrieved 15 August 2011, <http://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm>.
Field, RI 2008, ‘The FDA’s New Guidance for Off-Label Promotion Is Only a Start’, Pharmacy and Therapeutics, 33(4):220-249, retrieved 15 August 2011, <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730097/>.
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, 185(10): 544-548, retrieved 15 July 2011, <http://www.mja.com.au/public/issues/185_10_201106/gaz10250_fm.html#0_CHDIHHCF>.
Hathaway, C, Manthei, J & Scherer, C 2009, ‘Exclusivity Strategies in the United States and the European Union’, Update, (3): 34-39,retrieved 16 August 2011, <http://www.lw.com/upload/pubContent/_pdf/pub2655_1.pdf>.
Image reference
‘Law gavel’, uploaded to Wikimedia Commons on 6 June 2011 by Nodar Kherkheulidze <http://commons.wikimedia.org/wiki/File:Law_gavel.jpg>
