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Human Rights Defenders

“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

Article 1

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FDA Approval Process

The FDA, Off Label Promotion and Misbranding

The FDA, Off Label Promotion and Misbranding

In the United States new drugs are tested in clinical trials (research studies) before they are approved by the US Food and Drug Administration (FDA) for use in the general public. 

The clinical trials are done to show that the drug:
Works to treat a certain medical condition
Works the way it’s expected to
Is safe when used as directed

When the FDA is satisfied that the drug works and is safe, it and the maker of the drug create the drug label. This is not an actual label that sticks to a bottle, but a report of very specific information about the drug. The FDA must approve this report, which is made available to all health professionals who prescribe or sell the drug. The drug label gives information about the drug, including the specific medical condition(s) it’s approved for (called the indication(s) for use), the doses to be used, and how it’s to be given. When a drug is used in a way that is different from that described in the FDA-approved drug label, it’s said to be an “off-label” use. 

This can mean that the drug is:
Used for a different disease or medical condition
Given in a different way (such as by a different route)
Given in a different dose than in the approved label

The off-label use of FDA-approved drugs is not regulated, but it is legal in the United States and many other countries. While it’s legal for doctors to use drugs off label, it’s not legal for drug companies to market (advertise or promote) their drugs for off-label uses. Off-label marketing is very different from off-label use. Some of the problems of off-label drug use is that it often does not reflect “standard of care” treatment. This could cause a patient have an unwanted or bad outcome from the treatment. The FDA does not regulate the practice of medicine. In general, once the FDA approves a drug, licensed doctors can use it for any purpose they consider medically appropriate.

One of the biggest problems related to widespread off-label use is the lack of information about how to best use the drug other than for what it was approved. The drug label contains the information that’s been approved by the FDA, and it does not cover off-label uses. Lack of information on off-label drug use and outcomes puts patients at a higher risk for medication errors, side effects, and unwanted drug reactions. For proper medical use of an off labeled drug, the doctor should adequately inform the patient about the possible risks of using the drug and weigh them against the possible benefits. When a court of law decides that a patient should receive off-label drug medical treatment, the process of obtaining prior, free and informed consent does not occur. Off label promotion of misbranded prescription medications is very common in the vulnerable population of persons who are wards of the court because of the low risk of detection and low risk of medical malpractice liability. 

Off-label promotion can involve the following: 1) Paying incentives to sales representatives based on sales for off-label use;  2) Paying kickbacks to physicians to prescribe drugs for off-label use;   3) Disseminating misleading posters promoting off-label use;   4) Paying physicians: (a) To pretend to be the authors of articles about off-label uses when the articles were actually written by manufacturers’ agents; (b) To serve as members of “advisory boards” promoting off-label use; (c) To travel to resort locations to listen to promotions about off-label use; or (d) To give promotional lectures in favor of off-label use to fellow practitioners.  5) Providing advice to prescribers on how to code their claims and document their medical records to support payment for off-label uses not covered by Medicaid; 6) Publicizing studies showing efficacy of off-label uses while suppressing studies showing no efficacy;  and 7) Making false representations directly to Medicaid to influence decisions about payment for drugs used off-label.

Bad Medicine GlaxoSmithKline

Evidence of Big Pharma influence on FDA

FDA Regulation of Prescription Drugs

 

The Food and Drug Administration (FDA) is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, the Nation's food supply, cosmetics, and products that emit radiation. FDA is also responsible for advancing the public health by accelerating innovations to make medicines more effective and providing the public with accurate, science-based information on medicines and food to improve their health. FDA plays a significant role in addressing the Nation's counterterrorism capability and ensuring the security of the food supply.

Agency URL: http://www.fda.gov/

Food and Drug Act, Subchapter III, Prohibited Acts and Penalties, §§ 331-337a (“There is extraterritorial jurisdiction over any violation of this chapter relating to any article regulated under this chapter if such article was intended for import into the United States or if any act in furtherance of the violation was committed in the United States.”).

Or, “[t]he introduction or delivery for introduction into interstate commerce of any ... drug ... that is ... misbranded.” 21 U.S.C. § 331(a) (2006).

 

The government has repeatedly prosecuted — and obtained convictions against — pharmaceutical companies and their representatives for misbranding based on their off-label promotion.

 

Compliance Resources

 

The US FDA Office of Prescription Drug Promotion aims to protect public health by assuring prescription drug information is truthful, balanced, and accurately communicated; the FDA’s Bad Ads Program aims to educate health care professionals about the role they can play in ensuring that drug advertising and promotion is truthful and not misleading.


Information on the UK regulatory framework is available from the MHRA; the MHRA website also includes information on advertising investigations by the MHRA.


Information on the UK self-regulatory body, the PMCPA, is available; the PMCPA website includes information about the UK Code of Practice for medicines promotion.


Healthy Skepticism is an international non-profit membership association that aims to improve health by reducing harm from misleading health information

 

Safe and Effective in Long Term Use?

Whether a drug is safe or effective is important to consider when agreeing to take a prescription medication. All prescription medications have potential risks and potential benefits. Patients have the legal right to know what the risks are and also know what the potential benefits are – basically to know if the drug is safe or effective. The Food and Drug Administration is the federal agency which regulates the pharmaceutical companies and controls whether they are allowed to manufacture and market their pharmaceutical products in the U.S.A. Although a new drug may go through 7 or more years of human testing before it is approved, this usually encompasses several separate studies, each of which might last anywhere from a few months to a couple of years. The US drug safety system is not designed to detect the long-term risks of medications. A typical Phase I trial may last 60 days or less, a Phase II study may take from a few months to a couple of years, and a Phase III trial usually last a couple of years at most. Most drug safety data from clinical trials and post-marketing studies are collected from subjects who have been exposed to a medication for less than a few years. However, some health risks do not materialize until a person has been exposed to a substance for 5, 10, 15 or more years.

 

Some examples of medications causing harmful reactions are:

 

  • dexfenfluramine (Redux) weight loss medication used in combination with phentermine

     

  • selective serotonin reuptake inhibitors (SSRIs) used to depression can increase the risk of suicidal thinking and behavior in children and adolescents

     

  • rosiglitazone maleate (Avandia) for diabetes

     

  • rofecoxib (Vioxx) and celecoxib (Celebrex) arthritis medications

     

Pharmaceutical companies want to increase profits and so are very reluctant to remove a medication from the market even after multiple adverse events or even deaths. Merck Pharmaceuticals marketed Vioxx for over 5 years before withdrawing the product due to safety and liability concerns. But officials at Merck had evidence as early as November 1999 that their pharmaceutical product increased the risk of heart attacks and strokes. Approximately 88,000 Americans had heart attacks while taking Vioxx and 38,000 died. There were 13,000 lawsuits filed against the Merck Pharmaceutical company alleging harm caused by Vioxx. Merck knew about the adverse effects of Vioxx and even reported this information to the FDA, but still did not inform the consumers or the prescribing doctors of the risks. The Food and Drug Administration did not require labeling changes about the cardiac risk until 2002. A black box warding was finally required but with mounting deaths, the FDA finally pulled the drug from the market in September 2004.

 

 

 

Problems concerning quality and integrity of FDA regulation of the pharmaceutical industry are:

 

  • insufficient public funding of the FDA

  • over-reliance on user fees to support the FDA

  • conflicts of interest on FDA advisory panels

  • management problems at the FDA

  • lack of transparency and openness in industry-sponsored studies

  • inadequate post-marketing research and surveillance

 

The US Food and Drug Administration drug safety system is not designed to detect the long-term risks of medications. A “long-term” study is one that gathers data on research subjects for 5 years or more. Regulatory agencies do not currently have effective and reliable mechanisms for obtaining information about the long-term risks of drugs. Clinical trials gather data concerning risks that materialize from taking a drug for a couple of years, at most. Regulatory agencies do not currently have effective and reliable mechanisms for obtaining information about the long-term risks of drugs.

 

There are two mechanisms for collecting safety data after a drug is approved, post-marketing studies and the MedWatch program. Neither of these systems is thorough or reliable. The FDA does not require companies to conduct or publish post-marketing studies. It is estimated that pharmaceutical companies fail to complete the recommended post-marketing studies more than 50% of the time and also do not publish post-marketing clinical studies. Under the MeWatch program, physicians and companies report adverse drug reactions (ADRs) to the FDA. The Food and Drug Administration records and analyzes the data. Though companies are required by law to report ADRs they learn about, physicians are not. But the majoring of adverse events occurs when the medication is used by a patient's private physician – often off-label use. Physicians are not required to report Adverse Drug Reactions and so seldom report ADR's. Therefore the MedWatch program is woefully inadequate to catch adverse post-market outcomes of pharmaceutical drugs. The information regarding any long term use of the pharmaceutical drug is sporadic and incomplete and so medications are often still being extensively used by the public even after significant evidence of substantial risk to patients has been demonstrated.

 

Pharmaceutical companies have no incentive to pay for long-term, post-marketing studies that could link their medications to health risks. Once a drug is already on the market, a company’s main reason for funding additional research would be to compare the drug with competing drugs, or to determine whether the drug can be safely used in a manner different from its original approved use, eg, to treat a different medical condition or different population (off-label use).

 

Adverse Drug Reactions or ADRs are one of the leading causes of ill-health in the US, killing more than 100,000 people each year and seriously injuring more than 2 million (Public Citizen 2007). Though ADRs can occur due to improper drug dosage or administration, dangerous drug interactions, and allergic responses drugs, it is likely that many are due to the long-term effects of drugs on the body.

Protecting Patients Rights

The protection of patent rights as it pertains to pharmaceutical drugs is the first step toward off-label marketing of that drug within another nation. With the harmonization of pharmaceutical regulations between countries, a drug legally sold within one nation -  (for example has a valid USA patent) - gets reciprocal regulatory acceptance and licensing in another country without additional regulatory hurdles prior to marketing.  These reciprocal licensing agreements thus open the door to off-label and misbranded products to be sold in the other country through free trade agreements, as soon as the patent is approved.  Drugs with little evidence of the effectiveness or safety, are thus sold off-label in other countries with less regulatory control over pharmaceutical products.  When faced with public outcry, regulatory control or criminal prosecutions at home, pharmaceutical companies seek to market their products more aggressively in countries with reciprocal licensing agreements and less regulatory control.  So when there are adverse events and negative publicity about a drug, the pharmaceutical company will switch to trying to sell more of the drug in the expanding market in the developing world.   For example taking a medication that is in trouble because of sanctions against it from FDA iinvestigations and then marketing that same drug in South America, or Asia.  In developing countries monitoring is not sufficient to identify all the side-effects and adverse medical events of such medications. Thus problems with the off-label medications may not be detected immediately and adequate medical response may not be available to affected patients. These same countries have less resources to deal with massive numbers of patients suffering from iatrogenic ((medical conditions directly caused by the drug) or other medically caused chronic conditions.

 

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. In the UK  off-label promotion activities often involves trying to influence prescribing

doctor's attitudes and beliefs about the medication. The Qui Tam or Federal Whistleblower law in the United States

allows employees within the pharaceutical companies to come forward and report off-label promotion to US federal

Food and Drug Administration investigator. In the UK there is not the same level of whistleblowing from employees

within the industry like in the USA as there are not the same legal avenues for such whistleblowing.  

 

There are several types of off-label promotional activities: (1) prescriber-related practices, i.e., off-label promotion

intended to influence prescribers; (2) consumer-related practices, i.e., off-label promotion to consumers; (3) internal

practices, i.e., incentives and other practices directed at employees of the company, and (4) payer-related practices, i.e.,

practices aimed at encouraging insurers to pay for off-label prescription. Also sometimes the promotional efforts are to

expand the use of the medication to different patient subgroups rather than the patients the drug was originally

approved for. 

FDA not protecting USA from Unsafe drugs

Ethical Issues in Clinical Trials

Human Rights Issues Related to Use of Human Subjects in Research

The Nuremberg Code and the related Declaration of Helsinki delineates what is considered ethical conduct for human subjects’ research and forms the basis for the US Code of Federal Regulations - Title 45 Volume 46 (The Common Rule).   The  International Covenant on Civil and Political Rights covenant was adopted in 1966 and put in force in 1976, and is monitored by the United Nations Human Rights Committee.  The ICCPR is part of the International Bill of Rights.   Article 7 of the International Covenant on Civil and Political Rights, i states “no one shall be subjected without his free consent to medical or scientific experimentation.”  


The International Ethical Guidelines for Biomedical Research Involving Human Subjects, promulgated by the Council for International Organizations of Medical Sciences, define how the principles of the Declaration of Helsinki can be applied to human subjects of medical research.  


Human subject research includes experiments and observational studies in basic biology, clinical medicine, nursing, psychology, and all other social sciences. The Congress of the United States of America ratified the ICCPR including Article 7.  The United States Congress has also implemented Article 7 of the ICCPR in domestic legislation to protect human subjects from non-consensual experimentation – The Common Rule (45 CFR Part 46).   The United States Congress clearly intended to protect human subjects by the following actions 1) Ratifying the ICCPR (including Article 7), 2) Holding extensive discussions regarding the ethical need for human subjects protections, 3) Publishing The Belmont Report and 4) Legislating The Common Rule.  


The Convention on the Rights of Persons with Disabilities (CRPD) was signed by the President of the United States, Barack Obama.ii The UN Convention on the Rights of Persons with Disabilities was adopted to promote, protect, and ensure the full and enjoyment of human rights and fundamental freedoms by all persons with disabilities and to promote respect for their inherent dignity. Article 12 of the CRPD affirms the equal recognition before the law and legal capacity of the persons with disabilities. Article 13 of the CRPD affirms the effective access to justice for persons with disabilities. Article 25 specifies that "persons with disabilities have the right to the enjoyment of the highest attainable standard of health without discrimination on the basis of disability."  The Convention on the Rights of Persons with Disabilities (CRPD) also protects the integrity of the person.  Article 17 of the CRPD states that every person with disabilities has a right to respect for his or her physical and mental integrity on an equal basis with others.

On July 12, 1974, the United States National Research Act (Pub. L. 93-348) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the charges to the Commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider: 1) the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, 2) the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, 3) appropriate guidelines for the selection of human subjects for participation in such research and 4) the nature and definition of informed consent in various research settings.
 
The Belmont Report (1976) iii is a formal statement by the United States government regarding the ethical standards and accepted legal norms regarding the use of human subjects in medical, behavioral or scientific experimentation. The Belmont Report, which took nearly 4 years of deliberations, summarizes the basic ethical principles for research with human subjects. It is a statement of basic ethical principles and guidelines to consider in the use of human subjects in research. It was published in the U.S. Federal Register so it could become ethical guidance for U.S. researchers, scientists, governmental employees and Institutional Review Boards (IRB). 

The Belmont Report identifies three basic ethical principles that are particularly relevant to the ethics of research involving human subjects: the principles of respect of persons, beneficence and justice 1) The Principle of Respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.  2) The Principle of Beneficence means that persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being. 3) The Principle of Justice demands that the advantages of the medical research not only be available to those who can afford them, but that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent benefits of the research. Unfortunately, the burdens of serving as research subjects has historically fallen largely upon poor, socially disadvantaged groups like prisoners, welfare patients, institutionalized patients, and racial and ethnic minorities.  This may be because of their easy availability, their compromised position, or their ability to be manipulated.  The benefits of the research and improved medical care flowed to the higher economic status patients.  Those who participate in the medical research and bear the burden of potential harm have the right to benefit from the new medical treatments and improved medical care made possible by their volunteering.  An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. 

The United States has accepted ethical standards related to scientific or medical experimentation on human subjects and our moral obligations to human subjects by promulgating federal laws  – The Common Rule – “The Federal Policy for the Protection of Human Subjects.” The Common Rule (45 CFR Part 46) was adopted in 1991.  The Federal Policy for the Protection of Human Subjects or the “Common Rule” was codified in separate regulations by 15 Federal departments and agencies. The United States Department of Health and Human Services (HHS) regulations 45 CFR part 46 governs all federally-funded research in the United States. 

Medical practice is meant to enhance the well-being of an individual patient or client and is expected to have a reasonable expectation of success. The first rule of medicine is Do No Harm. Within clinical medical practice, physicians are ethically required to obtain free prior informed consent for any treatment.   Free prior informed consent for treatment is especially important when a clinician departs in any significant way from standard or accepted practice, or utilizes a medication that the FDA has not approved for that use.  Failure to obtain proper and legal free, prior and informed consent is considered medical malpractice.  The process of obtaining consent must involve three elements: information, comprehension and voluntariness. Consent obtained by deceit, misinformation, or coercion is not legally valid.  Information supplied in English to a patient whose only language is Spanish does not comply with the comprehension aspect of informed consent. Providing information only in very detailed scientific terminology that is not understood by lay person, is also not complying with the comprehension aspect of informed consent. Without free prior informed consent, experimental treatment on human subjects is prohibited by U.S. law. Thus, it is the responsibility of medical practice committees to demand that the ethical principles of the Belmont Report are applied and human rights of patients are protected.  

Unfortunately there has been a pattern of discrimination towards vulnerable populations worldwide being utilized for medical experimentation by U.S. researchers.  Beginning in 1946, the United States government conducted medical research on more than 5000 uninformed and unconsenting Guatemalan people who were intentionally infected with bacteria that cause sexually transmitted diseases.  Many have been left untreated to the present day. viii  ix   The researchers knew of the harm that they caused. Although the US Presidential Commission for the Study of Bioethical Issues found the Guatemalan experiments morally wrong, little if anything has been done to compensate the victims and their families.  U.S. President Barack Obama apologized in 2010. xii  The Guatemalan government issued a separate report, Consentir el Daño: Experimentos Médicos de Estados Unidos en Guatemala (To Agree to the Harm: Medical Experiments by the United States in Guatemala), which went beyond the US reports to state that the experiments were “a crime against humanity” and that racism and discrimination were present throughout the experiments in an explicit and conscious way.

Unethical Clinical Trials

Yale School of Medicine researchers found a clinical trial with neurontin was a seeding trial used by Big Pharma to promote the drug and increase prescriptions. Seeding trials are not illegal but are unethical because they offer no research. They took advantage of 2700 patients and 772 investigators to complete the publication. These people gained nothing for their participation.

In another study, surgeons in Medtronic trials failed to report serious complications that included 10-50% of patients who developed problems including cancer, sterility, infections, bone dissolutions and worsened back and leg pain. Fifteen surgeons collected $92 million from the company for their work!

Lastly, Joseph Biederman, MD from Harvard accepted more than a million dollars from Big pharma to further his work suggesting that most ADHD and ADD patients were actually bipolar and needed the medications sold by the companies supporting his work. What some people will do for money and fame is shocking.

 

Ethical Issues in Clinical Trials

Criminal Misbranding and Off Label Promotion

Criminal Misbranding and Off Label Promotion

 

The pharmaceutical companies have an extensive history of criminal off label promotion of their psychiatric medications. Off-label marketing of medications is the promotion of these drugs for uses that have never been approved by the Food and Drug Administration, and for which they had not been proven to be either safe or effective. The off-label use of these medications increased in adolescents, due to an organized effort by the pharmaceutical industry to proactively increase the diagnosis of depression in teenagers. One way they did this was through the “Teen Screen” program done through the public school system.

The public did not realize that these off-label uses had never been approved by the FDA. Pharmaceutical research financing is an important part of the budget of mental health facilities. Patients are without their prior informed consent, enrolled in clinical experimental trials financed and controlled by the pharmaceutical companies. Doctors do not go through the necessary steps required to protect the patient’s rights for human subjects in medical experimentation as required under The Common Rule. Patients are often not informed at all about the experimental use of the medication. This continues to be common practice within psychiatric hospitals and mental health clinics where they do emergency mental health interventions. Even in private practice, mental health professionals do not get patient’s prior informed consent prior to enrolling the patient into poorly supervised experimental off-label clinical use. Patients do not realize that these medications had not been proven safe or effective and the use of these products was essentially clinical experimental use of the product by their personal physicians.

Pharmaceutical companies are currently being criminally convicted by the U.S. Department of Justice of gross misrepresentations of their drug’s safety and efficacy and misbranding of their product. FDA can pursue misbranding cases criminally, and the consequences can be severe, especially when the FDA believes that the violation was committed with the intent to defraud or mislead.

Federal law in the United States - 21 USC § 331 makes clear that federal law prohibits “the introduction or delivery for introduction into interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded,” and “the adulteration or misbranding of any food, drug, device, tobacco product, or cosmetic in interstate commerce.” Additionally, 21 USC § 352(f) provides that a drug will be deemed to be misbranded unless its labeling contains adequate directions for use, which typically requires the directions to allow a layperson to use the drug safely and for the purposes for which it was intended.

In one recent case in 2012 for example, Abbott Laboratories Inc. plead guilty and agreed to pay $1.5 billion to resolve its criminal and civil liability for their off label promotion of Depakote. Abbott promoted Depakote to control behaviors in elderly dementia and schizophrenia patients without significant evidence of its effectiveness for that use, and even after clinical data established that it was not effective. The resolution includes a criminal fine and forfeiture totaling $700 million and civil settlements with the federal government and the states totaling $800 million. Abbott also will be subject to court-supervised probation and reporting obligations for Abbott’s CEO and Board of Directors.

Separate from the DOJ settlement, Abbott agreed to pay 45 states a total of $100 million to resolve liability under the state consumer-protection laws. That makes this the second-largest fraud settlement involving a drug company, behind only the $2.3 billion Pfizer settlement in 2010.

The company maintained a specialized sales force to market Depakote for off label purposes; targeting elderly dementia patients in nursing homes. Abbott has pleaded guilty to misbranding Depakote by promoting the drug to control agitation and aggression in elderly dementia patients and to treat schizophrenia when neither of these uses was FDA approved. The FDA approved Depakote for only three uses: epileptic seizures, bipolar mania and the prevention of migraines. The FDA never approved the drug as safe and effective for the off-label use of controlling behavioral disturbances in dementia patients.

In 1999, Abbott was forced to discontinue a clinical trial of Depakote in the treatment of dementia due to an increased incidence of adverse events, including somnolence (sleepiness), dehydration and anorexia (loss of appetite) experienced by the elderly study participants administered Depakote.

Abbott’s off-label promotion of Depakote was multifaceted. Abbott trained its sales force to promote Depakote to health care providers and employees of nursing homes as advantageous over antipsychotic drugs for controlling agitation and aggression in elderly dementia patients because Depakote was not subject to certain provisions of the Omnibus Budget Reconciliation Act of 1987 (OBRA). OBRA’s implementing regulations were designed to prevent the use of unnecessary medications in nursing homes. Exploiting the fact that certain OBRA provisions did not yet apply to Depakote, Abbott sales representatives stated that by using Depakote, nursing homes could avoid the administrative burdens and costs of complying with OBRA.

The company entered into contracts that provided long-term care pharmacy providers with payments of rebates based on increases in the use of Depakote in nursing homes serviced by the providers. The company wound up giving millions of dollars in rebates to pharmacists at long-term-care facilities that were based on increases in the use of the drug in nursing homes they serviced. Abbott created programs and materials to train the pharmacy providers' consultant pharmacists about the off-label use of Depakote to encourage them to recommend the drug for this unapproved use. Not only did Abbott engage in off-label promotion, but it targeted elderly dementia patients and downplayed the risks apparent from its own clinical studies, putting profits ahead of patient safety. Abbott offered and paid illegal remuneration to health care professionals and long term care pharmacy providers to unduly influence the content of company sponsored Continuing Medical Education programs, in violation of the Federal Anti-Kickback Statute.

In the agreed statement of facts, Abbott also admitted that from 2001 through 2006, the Company misbranded Depakote by marketing the drug to treat schizophrenia. Abbott funded two scientific studies of the use of Depakote to treat schizophrenia, and both failed to meet the main goals established for the study. When the second study failed to show a statistically significant treatment difference between antipsychotic drugs used in combination with Depakote and antipsychotic drugs alone, Abbott waited nearly two years to notify its own sales force about the study results and another two years to publish those results. During this time, Abbott continued to promote Depakote off-label to treat schizophrenia.

In another criminal case, Pfizer paid $1.3 billion in criminal fines for “misbranding” (the legal term for off-label marketing) drugs. And that was just the tip of the iceberg, considering the total package of the settlement was $2.3 billion when adding in Department of Justice (DOJ) fees and costs. The fine was so high because Pfizer was considered a “repeat offender” after it continued to promote Lipitor and Viagra for off-label uses following a request to cease and desist these practices by the FDA.

Large criminal fines of billions of dollars were awarded by the courts, but this did little to effectively curtail the direct marketing of these off-label uses of pharmaceutical products to consumers and to medical professionals. Drug manufacturers consider the monetary penalties as just another cost of doing business. So pharmaceutical companies continue to collect huge sums of profit from the allegedly illegal acts and even after the criminal convictions. Patients are not withdrawn from these dangerous medications. Instead, Medicaid and Medicare continue to pay for these off label medications for treatment of wards of the court (even after criminal prosecution). Judges who run mental health courts are not warned by the Department of Justice that the drugs they are forcing on wards of the court have been proven to be dangerous to patients and the pharmaceutical company criminally convicted.

Because the judgment and settlement penalties proved to be ineffective deterrents of these practices, the FDA and DOJ started to find other ways to try to stop the manufacturers from on-going unlawful activities. The federal agencies have begun to employ two new strategies: 1) bringing criminal charges against wayward company executives, and 2) barring the offending manufacturers from doing any business with or for the various and multiple federal prescription benefit plans (e.g., Medicare, Medicaid). The U.S. federal government is the largest single purchaser of drugs in the world.

The involvement of the court system to enforce these new deterrents is absolutely crucial. Thus the probate judges should enforce the patient’s right to free prior informed consent and the right to be free from non-consensual experimentation.

 

Glaxo Fined $ 3 million

Right To Health And Freedom Of Information

Right To Health And Freedom Of Information

In 2009 the Special Rapporteur on the Right to health stressed that the right to health is contingent on the right to access to information.  The Special Rapporteur stated that informed consent is a “voluntary and sufficiently informed decision, protecting the right of the patient to be involved in medical decision-making, and assigning associated duties and obligations to health-care providers.”  The right to receive and impart information is an integral element of the right to health. Completeness of information is among the required components of informed consent.  

To obtain prior informed consent requires disclosure of the associated benefits, risks and alternatives to a medical procedure.  The accuracy and completeness of information is necessary for valid informed consent for medical treatment.  Without truthful scientific information about the associated benefits, risks and alternatives to a medical procedure or treatment is required for consent to be valid.  The guarantee of informed consent is to respect the autonomy, self-determination and human dignity of individuals.   It constitutes a violation of a patient’s right to health to act, or fail to act, in a way that deprives that patient from the information he or she needs to provide informed consent.   

 

The UN Convention on the Rights of Persons with Disabilities was adopted to promote, protect, and ensure the full and

enjoyment of human rights and fundamental freedoms by all persons with disabilities and to promote respect for their

inherent dignity. Parties to the CRPD must ensure that persons with disabilities are able to exercise the right to freedom

of expression and that includes “the freedom to seek, receive and impart information and ideas on an equal basis with

others and through all forms of communication of their choice.”

 

Access to truthful scientific medical information is essential to patient informed consent. Unimpaired access to medical

information is necessary in the fight against pharmaceutical corruption and medical fraud, and impacts the public health.

By encouraging and creating a more transparent system for the distribution of medical information to the public, and

demanding criminal accountability for the deceptive off label promotion efforts by the pharmaceutical industry, the United

States could start eliminating corruption in the pharmaceutical marketing and health care systems.

 

GlaxoSmithKline Whistleblower

Off-Label Promotion Legal Cases

The legal cases that are strong off-label cases are those that emphasize misbranding or false and misleading promotion. The Department of Justice which prosecutes these FDA cases has had numerous successes and large money settlements for off-label FCA cases.

  • April 27, 2010, AstraZeneca agreed to pay $520 million and entered into a corporate integrity agreement to settle civil off-label claims related to the marketing of Seroquel.

  • September 1, 2010, Allergan pled guilty to misbranding and agreed to pay $600 million to settle civil and criminal liability related to the off-label promotion of Botox®.

  • June 9, 2011, UCB SA pled guilty to misbranding, agreed to pay $34 million and entered into a corporate integrity agreement to resolve civil and criminal liability related to the off-label promotion of Keppra.

  • June 10 2011, Novo Nordisk agreed to pay $25 million and entered into a corporate integrity agreement to resolve claims related to the off-label promotion of Novoseven.

  • May 7, 2012, Abbott Labs pled guilty to misbranding, agreed to pay $1.5 billion and entered into a corporate integrity agreement to resolve criminal and civil claims related to the off-label promotion of Depakote.

  • March 5, 2013, Par Pharmaceuticals pled guilty and agreed to pay $45 million to resolve civil and criminal allegations related to the off-label marketing and misbranding of Megace ES.

GlaxoSmithKline Corporate Greed

News Articles about Off-Label Marketing

  1. Press Release, United States Department of Justice, Pharmaceutical Giant AstraZeneca to Pay $520 Million for Off-label Drug Marketing (Apr. 27, 2010), available at http://www.justice.gov/opa/pr/2010/April/10-civ-487.html.
  2. Press Release, United States Department of Justice, Allergan Agrees to Plead Guilty and Pay $600 Million to Resolve Allegations of Off-Label Promotion of Botox® (Sept. 1, 2010), available at http://www.justice.gov/opa/pr/2010/September/10-civ-988.html. Disclosure: The author’s law firm was involved in the civil aspect of this case representing one of the three whistleblowers.
  3. Press Release, United States Department of Justice, U.S. Subsidiary of Belgian Pharmaceutical Manufacturer Pleads Guilty to Off-Label Promotion; Company to Pay More Than $34 Million (June 9, 2011), available at http://www.justice.gov/opa/pr/2011/June/11-civ-751.html.
  4. Press Release, United States Department of Justice, Danish Pharmaceutical Novo Nordisk to Pay $25 Million to Resolve Allegations of Off-Label Promotion of Novoseven (June 10, 2011), available at http://www.justice.gov/opa/pr/2011/June/11-civ-764.html.
  5. Press Release, United States Department of Justice, Abbott Labs to Pay $1.5 Billion to Resolve Criminal & Civil Investigations of Off-label Promotion of Depakote (May 7, 2012), available at http://www.justice.gov/opa/pr/2012/May/12-civ-585.html.
  6. Press Release, United States Department of Justice, Par Pharmaceuticals Pleads Guilty and Agrees to Pay $45 Million to Resolve Civil and Criminal Allegations Related to Off-Label Marketing (March 5, 2013), available at http://www.justice.gov/opa/pr/2013/March/13-civ-270.html.
  7.  

Discrimination against the disabled and need for protection

Persons with mental disabilities are often discriminated by reason of their condition. According to the Inter-American Convention on the Elimination of All Forms of Discrimination against Persons with Disabilities, States are obligated to properly supervise care and take actions necessary prevent all types of discrimination. Patients who live in psychiatric institutions or are undergoing treatment therein, are particularly vulnerable to torture and other types of cruel, inhuman or degrading treatment. These persons are more susceptible to mistreatment when hospitalized. The autonomy and right to self-determination of patients is severely curtailed in healthcare institutions which impinges on personal integrity. The States have the duty to supervise and guarantee that in all psychiatric institutions, either public or private, the patients´ right to receive a worthy, humane, and professional treatment be preserved and that said patients be protected against exploitation, abuse, and degradation.   States are also obligated to promote the full integration of such persons in society.   The rights of the disabled are delineated in federal policy and law most notably in the Americans with Disabilities Act (ADA).  

The international human rights treaty – The Convention on the Rights of Persons with Disabilities (CRPD) was signed by the President of the United States, Barack Obama.  Article 12 of the CRPD affirms the equal recognition before the law and legal capacity of the persons with disabilities. Article 13 of the CRPD affirms the effective access to justice for persons with disabilities. Article 25 specifies that "persons with disabilities have the right to the enjoyment of the highest attainable standard of health without discrimination on the basis of disability."  The Convention on the Rights of Persons with Disabilities (CRPD) also protects the integrity of the person.  Article 17 of the CRPD states that every person with disabilities has a right to respect for his or her physical and mental integrity on an equal basis with others.

Regarding individuals in psychiatric treatment, the United States cannot completely absolve itself of its responsibilities under international treaty law by delegating legal responsibility for determinations of legal capacity and guardianship to the law of the state rather than by federal law.  The federal government of the United States still has the obligation to guarantee and protect human rights and to ensure humane treatment. That legal capacity and guardianship are governed by the law of the state members of the United States of America, and not by federal law, does not absolve the federal government of its responsibility. The United States, as a nation state, still retains a duty to exercise supervision and control over public and private psychiatric institutions. The judicial system or judicial branch of government and administrative institutions of the United States must not only provide competent supervision on a regular basis of the confinement and medical treatment, but also whether it is justified.  

Database of Clinical Trials Information

Current informed consent regulations  require a new element for informed consent documents and processes that will inform the potential clinical trial participant that information about applicable clinical trials has been, or will be, entered into a databank that is publicly accessible at

http://www.ClinicalTrials.gov.

FDA & Children in Clinical Trials

The Food and Drug Administration (FDA) is amended its regulations to provide additional safeguards for children enrolled in clinical investigations of FDA-regulated products. FDA regulation on protection of human subjects (21 CFR Part 50) and institutional review boards (21 CFR Part 56) is to provide additional safeguards for children enrolled in clinical investigation.The 2001 changes are  to bring FDA regulations into compliance with provisions of the Children's Health Act of 2000 (the Children's Health Act). The Children's Health Act requires that all research involving children that is conducted, supported, or regulated by the Department of Health and Human Services (HHS) be in compliance with HHS regulations providing additional protections for children involved as subjects in research. FDA is taking this action both to comply with the congressional mandate and because of increases in the enrollment of children in clinical investigations  of FDA regulated trials - pediatric initiatives.

 

FDA & Pharmaceutical Regulation

Carpenter, author of Reputation and Power:Organizational Image and Pharmaceutical Regulation at the FDA will join us to discuss the FDA and the pharmaceutical industry. The U.S. Food and Drug Administration is the most powerful regulatory agency in the world. How did the FDA become so influential? And how exactly does it wield its extraordinary power? Carpenter traces the history of FDA regulation of pharmaceuticals, revealing how the agency's organizational reputation has been the primary source of its power, yet also one of its ultimate constraints

Human Subjects Protections

The authority citation for 21 CFR part 50 continues to read as follows:

Authority:

21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262, 263b-263n.

 § 50.3 Definitions.

 
* * * * *
(n) Assent means a child's affirmative agreement to participate in a clinical investigation. Mere failure to object should not, absent affirmative agreement, be construed as assent.
* * * * *
(r) Permission means the agreement of parent(s) or guardian to the participation of their child or ward in a clinical investigation.
(s) Guardian means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.
 
Clinical investigation should involve no greater than minimal risk to children as subjects.
§ 50.53 Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects' disorder or condition. 

 

§ 50.54 Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. 

PART 56—INSTITUTIONAL REVIEW BOARDS

 
8.The authority citation for 21 CFR part 56 continues to read as follows:
 

Authority:

21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262, 263b-263n.
 
 

FDA & Informed Consent

The Food and Drug Administration (FDA) is amending the current informed consent regulations to require that informed consent documents and processes for applicable drug (including biological products) and device clinical trials include a specific statement that clinical trial information will be entered into a databank. The databank referred to in this final rule is the clinical trial registry databank maintained by the National Institutes of Health/National Library of Medicine (NIH/NLM) which was created by statute. The submission of clinical trial information to this data bank also is required by statute. This amendment to the informed consent regulations is required by the Food and Drug Administration Amendments Act of 2007 (FDAAA) and is designed to promote transparency of clinical research to participants and patients.

Big Pharma Manipulating Doctors

Discrimination against the disabled and need for protection

Persons with mental disabilities are often discriminated by reason of their condition. According to the Inter-American Convention on the Elimination of All Forms of Discrimination against Persons with Disabilities, States are obligated to properly supervise care and take actions necessary prevent all types of discrimination. Patients who live in psychiatric institutions or are undergoing treatment therein, are particularly vulnerable to torture and other types of cruel, inhuman or degrading treatment. These persons are more susceptible to mistreatment when hospitalized. The autonomy and right to self-determination of patients is severely curtailed in healthcare institutions which impinges on personal integrity. The States have the duty to supervise and guarantee that in all psychiatric institutions, either public or private, the patients´ right to receive a worthy, humane, and professional treatment be preserved and that said patients be protected against exploitation, abuse, and degradation.   States are also obligated to promote the full integration of such persons in society.   The rights of the disabled are delineated in federal policy and law most notably in the Americans with Disabilities Act (ADA).  

The international human rights treaty – The Convention on the Rights of Persons with Disabilities (CRPD) was signed by the President of the United States, Barack Obama.  Article 12 of the CRPD affirms the equal recognition before the law and legal capacity of the persons with disabilities. Article 13 of the CRPD affirms the effective access to justice for persons with disabilities. Article 25 specifies that "persons with disabilities have the right to the enjoyment of the highest attainable standard of health without discrimination on the basis of disability."  The Convention on the Rights of Persons with Disabilities (CRPD) also protects the integrity of the person.  Article 17 of the CRPD states that every person with disabilities has a right to respect for his or her physical and mental integrity on an equal basis with others.

Regarding individuals in psychiatric treatment, the United States cannot completely absolve itself of its responsibilities under international treaty law by delegating legal responsibility for determinations of legal capacity and guardianship to the law of the state rather than by federal law.  The federal government of the United States still has the obligation to guarantee and protect human rights and to ensure humane treatment. That legal capacity and guardianship are governed by the law of the state members of the United States of America, and not by federal law, does not absolve the federal government of its responsibility. The United States, as a nation state, still retains a duty to exercise supervision and control over public and private psychiatric institutions. The judicial system or judicial branch of government and administrative institutions of the United States must not only provide competent supervision on a regular basis of the confinement and medical treatment, but also whether it is justified.  

Criminal Misbranding and Off Label Promotion

Criminal Misbranding and Off Label Promotion

The pharmaceutical companies have an extensive history of criminal off label promotion of their psychiatric medications. Off-label marketing of medications is the promotion of these drugs for uses that have never been approved by the Food and Drug Administration, and for which they had not been proven to be either safe or effective. The off-label use of these medications increased in adolescents, due to an organized effort by the pharmaceutical industry to proactively increase the diagnosis of depression in teenagers.  One way they did this was through the “Teen Screen” program done through the public school system. 


The public did not realize that these off-label uses had never been approved by the FDA. Pharmaceutical research financing is an important part of the budget of mental health facilities. Patients are without their prior informed consent, enrolled in clinical experimental trials financed and controlled by the pharmaceutical companies.  Doctors do not go through the necessary steps required to protect the patient’s rights for human subjects in medical experimentation as required under The Common Rule. Patients are often not informed at all about the experimental use of the medication.  This continues to be common practice within psychiatric hospitals and mental health clinics where they do emergency mental health interventions. Even in private practice, mental health professionals do not get patient’s prior informed consent prior to enrolling the patient into poorly supervised experimental off-label clinical use. Patients do not realize that these medications had not been proven safe or effective and the use of these products was essentially clinical experimental use of the product by their personal physicians.  


Pharmaceutical companies are currently being criminally convicted by the U.S. Department of Justice of gross misrepresentations of their drug’s safety and efficacy and misbranding of their product. FDA can pursue misbranding cases criminally, and the consequences can be severe, especially when the FDA believes that the violation was committed with the intent to defraud or mislead.


Federal law in the United States - 21 USC § 331 makes clear that federal law prohibits “the introduction or delivery for introduction into interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded,” and “the adulteration or misbranding of any food, drug, device, tobacco product, or cosmetic in interstate commerce.” Additionally, 21 USC § 352(f) provides that a drug will be deemed to be misbranded unless its labeling contains adequate directions for use, which typically requires the directions to allow a layperson to use the drug safely and for the purposes for which it was intended.


In one recent case in 2012 for example, Abbott Laboratories Inc. plead guilty and agreed to pay $1.5 billion to resolve its criminal and civil liability for their off label promotion of Depakote.  Abbott promoted Depakote to control behaviors in elderly dementia and schizophrenia patients without significant evidence of its effectiveness for that use, and even after clinical data established that it was not effective.  The resolution includes a criminal fine and forfeiture totaling $700 million and civil settlements with the federal government and the states totaling $800 million. Abbott also will be subject to court-supervised probation and reporting obligations for Abbott’s CEO and Board of Directors. 


Separate from the DOJ settlement, Abbott agreed to pay 45 states a total of $100 million to resolve liability under the state consumer-protection laws. That makes this the second-largest fraud settlement involving a drug company, behind only the $2.3 billion Pfizer settlement in 2010.


The company maintained a specialized sales force to market Depakote for off label purposes; targeting elderly dementia patients in nursing homes. Abbott has pleaded guilty to misbranding Depakote by promoting the drug to control agitation and aggression in elderly dementia patients and to treat schizophrenia when neither of these uses was FDA approved. The FDA approved Depakote for only three uses: epileptic seizures, bipolar mania and the prevention of migraines. The FDA never approved the drug as safe and effective for the off-label use of controlling behavioral disturbances in dementia patients. 


In 1999, Abbott was forced to discontinue a clinical trial of Depakote in the treatment of dementia due to an increased incidence of adverse events, including somnolence (sleepiness), dehydration and anorexia (loss of appetite) experienced by the elderly study participants administered Depakote. 


Abbott’s off-label promotion of Depakote was multifaceted. Abbott trained its sales force to promote Depakote to health care providers and employees of nursing homes as advantageous over antipsychotic drugs for controlling agitation and aggression in elderly dementia patients because Depakote was not subject to certain provisions of the Omnibus Budget Reconciliation Act of 1987 (OBRA).  OBRA’s implementing regulations were designed to prevent the use of unnecessary medications in nursing homes. Exploiting the fact that certain OBRA provisions did not yet apply to Depakote, Abbott sales representatives stated that by using Depakote, nursing homes could avoid the administrative burdens and costs of complying with OBRA. 


The company entered into contracts that provided long-term care pharmacy providers with payments of rebates based on increases in the use of Depakote in nursing homes serviced by the providers.  The company wound up giving millions of dollars in rebates to pharmacists at long-term-care facilities that were based on increases in the use of the drug in nursing homes they serviced.  Abbott created programs and materials to train the pharmacy providers' consultant pharmacists about the off-label use of Depakote to encourage them to recommend the drug for this unapproved use. Not only did Abbott engage in off-label promotion, but it targeted elderly dementia patients and downplayed the risks apparent from its own clinical studies, putting profits ahead of patient safety.  Abbott offered and paid illegal remuneration to health care professionals and long term care pharmacy providers to unduly influence the content of company sponsored Continuing Medical Education programs, in violation of the Federal Anti-Kickback Statute.


In the agreed statement of facts, Abbott also admitted that from 2001 through 2006, the Company misbranded Depakote by marketing the drug to treat schizophrenia. Abbott funded two scientific studies of the use of Depakote to treat schizophrenia, and both failed to meet the main goals established for the study. When the second study failed to show a statistically significant treatment difference between antipsychotic drugs used in combination with Depakote and antipsychotic drugs alone, Abbott waited nearly two years to notify its own sales force about the study results and another two years to publish those results. During this time, Abbott continued to promote Depakote off-label to treat schizophrenia.  


In another criminal case, Pfizer paid $1.3 billion in criminal fines for “misbranding” (the legal term for off-label marketing) drugs. And that was just the tip of the iceberg, considering the total package of the settlement was $2.3 billion when adding in Department of Justice (DOJ) fees and costs. The fine was so high because Pfizer was considered a “repeat offender” after it continued to promote Lipitor and Viagra for off-label uses following a request to cease and desist these practices by the FDA.


Large criminal fines of billions of dollars were awarded by the courts, but this did little to effectively curtail the direct marketing of these off-label uses of pharmaceutical products to consumers and to medical professionals.  Drug manufacturers consider the monetary penalties as just another cost of doing business.  So pharmaceutical companies continue to collect huge sums of profit from the allegedly illegal acts and even after the criminal convictions. Patients are not withdrawn from these dangerous medications. Instead, Medicaid and Medicare continue to pay for these off label medications for treatment of wards of the court (even after criminal prosecution). Judges who run mental health courts are not warned by the Department of Justice that the drugs they are forcing on wards of the court have been proven to be dangerous to patients and the pharmaceutical company criminally convicted. 


Because the judgment and settlement penalties proved to be ineffective deterrents of these practices, the FDA and DOJ started to find other ways to try to stop the manufacturers from on-going unlawful activities. The federal agencies have begun to employ two new strategies: 1) bringing criminal charges against wayward company executives, and 2) barring the offending manufacturers from doing any business with or for the various and multiple federal prescription benefit plans (e.g., Medicare, Medicaid). The U.S. federal government is the largest single purchaser of drugs in the world. 
The involvement of the court system to enforce these new deterrents is absolutely crucial.  Thus the probate judges should enforce the patient’s right to free prior informed consent and the right to be free from non-consensual experimentation.

ADHD drug company $58.9 Million

Depakote Abbott Labs Whistleblower

Interview with Reuben Guttman,  Attorney for Whistlerblower in Lawsuit against Abbott Laboratories, concerning the off-label marketing of Abbott's drug, Depakote.  Settled for $1.6 billion.

Teen Screen Pharma Dragnet

“Too often we underestimate the power of a touch, a smile, a kind word, a listening ear, an honest compliment, or the smallest act of caring, all of which have the potential to turn a life around.”
 
― Leo Buscaglia

Medical Whistleblower Advocacy Network

MEDICAL WHISTLEBLOWER ADVOCACY NETWORK

P.O. 42700 

Washington, DC 20015

MedicalWhistleblowers (at) gmail.com

CONTACT

"Never impose on others what you would not choose for yourself."  Confucius

"It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat."

Theodore Roosevelt- Excerpt from the speech "Citizenship In A Republic", delivered at the Sorbonne, in Paris, France on 23 April, 1910