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“All human beings are born free and equal in dignity and rights. They are endowed with reason and conscience and should act towards one another in a spirit of brotherhood.”

 Universal Declaration of Human Rights

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Off Label Promotion

The FDA has pursued criminal prosecutions of corporations that do off-label promotion of prescription drugs.  In 2009, Eli Lilly agreed to pay $1.4 Billion in criminal and civil penalties for such off-label promotion of Zyprexa.  Pfizer agreed to pay $2.3 Billion for the illegal off-label promotion of Geodon and other drugs.  In 2010, Astra-Zeneca agreed to pay $520 million for the illegal off-label promotion of Seroquel for use in children, and Forest Laboratories agreed to pay $309 million for the illegal off-label promotion of the use of Lexapro and Celexa in children.  However, despite these large penalties by the drug companies, the practice of off-label has not stopped.

Although Pfizer paid $2.3 billion to settle claims associated with the off-label promotion of Bextra and three other drugs, the $16.8 billion in revenues that it earned from those drugs demonstrates how profitable  off-label marketing really is and how the risk is transferred to patients and the  healthcare system.   The profits are so high that the company knows that the proportion that they pay in fines and judgements is worth the risk.

 Neurontin®  was  FDA-approved for treating epilepsy were projected at approximately $500 million. With off-label marketing  sales went from $97.5 million to $2.7 billion by 2003, with nearly 90% of Neurontin prescriptions written for off-label uses. Neurontin’s manufacturer ultimately paid $430 million to settle civil and criminal charges associated with off-label promotion—a fraction of its increased profits from the drug’s off-label sales.

 Most off-Label marketed drugs lack clinical efficacy and less than one third of them were backed by scientific evidence.  This means that patients were subjected to unsafe drugs which were ineffective.

  • Gardiner Harris, Pfizer Pays $2.3 Billion to Settle Marketing Case, N.Y. Times (Sept. 3, 2009), http://www. nytimes.com/2009/09/03/business/03health.html.
  • Press Release, Dep’t of Justice, Warner-Lambert to Pay $430 Million to Resolve Criminal & Civil Health Care Liability Relating to Off-Label Promotion (May 13, 2004), available at http://www.justice.gov/opa/pr/2004/May/04_civ_322.htm.
  •  David C. Radley et al., Off-label Prescribing Among Office-Based Physicians, 166 Archives Internal Med. 1021, 1023 (2006), underscores this problem.

European Union law prohibits off-label marketing of drugs

European Union law prohibits companies from marketing drugs off-label. In the United Kingdomas in some other European countries, but unlike the United Statesindustry self-regulatory bodies are tasked with supervising compliance with marketing rules.  The UK self-regulatory system for exposing marketing violations relies largely on complaints from company outsiders, which may explain why most off-label promotion rulings relate to plainly visible promotional activities such as advertising. This contrasts with the US, where Department of Justice investigations and whistleblower testimony have alleged complex off-label marketing campaigns that remain concealed to company outsiders. UK authorities should consider introducing increased incentives and protections for whistleblowers combined with US-style governmental investigations and meaningful sanctions. UK prescribers should be attentive to, and increasingly report, off-label promotion.

 

Before a pharmaceutical company can market a new prescription drug, the drug has to go through a long approval process. After extensive studies in the laboratory and in animals, the company must test the drug’s safety and efficacy in series of clinical trials in which patients with specific diseases receive the drug under carefully controlled conditions. Regulatory bodies such as the US FDA, the UK MHRA and the European Medicines Agency (EMA) then review the results of these trials and, when they are satisfied that the drug is safe and effective for the conditions in which it was tested, give the pharmaceutical company approval to market the drug in the relevant country. An important part of the approval process is the creation of the “drug label,” a detailed report that specifies the exact diseases and patient groups in which the drug can be used and the drug’s approved doses.

 

Physicians can use approved drugs “off-label.” That is, they can prescribe drugs for a different disease, in a different group of patients, or at a different dose to that specified in the label. However, in the UK, the US, and other countries, national law prohibits the promotion of off-label uses of prescription drugs by pharmaceutical companies, which stand to benefit financially from off-label use through increased drugs sales. The primary rationale for banning off-label promotion is that it might encourage the widespread use of drugs in settings where they have not been rigorously tested, thereby exposing patients to uncertain benefits and possible adverse effects. In the US, the FDA regulates and prosecutes off-label promotion, but enforcement actions against companies can also be brought by federal and state prosecutors and private citizens. In the UK, the MHRA has delegated an important part of its responsibility for supervising off-label marketing to a self-regulatory body set up by the pharmaceutical industry—the PMCPA.

 

The most commonly cited off-label promotional tactic in the UK, was attempts to influence prescribers using advertisements and other print material; competing companies lodged 57% of complaints whereas prescribers (the prime target of off-label promotion) lodged only 22% of the complaints. Unlike US whistleblower complaints, which often alleged promotional tactics targeting consumers, payers and company staff, few UK rulings described practices targeting these classes of individuals. Finally, although several US whistleblower-initiated cases alleged multifaceted and covert marketing activities, the UK cases typically related to one or a few claims made in printed material.

 

Off Label Promotional activity uncovered by US DOJ investigations typically involved a range of diverse, yet carefully coordinated, corporate practices aimed at expanding sales through off-label use of drugs, including attempts to promote more than one off-label use. UK allegations, in contrast, described a much more restricted range of promotional activities and typically referred to a single advertisement, or other printed material, focused on a single off-label use. This finding held true even in cases in which the same transnational companies were discovered promoting the same drug product for the same off-label use in the UK and the US.

 

The differences in which the UK versus the USA detects violations lies in differences in the types of complainant and in the nature and extent of investigations pursued. Crucially, US complainants are whistleblowers that offer first-hand testimonies and documentation of company practices. Complainants’ allegations are in turn subject to wide-ranging and prolonged investigations by the DOJ that will involve, for example, in-depth interrogation of complainants, subpoenas for documents or electronic records, witness interviews, consultations with experts, and sometimes search warrants to obtain further evidence. In the UK, the majority of complaints are lodged by individuals or organizations from outside the violating company, which means that evidence of internal practices and pressures on company staff will be rare. Indeed, the majority of allegations considered by the PMCPA involve promotional material with high-to-medium visibility and the greatest risk of detection.

 

See the research findings Andreas Vilhelmsson,Courtney Davis,Shai Mulinari, "Pharmaceutical Industry Off-label Promotion and Self-regulation: A Document Analysis of Off-label Promotion Rulings by the United Kingdom Prescription Medicines Code of Practice Authority 2003–2012", Published: January 26, 2016 https://doi.org/10.1371/journal.pmed.1001945

 

 

  1. Mello MM, Studdert DM, Brennan TA. Shifting Terrain in the Regulation of Off-Label Promotion of Pharmaceuticals. New Engl J Med. 2009;360(15):1557–66. pmid:19357413

  2. Kesselheim AS, Mello MM, Studdert DM. Strategies and practices in off-label marketing of pharmaceuticals: a retrospective analysis of whistleblower complaints. PLOS Med. 2011;8(4):e1000431. pmid:21483716

  3. United States Government Accountability Office (GAO). FDA’s oversight of the promotion of drugs for off-label uses. 2008. http://www.gao.gov/assets/280/278832.pdf. Accessed 27 July 2015.

  4. Lindefeld CS, Steinman MA. The neurontin legacy—marketing through misinformation and manipulation. New Engl J Med. 2009;360(2):103–6. pmid:19129523

  5. Kesselheim AS, Studdert DM, Mello MM. Whistle-blowers’ experiences in fraud litigation against pharmaceutical companies. New Engl J Med. 2010;362(19):1832–9. pmid:20463344

  6. Almashat S, Wolfe S. Public Citizen Report: Pharmaceutical Industry Criminal and Civil Penalties: An Update. 2012. http://www.citizen.org/hrg2073 Accessed 27 July 2015

  7. Steinman MA, Bero LA, Chren MM, Landefeld CS. Narrative review: the promotion of Gabapentin: an analysis of internal industry documents. Ann Intern Med. 2006;145(4):284–93. pmid:16908919

  8. Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: A case study of industry documents from rofecoxib litigation. JAMA. 2008;299(15):1800–12. pmid:18413874

Zyprexa Drug Rep

Why is Off-Label Promotion Dangerous to Patients

It is wise to consider why the regulation of pharmaceutical products and their marketing is so crucial to the Right to Health. A terrible international human rights tragedy was caused by the promotion and sale of the drug, Thalidomide. It was marketed worldwide with little regard to the research findings that the drug could cause severe birth defects in children born to women taking the drug. Thalidomide was synthesized in West Germany in 1954 by the pharmaceutical company Chemie Grünenthal. It was marketed (available to patients) from October 1, 1957 (West Germany) into the early 1960's. Thalidomide was present in at least 46 countries under many different brand names.  Thalidomide was a morning sickness drug taken by pregnant women. It continued to be sold and assertively marketed to pregnant women, even after it was known by both research findings and clinical experience, that it caused congenital defects. Thalidomide, was promoted and marketed by the pharmaceutical company as a "wonder drug" that provided a "safe, sound sleep". Thalidomide was a sedative that was found to be effective when given to pregnant women to combat many of the symptoms associated with morning sickness.

 

Thalidomide was a catastrophic drug with tragic side effects. Initially, it was not realized that thalidomide molecules could cross the placental wall affecting the fetus.  But when the first reports of birth defects became known to the pharmaceutical company, the evidence was suppressed and the company continued to market the drug because it was extremely profitable.  A percentage of the affected patients experience the effects of peripheral neuritis, a devastating and sometimes irreversible side effect.  But thalidomide became notorious as the killer and disabler of thousands of babies. When thalidomide was taken during pregnancy (particularly during a specific window of time in the first trimester), it caused startling birth malformations, and death to babies. Any part of the fetus that was in development at the time of ingestion could be affected.  For those babies who survived, birth defects included: deafness, blindness, disfigurement, cleft palate, many other internal disabilities, and of course the disabilities most associated with thalidomide: phocomelia. Phocomelia is a condition that involves malformations of the arms and legs. The birth defect results in hands and feet that are attached to abbreviated arms and legs.

 

The number of thalidomide victims has never been adequately quantified, but it has been estimated that there were between ten and twenty thousand babies born disabled.  Within a few years of the widespread use of thalidomide in Europe, Australia, and Japan, approximately 10,000-20,000 children were born with phocomelia, leading to the ban of thalidomide in most countries in 1961.  There are approximately 5,000 survivors alive today, around the world.  The number of babies miscarried, or stillborn, let alone the number of family members and parents who have suffered over the years will never be known. (Suffer the Children: The Story of Thalidomide, by the Insight team of The Sunday Times of London, The Viking Press, New York)

Around the world, in the late 1960's and into the early 1970's, the victims of the drug thalidomide and their families entered into class action legal suits, or threatened actions, against the various drug companies who manufactured and/or distributed the drug, and they were eventually awarded settlements. In most countries, these settlements included monthly or annual payments based on the level of disability of the individual.  But in some countries, victims of the drug were often forced to face the human tragedy and the legal and medical costs alone, family by family. The victims of this human rights tragedy did not receive adequate redress for their injuries. Often cases never received a trial verdict.  Rather, many families were forced to settle out-of-court with gag orders imposed on them not to discuss the amounts of their settlements. This resulted in wide disparity in the compensation amounts, with settlements for individuals with the same levels of disability varying by hundreds of thousands of dollars. The victims faced the extraordinary medical costs because of their disabilities and now, decades later, any settlement money is long gone. Survivors of the thalidomide tragedy, who are now in their fifties and sixties, are experiencing physical deterioration due to stress placed on their different body structures, further limiting their abilities.  This often results in new disabilities, thus compounding this human rights tragedy. There are many unaddressed needs and overwhelming problems of these victims of a pharmaceutical company. The long term social and medical costs are extensive and borne by the affected individuals themselves, their families, their communities and their home nations.

 

When the company is facing regulatory actions or criminal sanctions, they often seek to market in another country the medication they can no longer effectively market at home. Pharmaceutical companies frequently repackage medications for a different condition than the one for which the drugs had been tested in clinical trials.  This expands the market for drugs that don’t bring in enough profits when marketed for a particular condition.  When they do this they often do not provide the human consumers of their products with accurate information about the medication's side effects and adverse effects,  Pharmaceutical companies are often deceptive about the drug's effectiveness for the condition for which it was sold.  (for example Eli Lilly's marketing of Strattera in China) 

 

Historically pharmaceutical companies have shown little willingness to abide by human rights principles and have done human rights abuses especially in regards to the use of human subjects for non-consensual experimentation in pharmaceutical research. These corporations actively promote deceptive marketing practices that impede the patient's right to the knowledge necessary to give informed consent prior to treatment. There is a huge disparity between the political power and financial power of transnational pharmaceutical corporations and the victims of their business related human rights abuses. Through the global reach of these corporations, the violations of human rights by such entities disproportionately affect marginalized and impoverished groups and exacerbate existing human rights concerns.  It is essential to find effective means of preventing and redressing human rights abuses related to transnational pharmaceutical corporations and of ensuring greater accountability and access to remedy for victims.  Much more remains to be done to prevent abuses in connection with activities by transnational pharmaceutical corporations and other medical business enterprises and to enable victims to have meaningful  access to remedy when abuses occurred.   

Ex-Pharmaceutical Representative

Misbranding and Off-Label Promotion of Pharmaceuticals is very profitable

For example, the U.S. pharmaceutical company Pfizer repeatedly criminally marketed drugs for things they knew they couldn’t demonstrate efficacy for. In 2004, Pfizer agreed to pay $430 million in criminal fines and civil penalties, and assured U.S. prosecutors that Pfizer and its units would stop promoting drugs for unauthorized purposes. But Pfizer managers were off-label marketing in another Pfizer unit, Pharmacia & Upjohn.,In 2009, Pharmacia & Upjohn, agreed to plead guilty to the same crime. This time, Pfizer executives had been instructing more than 100 salespeople to promote Bextra, a drug approved only for the relief of arthritis and menstrual discomfort, for treatment of acute pains of all kinds. For this new felony, Pfizer paid the largest criminal fine in U.S. history: $1.19 billion. On the same day, it paid $1 billion to settle civil cases involving the off-label promotion of Bextra and three other drugs with the U.S. and 49 states. The FDA found Bextra to be so dangerous that Pfizer took it off the market for all uses in 2005.


Across the U.S.A., pharmaceutical companies have been pleading guilty to criminal charges or paying penalties in civil cases when the U.S. Department of Justice finds that they deceptively marketed drugs for unapproved uses, putting millions of people at risk of kidney and liver failure, diabetes, chest infections, heart attacks, suicidal impulses or death. Doctors influenced by the direct to doctors pharmaceutical promotions, write more than 10 million such prescriptions each year. This high volume of off-label prescribing is done in the absence of good scientific evidence to support the use of these drugs – especially antidepressants, antipsychotics, and anxiolytic-sedatives. About 15 percent of all drug sales in the U.S. are for unapproved uses without adequate evidence the medicines work. (Randall Stafford, a medical professor at Stanford University in Palo Alto, California.)


Pharmaceutical companies view the $7 billion paid in penalties for misbranding and off-label promotional marketing criminal fines as just the cost of doing business. Since May 2004, Pfizer, Eli Lilly & Co., Bristol-Myers Squibb Co. and four other drug companies have paid a total of $7 billion in fines and penalties. Six of the companies admitted in court that they marketed medicines for unapproved uses. In 2007, Bristol-Myers paid $515 million — without admitting or denying wrongdoing — to federal and state governments in a civil lawsuit brought by the Justice Department. The six other companies pleaded guilty in criminal cases. In 2009, Eli Lilly, the largest U.S. psychiatric drug maker, pleaded guilty and paid $1.42 billion in fines and penalties to settle charges that it had for at least four years illegally marketed Zyprexa, a drug approved for the treatment of schizophrenia, as a remedy for dementia in elderly patients. In five company-sponsored clinical trials, 31 people out of 1,184 participants died after taking the drug for dementia — twice the death rate for those taking a placebo. These findings were reported in the Journal of the American Medical Association in October 2005. The Pfizer and Lilly cases involved the illegal promotion of drugs that have been shown to cause substantial harm and death to patients.

Investor-State Dispute Settlement (ISDS) systems are designed to grant new rights to thousands of multinational corporations to bypass domestic courts and their existing constitutional and human rights protections. The ISDS system enables foreign companies to challenge public health, environmental and social protection laws that harm their profits. The rules of such settlement systems contain conflicts of interest that would be deemed unethical under most legal systems. In the ISDS provisions there is no obligatory code of conduct for arbitrators, to tackle the problem of conflicts of interest or human rights issues. The ISDS system does not provide adequate legal requirements for transparency and accountability for human rights protections and public policy protections for safety and effectiveness of medications. The decisions are not bound by legal precedents or the opinions of governments. There is no outside appeal to their rulings, even when those rulings may impact the human rights of hundreds of thousands of patients. The ISDS system was designed to give multinational firms the ability to challenge new policies of governments, including social public policy designed to protect the right to health for patients. The investor-state dispute settlement clause, within free trade agreements, is intended to protect foreign investors from discrimination by governments. In practice, it means that companies will have the right to sue foreign governments if they don't like the local legislation. There is little transparency to the process as the cases are heard in private.


In 2013 Eli Lilly Corporation used the NAFTA Foreign Investor Privileges to attack Canada's patent policy and demanded $100 million for invalidation of a patent for Strattera. Eli Lilly sued Canada for violating the North American Free Trade Agreement because Canadian courts had found patents for two of its drugs to be invalid under Canadian law. The Canadian court decisions, Lilly claimed, violated minimum standards of treatment guaranteed to foreign investors under NAFTA and expropriated Lilly’s investment in Strattera, used in the treatment of ADHD, and Zyprexa, used to treat mood conditions including bipolar disorder and depression. Eli Lilly was demanding to market Strattera in Canada for off-label uses, because sales in the U.S.A. had dropped due to many reports of adverse medical events for individuals using the drug and lack of evidence that it was safe or effective for the purpose it was marketed. Canada had demanded that Eli Lilly prove that the medication was actually useful (had utility). Eli Lilly claimed that the patent protections in other countries did not need to prove that the drug have utility, therefore Canada was interfering with their right to free trade. Canada was trying to protect their citizens from the sale of a medication with a proven history of medical problems and no greater effectiveness over generic medications already in use in Canada. By allowing investors to sue governments for damages, trade agreements with ISDS provisions may be elevating the rights of foreign investors over domestic sovereignty.

Attorney Jim Gottstein

Psych Rights Qui Tam

http://psychrights.org/education/ModelQuiTam/ModelQuiTamPowerPoint.pdf

Lobbies Rule America

GlaxoSmithKline Whistleblower

Psych Rights

Ex-Lilly Rep

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