Off-Label Drug Use

Here's the third paper I turned in this semester.  100/100 points!  Again, for BIOT640, Ethical Considerations in Biotechnology.  5000-6000 words on an assigned topic.  My topic was "Off-Label Drug Use" which is fitting because I did seem to turn potato starch into the #1 abused drug in the blogosphere...



This is an interesting topic, I had no idea this sort of stuff goes on and it makes me shake my head at our system of government regulation trying to keep a handle on Big-Pharma while the patient suffers.


Read only if you are very bored, or need something to put you to sleep.  Don't say I didn't warn you!

Societal Issues of Off-Label Drug Use

             

The Patient Protection and Affordable Care Act, or “Obamacare,” has changed the policy landscape of public health as medical establishments are attempting to make health care insurance more affordable (Rosenbaum, 2013). The use of prescription drugs in “off-label” applications is an area of concern under this new act. Off-Label drug use is commonplace and legal, yet there are numerous misconceptions and inconsistencies in the regulation of off-label drug use. A thorough understanding of the issues surrounding off-label drug use is vital to ensuring patients receive the best care possible under any new legislation that may arise from Obamacare.

“Off-Label drug use” is defined as the use of drugs in ways not approved by the Food and Drug Administration (FDA). Off-Label uses should not be confused with “inappropriate” or “improper” use of drugs (Beck and Azari, 1998).  Drugs have been used “off-label” since the FDA began regulating drug marketing in the 1930’s. The FDA does not regulate medical practices, only the sales and advertisement of drugs based on predicted outcomes (Gupta and Nayak, 2014). Physicians often use drugs marketed for a particular condition to treat completely unrelated conditions; an example is the use of antidepressants to treat gastrointestinal distress. Physicians require specialized knowledge of drugs to prescribe off-label and insurance companies will often not pay for off-label prescriptions unless their use is specifically allowed. The combination of specialist physicians and tighter controls by insurance companies is at the heart of concerns that off-label drug use will be impeded in cases where they would save lives or when more suitable drugs are unavailable. A recent paper published by the Journal of Oncology Practice highlighted the fact that, under Obamacare, “In a state without a law requiring off-label drug coverage, a patient may not have access to a life-saving medication (Hutchins, Samuels, and Lively, 2013, p. 76).” Under Obamacare, patients may not have the flexibility to see specialists and will be encouraged to use only doctors recommended by their insurance provider. This lack of flexibility is a confounder in obtaining the best care possible, especially when seeking a specialist.

Though off-label drug use has a long and storied history, there are nuances to these uses and ethical issues abound. Physicians are often reluctant to use off-label drugs as they may be held financially liable if their insurance company does not cover the use (Gillick, 2009).  Biotechnology will become an increasingly important component to off-label drug use as medical care becomes tailored to the genomic traits of the patient and biotech companies produce more of the drugs used off-label (Kesselheim, Myers, Solomon, Winkelmayer, Levin, and Avorn, 2012). The legalities of off-label prescriptions and their reimbursement require thorough examination to prevent unfair advantages in different levels of insurance coverage (Gupta and Nayak, 2014). Additionally, ethical considerations, such as the issue of “orphan drugs” for rare diseases, cancer treatment where nearly 50% of drugs used are off-label, and circumstances where off-label drugs save lives though not cost-effective must be taken into account under Obamacare rulings (Mellor, Van Koeverden, Yip, Thakerar, Kirsa, & Michael, 2012). This paper will explore the issues surrounding off-label drug use so that informed decisions can be made concerning the use of off-label drugs in this new era of healthcare legislation.

The History of Off-Label Drug Use

The FDA was given authority to ensure new medications were “safe” in 1938. In 1962, the Kefauver-Harris Amendment further gave the FDA authority to ensure new drugs are “effective.” The FDA only regulates pharmaceuticals, not the practicing of medicine (Gupta and Nayak, 2014). Medical doctors must rely on their own judgment when treating illnesses that don’t respond to conventional drugs, or in populations/age groups not covered in the drug manufacturer’s literature. Pregnant women and children, for instance, may require a drug when there is no FDA approval for these demographics. Recommended doses are often titrated to off-label levels when the FDA approved dosage is not effective (Meadows, 2007). Additionally, off-label use of drugs is commonly used in life-threatening conditions by doctors willing to try ‘hail Mary’ treatments (Meadows, 2007). Doctors routinely prescribe drugs from a class of drugs, or for a family of illnesses, for reasons of economics, or availability (Gupta and Nayak, 2014). Physicians get off-label information from medical journals, peers, or their intellect and observations (Kohen, et al., 2009. The passage of the 1993 Rockefeller-Levin Bill was a key event in the history of off-label drug use. It mandated that Medicare must allow off-label drugs in the treatment of cancer if the off-label use is listed in drug compendia or showed promising use in peer-reviewed scholarly articles (Meadows, 2007). 

The Role of the FDA in Off-Label Drug Use

 The FDA mandates that drug companies cannot advertise off-label uses of their drugs because these drugs have not been thoroughly tested to FDA standards. Off-Label uses are often safe and effective and the drug companies are fully aware of these off-label uses, however, they are not allowed to recommend their drugs in this manner (Gupta and Nayak, 2014).  Pharmaceutical companies must comply with 21 Code of Federal Regulations (CFR) 202.1 in their promotional use of television, newspapers, magazines, journals, internet, and other media. The FDA’s mission is to ensure drugs are sold in a way not misleading to the public or healthcare professionals (Wittich, Burkle, and Lanier, 2012).

The FDA historically has not directly regulated information contained in drug reference handbooks, major compendia, or textbooks. An exception is made when drug companies provide financial support or other benefits (Wittich, et al., 2012). Drug companies profit greatly when their products are included in medical literature and must take strides to ensure there is no conflict of interest with published medical works to avoid punitive action by the FDA. Insurance companies often rely on medical journals to decide if off-label uses are coverable under their plans, further making off-label inclusions profitable to drug companies (Wittich, et al., 2012).

Pharmaceutical companies continually challenge the FDA to gain toe-holds inside the medical community. The FDA allows drug companies to establish “medical liaisons” to answer questions from physicians about off-label uses of their drugs. These medical liaisons must not be a part of the sales and marketing division. The advice given by medical liaisons must be backed by medical journals or other non-promotional material (Wittich, et al., 2012). Drug companies often sponsor “key opinion leaders” (KOL) who become subject matter experts, write journal articles, or speak at medical learning events (Ventola, 2009). Drug companies have also been known to organize events for medical establishments with their KOLs acting as independent speakers. The FDA allows drug companies to give grants to medical centers for Grand Rounds or continuing medical education events, but the full disclosure of any financial relationship is mandated (Ventola, 2009).

FDA Policy Concerning Electronic and Printed Materials

The internet age has made new inroads for drug companies to the consternation of FDA regulators. Company websites are strictly limited in what can be said about drugs the manufacturers sell, exactly as they are with printed media (Meadows, 2007). Blogs and other unregulated websites can freely dispense off-label drug use information as long as they are not acting on behalf of a drug company. Proving conflicts of interest in this area exceeds the funding and manpower of the FDA’s current design (Meadows, 2007).

   Scholarly journals encourage the publication of articles and studies relating to off-label uses of pharmaceuticals, and don’t consider off-label drug use a derogatory term, in fact, quite the opposite. The medical establishment often finds itself at odds with the FDA’s labelling of drugs and many lawsuits have been filed when outcomes are less-than-desirable. The inclusion of off-label uses of drugs in scholarly journals gives credibility to their use and gives doctors a research tool when choosing drugs. This presents no legal conflict as the FDA has formally agreed that (Meadows, 2007):

●        The FDA has no oversight of the practice of medicine, including off-label use of drugs.

●        The FDA acknowledges that off-label uses of drugs are the “standard of care” in many instances.

●        The FDA acknowledges doctors are not responsible for disclosing their off-label use of drugs to patients.

Off-Label drug use has a long history of successful implementation despite lack of federal oversight. The FDA has continually maintained that off-label drug use is acceptable and often the best practice. Attempts to categorize off-label drug use in sweeping policy changes under Obamacare should be dealt with systematically. Policymakers must take into account historical uses of off-label drugs and become aware of the legal issues and precedents of off-label drug use.

Legal Issues Concerning Off-Label Drug Use

The FDA has the authority to use administrative and legal actions to protect the public from improper activities involving the sale of pharmaceutical substances. The FDA can punish anyone who violates FDA regulations, spelled out in 21CFR, and the FDA has the full backing of the Department of Justice. The FDA regularly issues warnings, confiscates property, withdraws drug licenses, and fines companies who violate drug labelling or merchandising law (Ventola, 2009).

While the FDA does not enforce the way doctors practice medicine, their sometimes strong-armed tactics against pharmaceutical companies dictate the way medicine is practiced at a functional level (Steinman, 2012). Even though a drug company may be fully aware that an off-label use of one of their products will save many lives, they are barred from disclosing this information unless specifically questioned by a medical doctor. All recommendations must be cited from published, scholarly journals or drug compendia (Steinman, 2012).

Below are examples of FDA actions that have affected the practice of medicine through enforcement actions on drug companies:

●        Genzyme Corp, 2014, ordered to pay $22.8 million for off-label marketing. Genzyme Corp was found guilty of teaching doctors to alter one of their Seprafilm product, a bio-film used during surgeries, for use in less invasive procedures (Securities and Exchange Commission, 2010).

●        Endo Pharmaceuticals Inc., 2014, ordered to pay $192.7 million for off-label marketing. Endo advertised their Lidoderm product for back pain and carpal tunnel when it was approved for complications of shingles (Department of Justice, Endo, 2014).

●        Johnson & Johnson, 2013, ordered to pay $1.72 billion for off-label marketing and kickback schemes. The allegations were that Johnson & Johnson targeted their drug Risperdal to doctors treating elderly patients with depression and anxiety although Risperdal is only approved for schizophrenia (Department of Justice, Johnson, 2014).

●       Amgen Corp, 2012, ordered to pay $612 million for promoting sales of drugs for off-label uses. Amgen was also found guilty of offering kickbacks to doctors who used their off-label drugs and also for defrauding Medicaid and Medicare from 2001 to 2011. The crime that Amgen committed involved their Aranesp product, a drug approved for anemia from chemotherapy. Amgen advertised it as a cure for anemia not related to chemotherapy. Aranesp raises red blood cell counts and corrects anemia for any anemic person. The prosecutor in this case made a statement that, “biotechnology giants are not above the law and my office will continue to ensure that prescriptions be written based on medical judgment—not profit motive (Department of Justice, Amgen, 2014).”

●        GlaxoSmithKline, 2012, fined $3 billion for off-label marketing of several brands of drugs they sell including Paxil, Wellbutrin, and Avandia. Their crimes involved advertising these drugs for age groups and conditions not specifically approved by the FDA. They were also accused of several price-fixing schemes, kickbacks, and insurance fraud (Department of Justice, GlaxoSmithKlein, 2014).

In none of the cases presented was it noted that patients were harmed, or doctors were lied to. At the heart of these crimes was profit. The global pharmaceutical market is worth an estimated $300-400 billion (World Health Organization, 2004). Drug companies are profit-driven enterprises and are a prime target of the FDA. Downstream effects of these legal actions impact the practice of medicine by reinforcing the illegality of drug company promotions of off-label uses of drugs (Steinman, 2012).

Freedom of Speech

Drug companies have attempted to turn off-label drug use into a First Amendment issue, stating that it is their fundamental right to promote legal and safe off-label uses of their drugs (Steinman, 2012). The public perception is that off-label drug use is illegal and that large pharmaceutical companies are manipulating the facts for sales. In most cases, this is nowhere near the truth. There have been cases of drug companies outright lying about their products, and for that they have been punished, but these cases are not about off-label drug use promotions. One such case involved the drug “gabapentin.” The manufacturer, Pfizer, was convicted of using many different tactics to suppress less than favorable results of trials of its drug. Pfizer used scholarships and manipulated promotions to send false messages (Steinman, 2012).

Public safety and truthful advertising are at the heart of the FDA’s concern over off-label drug use is. Drug companies have countered that the FDA is concerned more about the money the drug companies make than public safety. The drug companies claim that their knowledge of off-label uses come from doctors and scholarly journals, yet they are not allowed to promote these advances.

Drug Development

The FDA requires specific steps when a drug company wishes to market a new drug or an existing drug for new uses. These steps involve (FDA, Drug, 2014):

●        Submitting “new drug application” to the FDA.

●        Completion of animal testing.

●        Completion of human testing.

●        FDA’s Center for Drug Evaluation and Research reviews tests and labeling proposals.

●        FDA approves or denies the new drug application.

This simplified outline can take over ten years and over $300 million to complete. The permitting and animal process takes an average of three years and human testing is a phase-dependent process involving thousands of people over five to six years. Drug testing is a $12 billion industry in the United States (FDA, Drug, 2014).

The FDA has several programs to speed the process for new drug approvals where few or no treatments exist. These programs are Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review (FDA, Fast Track, 2014). These expedited processes ensure speedy approval of a new drug application and final review.

Whistleblower Act

Adoption of Whistleblower, or Qui Tam rules, of the False Claims Act have cost drug companies millions of dollars and halted many illegal practices. Under this framework, private citizens or company insiders can file suit against drug companies for illegal promotion of off-label drug use. Once the action has commenced, the federal government may step in to help prosecute the case, but a substantial portion of any money seized goes to the ‘whistleblower.’ This system of ‘bounty’ for illegal acts is designed to ensure that drug companies cannot trust their people to keep secrets of illegal activity in their processes. In 2010, the drug company AstraZeneca was ordered to pay $520 million for off-label drug promotions filed under the Whistleblower Act (Kesselheim, Mello, and Studdert, 2012). The sheer number of dollars recovered under the Whistleblower act should give any drug company pause. Among 379 cases from 1996 and 2005, $9.3 billion was fined to various healthcare companies with $1 billion going directly to the whistleblowers, who are often company executives, doctors, or employees. Of the total, $3.6 billion came from drug companies (Kesselheim and Studdert, 2005).

The legal ramifications of off-label drug use extend from the FDA to drug companies to physicians and patients. While off-label drug use will certainly continue, the recent heavy fines levied by the FDA will deter drug companies from passing on off-label information to health care providers. 
 

Ethical Considerations of Off-Label Drug Use

Ethical Use

 Off-label drug use is not illegal, but is it ethical? The question of ethics, in this case, may be a bit unclear. In pediatric hospitals, nearly 50% of the prescriptions are off-label and in the fields of ophthalmology and cancer, off-label drugs are routine (Wong, 2006). Medical doctors must use their judgment in prescribing drugs off-label and ensure they have the backing of insurance underwriters and hospital management. To withhold off-label drugs is a bigger ethical dilemma than prescribing them (Rodwin, 2013).

When prescribing off-label, a physician must first weigh the risks. As these drugs have not been clinically tested for the off-label use, there is an inherent danger of unexpected consequences (Rodwin, 2013). Any time a newly introduced and “fully labeled” drug is used, there is also a risk of unforeseen consequences. It often takes several years and thousands of prescriptions before serious side-effects are cataloged. With off-label drugs, it is normally the case that these drugs have been on the market for many years and their side-effects well-known in studied populations, therefore, doctors can make intelligent decisions regarding risk. Oftentimes the off-label use is kept in a class of drugs, only the population is in question, for example, drugs approved for adults given to children in lesser dosages (Rodwin, 2013).

Ethical Salesmanship

The lines between ethical and legal become blurred when pharmaceutical companies provide the information. If a doctor is prescribing off-label based on a recommendation from a peer-reviewed journal, it is seen as legal and ethical. When a doctor prescribes off-label solely because a drug company recommends it and offers financial recompense for its use, it is most definitely illegal and unethical. Even in this case, it may be safe, but here, clearly, the emphasis is on the monetary transaction. There have been many attempts in the past to curtail this type of behavior (Rodwin, 2013). The monitoring and reporting of off-label prescriptions have become standard practice in many healthcare centers. Insurance companies have instituted policies in which drug companies do not profit from off-label prescriptions any more than standard prescriptions. Legislation has been introduced to require drug companies to pay for independent tests of off-label drug uses when a certain level of prescriptions have been written off-label. Additionally, drug companies are advised to issuing warning for off-label uses that have been seen as unsafe (Rodwin, 2013).

Governmental Ethics

The ethics of off-label drug use has been questioned in the United States Armed Forces. Several instances of off-label uses have resulted in unintended consequences and are seen as the “agent orange” of the day by many veteran watchdog groups. Prophylactic administrations of drugs to counteract expected attacks by nerve and biological agents have been used widely since the Gulf Wars of the 1990’s and 2000’s (Food and Drug Administration, 2009). Pyridostigmine, a drug approved for muscle weakness, was regularly administered to combat troops in the1990’s wars to ward off effects of nerve agents, but now blamed for thousands of cases of Gulf War Syndrome. In 2003 the FDA approved pyridostigmine to increase the chances of combat troops surviving a nerve agent attack. Pyridostigmine now comes with specific instructions for the situations this drug may be used in and exact dosages (Food and Drug Administration, 2009).

The US military has also come under scrutiny for its off-label use of a broad spectrum antibiotic ciprofloxacin. Ciprofloxacin was administered to thousands of troops after the 9/11 attacks in an effort to ensure they could survive an anthrax assault (Gebhardt, 2005). Military doctors used ciprofloxacin at many times the recommended dosage for prolonged times which caused widespread destruction of the immune systems of those taking the drug (Centers for Disease Control, 2002). The loss of critical immune system protection caused many confirmed cases of autoimmune diseases and mental disorders in troops returning from combat stations (Nass, 2002). The Veteran’s Administration has issued “watch lists” for those who were prescribed ciprofloxacin and anthrax vaccines in this manner (Air Force Times, 2013).

Ethics in Scholarly Journals

The efficacy of peer-reviewed journals alone as a source of off-label drug use information has also come under scrutiny. The peer-review process has failed on many occasions as drug companies have sought publication for positive trial results and quashed negative results. They have also provided misleading data for poor outcomes in studies, suppressed safety risks, and hired ghostwriters for peer-reviewed journal entries (Ventola, 2009).

Scholarly journals are plagued by articles written for ulterior motives such as off-label drug use. Drug companies profit greatly when researchers mention their drugs in a favorable way, and these drug companies often won’t wait for the articles to get written (Flaherty, 2013). Drug companies hire writers to write articles for submission to peer-reviewed journals and fail to disclose the financial relationship. In many instances, side effects and serious risks are hidden. These questionable tactics cast a shadow over all peer-reviewed journals when they come to light. The FDA relentlessly pursues drug companies who use these tactics to market drugs off-label, and have brought many to justice. One of the more egregious cases involved Dr. Scott Reuben. In 2010, Dr. Reuben was sentenced to six months in prison and fined $400,000 for willfully submitting falsified drug trials to dozens of medical journals (Department of Justice, Reuben, 2010).

In general terms, the legal issues of off-label drug use are placed on the drug companies and the ethical considerations are borne by prescribing physicians and pharmacists. Ethical dilemmas can be avoided if doctors use established methodology regarding off-label uses of drugs and follow the guidelines of their medical establishment. Doctors who continue to fall for the “wooing” and kickbacks from drug companies are committing unethical acts. The FDA allows for drug companies to answer physician’s questions regarding off-label uses of their products. The FDA does not condone active marketing by drug companies or drug company representatives who persuade doctors to use drugs in an off-label manner.

Insurance Companies’ Policies Regarding Off-Label Drug Use

Medicare and Medicaid

  Medicare and Medicaid have historically been the “powerhouses” in the insurance world. These two programs are backed by the federal government, and smaller insurance companies follow their lead. It is important to look at how these industry leaders handle off-label drug use claims. Nearly all off-label drug use could be stopped dead in its tracks if insurance companies refused to pay for the drugs (Keech, 2006).

Prior to the adoption of Obamacare, Medicare and Medicaid both would reimburse the appropriate use of off-label prescriptions. They both used the criteria that the prescriptions must be recommended in peer-reviewed journals articles. Until 1993, Medicare and Medicaid utilized a case-by-case review for off-label drug reimbursements, but the passage of the Omnibus Budget reconciliation Act that year allowed for across-the-board off-label reimbursements. Since 1993, 39 states have enacted similar laws to allow state-run insurance programs the same leniency in reimbursing for off-label drug use (Keech, 2006).

Provisions under Obamacare are loosely worded with regards to off-label drug use and reimbursement, deferring to individual states policies. As only 31 states have policies at present, this leaves a tremendous gap in the care promised by Obamacare (Hutchins, 2013). In states with no statutes concerning off-label drug use, patients in those states may not have access to lifesaving drugs. The ambiguously worded provisions of off-label drug use under Obamacare are a major change from the concrete terms used by Medicare and Medicaid. While Obamacare is not designed to replace Medicare and Medicaid, these federally operated insurances are in flux with current trends in reimbursement (Hutchins, 2013).

While Medicare and Medicaid have always been transparent in their dealings with off-label drug use reimbursements, private insurers have not been so forthcoming (American Society of Clinical Oncologists, 2006). 50% of the surveyed medical professionals remarked they had changed treatment strategies due to non-coverage of off-label prescriptions by private insurers (Cohen, Wilson, and Faden, 2009).

Insurance Fraud

Insurance fraud is a common crime in the pharmaceutical industry. Billions of dollars have been recovered in Whistleblower Act lawsuits and even the largest, most respected drug companies have been implicated. In 2008, Merck Pharmaceuticals was forced to pay $399 million for a Medicaid rebate scam it operated for nearly ten years. Merck admitted guilt in a $650 million settlement involving insurance fraud, kickbacks, and off-label drug use promotions (Department of Justice, Merck, 2014).

Under Obamacare, all eyes will be on Medicare and Medicaid in the legal battles over off-label drug reimbursements. Many lobbyist groups have already begun launching impressive initiatives to either loosen or strengthen the reimbursement of off-label drug prescriptions. One of the most vocal “pro off-label litigants” is the American Society of Clinical Oncologists who have shown that nearly 50% of drugs given in cancer treatments are of the off-label variety. Any reduction in reimbursements, they claim, would cause undue hardships to nearly every cancer patient in America (Keech, 2006).

Conclusion

Off-Label drug use is a mounting concern as the healthcare landscape changes under Obamacare. Off-Label drug use has a long history in US medical care with many off-label uses of drugs being the “standard of care.” The FDA does not regulate the practice of medicine, only the selling of drugs, and has shown its authority in going after biotechnology giants in the pharmaceutical world. Legal and ethical arguments are being presented to lawmakers now. Key decisions are presently being made regarding off-label drug use under Obamacare. It is in everyone’s best interest to have a full understanding of the issues surrounding off-label drug use. Medicare and Medicaid can no longer be relied on to provide guidance as smaller, private insurers come onto the scene with the same federal backing enjoyed previously by only Medicare and Medicaid. The medical establishment is in a dangerous time in that precedents set now could affect the lives of many in the future. As more and more Whistleblower cases come to light putting the term “off-label drug use” in the public vernacular, a negative connotation is starting to form. Perhaps a better choice of words for these non-FDA approved prescriptions would be in order. The goal of Obamacare is to give Americans access to affordable, quality health insurance, and to reduce the growth in health care spending (Rosenbaum, 2011). If this goal is to be met, the complications and inequities of off-label drug use must be identified and corrected.  

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