Effective enforcement of regulations requires more resources and determination to impose robust sanctions
Nearly 30 years ago, Braithwaite’s Corporate Crime in the Pharmaceutical Industry showed that unethical and corrupt behaviour was endemic in the sector. Sadly, there is growing evidence that little has changed. Recent research suggests that violation of the law continues to be widespread. Most new medicines offer little or no therapeutic advantage over existing products, so promotion plays a huge role in achieving market share. In a crowded and competitive marketplace the temptation for companies to resort to misleading claims is great. According to Gøtzsche (doi:10.1136/bmj.e8462),1 as of July 2012, nine of the 10 largest drug companies were bound by corporate integrity agreements under civil and criminal settlements or judgments in the United States. The corporate activity that has led to recent government investigations has involved unethical and unlawful practices that are well beyond mere administrative offences.
Whistleblowers’ and other “insider” accounts in the US typically include allegations that companies systematically planned complex marketing campaigns to increase drug sales, which involved illegal and fraudulent activities. These included active promotion of off label, or otherwise inappropriate, use of drugs, despite company knowledge that such use could seriously harm patients.2 3
How successful, then, have governments responsible for protecting citizens been in curbing illegal activity by the transnational research based drug industry? The recent introduction of Regulation 658/2007 in the European Union empowers the EU Commission to impose financial penalties for corporate violation of EU legislation on medicines. However, this may be too little, too late. Multi-million dollar fines imposed under US settlements seem to have failed to deter companies from violating regulations, given that several companies are repeat offenders. This has led to calls for sanctions to be strengthened. Imposing bigger fines is one option, but courts might be reluctant to impose penalties that would threaten the financial survival of companies. Other sanctions being debated include removing companies’ patent rights and holding senior managers criminally liable.4 Corporate integrity agreements could also serve as more effective vehicles for corporate probation by imposing escalating restrictions on company freedom appropriate to the offences committed. For instance, if companies hide clinical trial data, regulators could take over control of future clinical trials and charge offending companies for the cost of doing so.
Although stronger sanctions are needed to deter drug companies from wrongdoing, this may be insufficient to protect the public because legal resolution of complex criminal and civil investigations takes years, during which time unethical and illegal behaviour may continue unabated. For example, during all phases of the US Justice Department’s seven year investigation of Warner-Lambert’s promotion of the drug’s unapproved use, off label prescriptions for gabapentin (Neurontin) increased dramatically, which has raised suspicions that the firm’s off label promotion persisted throughout.5 Warner-Lambert, of which Pfizer is a parent company, pleaded guilty to charges of promoting gabapentin for the non-approved use. It was subsequently established that gabapentin was not efficacious for the non-approved indication, meaning that patients were exposed to the potentially harmful side effects of a drug when there was no scientific evidence to support a therapeutic effect in the condition for which it was prescribed.
In such cases, prompt action by regulatory agencies to prohibit further violation of the law is also needed to protect public health. However, it is striking that the Food and Drug Administration has played a marginal role in detecting cases of fraud or enforcing compliance with the law. Of the 11 civil or criminal cases involving off label promotion by major drug companies settled by the US Justice Department between 2003 and 2007, none was referred by the FDA.6 In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) initiated 101 prosecutions for breaches of medicines legislation between 2005 and 2012, but none involved a large research based drug company. In addition, there was only one (unsuccessful) referral for potential prosecution of such a company—GlaxoSmithKline regarding paroxetine (Seroxat).7
Why have drug regulatory agencies played such a small role in prosecuting large companies given the evidence of extensive illegal activity uncovered in recent cases in the US that were brought by other prosecuting or investigating bodies? The reality is that, with current resources, medicines regulators can police only a fraction of the industry’s ever expanding promotional activities. The MHRA currently vets print advertisements for around 50 medicinal products each year.8 Because of the complex and varied ways in which companies promote their drugs,2 gathering evidence of systematic illegal marketing requires far greater commitment in terms of time, money, and human capital.
Increased resources and expanded legal authority may need to be backed up by a more probing regulatory culture. Both the MHRA and the FDA claim that they can generally achieve compliance through informal communication and negotiation with large firms, but regulators seem to treat evidence of non-compliance as isolated incidents rather than signals that firms may be engaged in extensive offending. Indeed, US government investigations indicate that even when faced with evidence of serious wrongdoing or persistent violation the FDA may be reluctant to initiate formal investigations or escalate its response against individual companies.6 9 Such timid regulatory behaviour may be symptomatic of the extent to which regulators have been encouraged by governments to be responsive to the commercial interests of industry and to view large drug firms as clients whose fees increasingly fund these agencies.10
There are some signs that change is afoot in the US, with additional funding granted for FDA fraud detection and prosecution alongside other signals from Congress that the agency should increase its enforcement activity.11 A similar shift in the UK is less likely given successive governments’ determination to “reduce burdens on business.” Whether government authorities in the EU are willing to take enforcement action against large drug companies will become clearer on resolution of the European Medicines Agency’s investigation of Roche for safety reporting violations12 and a French manslaughter investigation of Servier Laboratories’ former president in relation to the antidiabetes drug, benfluorex (Mediator).13
Individual instances of corporate malfeasance are indicative of wider systemic problems. Whether companies continue to “get away with it” depends, in part, on whether regulators can develop credible systems of detection, enforcement, and punishment.
Courtney Davis, senior lecturer in sociology, John Abraham, professor of sociology
Cite this as: BMJ 2013;346:f755
Personal view, doi:10.1136/bmj.e8462
Competing interests: Both authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.
↵Gøtzsche PC. Big pharma often commits corporate crime, and this must be stopped. BMJ2012;345:e8462.FREE Full Text
↵Kesselheim AS, Mello MM, Studdert DM. Strategies and practices in off-label marketing of pharmaceuticals: a retrospective analysis of whistleblower complaints. PLoS Med2011;8:1-9.
↵US Department of Justice. GlaxoSmithKline to plead guilty and pay $3 billion to resolve fraud allegations and failure to report safety data. 2012. Press release. www.justice.gov/opa/pr/2012/July/12-civ-842.html.
↵Kennedy K. Experts seek alternatives to excluding drug companies. USA Today2012 March 5. http://usatoday30.usatoday.com/news/washington/story/2012-03-05/penalties-drug-companies/53372918/1.
↵Kesselheim AS, Darby D, Studdert DM, Glynn R, Levin R, Avorn J. False Claims Act prosecution did not deter off-label drug use in the case of Neurontin. Health Affairs 2011;30:2318-27.FREE Full Text
↵US Government Accountability Office. FDA’s oversight of the promotion of drugs for off-label uses. 2008, GAO-08-835. www.gao.gov/products/GAO-08-835.
↵Medicines and Healthcare Products Regulatory Agency. MHRA investigation into Glaxosmithkline/Seroxat. 2008. www.mhra.gov.uk/home/groups/es-policy/documents/websiteresources/con014155.pdf.
↵Medicines and Healthcare Products Regulatory Agency. Delivering high standards in medicines advertising regulation. Sixth annual report January-December 2011. www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con143738.pdf.
↵US Committee on Energy and Commerce, House of Representatives. Ketek clinical study fraud: what did Aventis know?’ 2008. www.gpo.gov/fdsys/pkg/CHRG-110hhrg48587/pdf/CHRG-110hhrg48587.pdf.
↵Abraham J, Davis C. Interpellative sociology of pharmaceuticals: problems and challenges for innovation and regulation in the 21st century. Technol Anal Strategic Manage2007;19:387-402.CrossRef
↵Skadden. FDA Revamps Criminal Prosecution Guidelines and Expands Health Care Fraud-Related Investigations. 2011. https://www.skadden.com/sites/default/files/publications/FDA_Revamps_Criminal_Prosecution_Guidelines_0.pdf.
↵European Medicines Agency. European Medicines Agency acts on deficiencies in Roche medicines-safety reporting. EMA/405725/2012. 2012. www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/06/WC500129047.pdf.