Tag: Marcia Angell

11/19/19

A Shot Across the Bow of Pharma

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Ending a four year-long federal investigation, Avanir Pharmaceuticals agreed to pay an estimated $116 million in criminal penalties and civil damages in a settlement reached with the Department of Justice (DOJ) on September 26, 2019. According to FiercePharma, the company also agreed to assist in the prosecution against former employees and a top prescriber of its bestselling drug, Nuedexta. As a part of the deal, Avanir agreed to a five-year Corporate Integrity Agreement with the Department of Health and Human Services (HHS). Avanir CEO Wa’el Hashad said the “company takes its responsibilities to patients, their families and caregivers, and healthcare providers very seriously. . . . Avanir is deeply committed to regulatory and legal compliance, integrity and ethical behavior, and the health and safety of patients.”

The DOJ reported Avanir agreed to pay over $95 million to resolve civil False Claims Act allegations that the company paid kickbacks to a physician to prescribe Nuedexta, and that it made false and misleading marketing claims about Nuedexta to long-term care facilities. Allegedly the false claims were targeted to influence providers to prescribe Nuedexta as an alternative to antipsychotic drugs. The federal government was trying to limit the use of antipsychotics as “chemical restraints” used to manage behaviors commonly associated with dementia patients.

Avanir has agreed to pay $95,972,017 to the United States to resolve allegations under the False Claims Act related to its marketing of Nuedexta. The government alleged that between October 29, 2010, and December 31, 2016, Avanir provided remuneration in the form of money, honoraria, travel, and food to certain physicians and other health care professionals to induce them to write prescriptions for Nuedexta. One form of remuneration included Avanir’s payment to certain health care professionals to give talks (commonly known as “speaker’s programs”) about Nuedexta based on their willingness to prescribe Nuedexta. These events were primarily social, with no educational value.

Nuedexta is only approved as a treatment for a rare condition called pseudobulbar affect (PBA) that causes uncontrollable laughing or crying that is not connected to a person’s mood. PBA is extremely rare in dementia patients, affecting less than 5%. It is most commonly associated with people who have multiple sclerosis (MS) or Lou Gehrig’s disease, ALS. Doctors were found to be inappropriately diagnosing PBA to justify using Nuedexta to treat difficult to manage elderly patients. There was a CNN investigation in 2017 that  indicated between 2012 and 2016 Nuedexta sales jumped 400%; more than half of which had gone to long-term care facilities. For more on this, see: “Conjuring Diagnoses For the Elderly.”

According to a recent CNN report, whistleblowers alleged that from the drug’s early years Avanir illegally directed salespeople to market Nuedexta in nursing homes as an alternative to antipsychotic drugs specifically for “use in controlling the behavior of patients prone to disruptive outbursts.” They also claimed salespeople coached doctors on how to describe patients’ conditions in order to guarantee approval, and even forged physician signatures on paperwork for insurers. One lawsuit stated, “At least one Avanir (salesperson) went so far as to dress in scrubs, review patients’ files at the nurses’ station in nursing homes, and write the diagnosis for PBA in the medical files of patients.” These tactics were allegedly praised by an executive on a national sales call. Government data indicated Medicare Part D spent around $225 million on Nuedexta in 2017, a 700% increase since 2012.

Assistant Attorney Jody Hunt of the DOJ said kickbacks can corrupt a provider’s medical judgment. “And it is particularly concerning when a pharmaceutical company uses kickbacks to drive up sales in connection with a vulnerable population, such as elderly patients in nursing care facilities.” The government alleged Avanir sought to take advantage of efforts by the Centers for Medicare and Medicaid Services to reduce the use of antipsychotics with dementia patients. Avanir instructed its sales force to initiate discussions in long-term care (LTC) facilities about antipsychotic use and how Nuedexta could be used to reduce their reliance on antipsychotics.

Avanir’s own studies demonstrated that the actual population of patients with PBA is limited. In order to counter the objection by certain physicians that they had few, if any, patients that exhibited signs of PBA in their facilities, Avanir instructed sales representatives to provide false and misleading information that PBA patients could be exhibiting a wide variety of “behaviors” such as crying without tears, moaning, or making other inarticulate sounds, when, in fact, those symptoms are commonly observed in patients who have dementia but do not have a diagnosis of PBA. This strategy worked, and Nuedexta utilization in LTC facilities increased.

The DOJ reported the civil settlement resolved lawsuits by three whistleblowers, who were all former employees of Avanir. Under the whistleblower provisions of the False Claims Act, private citizens are permitted to sue on behalf of the government for false claims and to share in any recovery.

The Employment Law Group® law firm reported Kevin Manieri was the first person to report the company’s activities to authorities. A biopharmaceuticals executive with decades of experience, he was fired only months after joining Avanir in 2014 when he complained to an Avanir vice president about the company using “speaker fees” to reward doctors for writing unnecessary prescriptions for Nuedexta. Many of Avanir’s speaking engagements were small, sparsely attended gatherings at local restaurants. The speakers tended to be individuals willing to diagnose PBA “based upon a bare minimum of symptoms,” according to Kevin Manieri’s complaint. A press release issued by the U.S. Attorney’s Office for the northern District of Ohio said many of the Nuedexta speaking engagements had “little to no educational value.”

According to the complaint filed by Mr. Manieri, whom the drug company hired to oversee Nuedexta sales to physicians in the northern U.S., Avanir pushed its reps to focus on a few high-volume prescribers who were willing to recommend Nuedexta to patients who likely didn’t need the drug. He cited a vivid example in the complaint: A Cleveland-area neurologist who wrote twice as many Nuedexta prescriptions as any other doctor in the U.S. — and who also was Avanir’s highest-paid speaker, with 42 engagements in 12 months yielding more than $56,000 in payments.

Sadly, Avanir’s marketing strategy is not unusual in the world of pharmaceutical companies. According to Dr. Marcia Angell in The Truth About Drug Companies, Parke-Davis paid academic experts to put their names on flimsy research papers that supposedly showed Neurontin (gabapentin) was effective for certain off-label conditions. The result was Neurontin becoming a blockbuster drug, with over 2 billion in sales for 2003. “About 80 percent of prescriptions that year were for unapproved uses—conditions like bipolar disorder, post-traumatic stress disorder, insomnia, restless legs syndrome, hot flashes, migraines, and tension headaches.” In fact, Neurontin became an all-purpose restorative for chronic discomfort. An internal company e-mail described Neurontin as “the ‘snake oil’ of the twentieth century.”

In May of 2004, Warner-Lambert, of which Parke-Davis was then a division, agreed to pay $430 million to resolve criminal charges and civil liabilities related to its “illegal and fraudulent promotion of unapproved uses” for Neurontin. See the Department of Justice announcement here. Also see “Twentieth Century Snake Oil” for more on this.

The larger issue is that we can no longer trust much of the clinical research that is published. Among the concerns are reportedly selective publication of clinical trials, rigging the outcomes of those trials, publication bias and industry payments to medical journals and their editors. Richard Horton, and editor in chief of The Lancet said: “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.” Marcia Angell, a former editor in chief of the New England Medical Journal (NEJM) said: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor.” See “Corrupted Clinical Trials” for more on this.

So, the actions of whistle blowers like Kevin Manieri are not simply the acts of disgruntled ex-pharmaceutical employees in the long run. What happened to a relatively small pharmaceutical company, Avanir, and its attempts to expand the marketing reach of its featured drug, Nuedexta, are hopefully a warning shot across the bow of Pharma. Marketing rhetoric disguised as “treatment” or “evidence-based medicine” will not be tolerated. And there will be individuals and firms like The Employment Law Group® ready to hold you accountable for your actions. For more on Avanir and Nuedexta, also see “A Reason to Cry Uncontrollably.”

06/22/18

Corrupted Clinical Trials

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Dr. Jason Fung opened his article, “The Corruption of Evidence Based Medicine—Killing for Profit” with the following: “The idea of Evidence Based Medicine (EBM) is great. The reality, though, not so much.” He said if the evidence base was false or corrupted, then evidence-based medicine was completely worthless. “It’s like building a wooden house knowing the wood is termite infested.” He’s not alone in this opinion and he quoted three current or former editors of the two most prestigious medical journals in the world who corroborated his statement.

Richard Horton, editor in chief of The Lancet said: “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.”

Dr. Marcia Angell, former editor in chief of the New England Medical Journal (NEJM) said: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor.”

Dr. Arnold Relman, the former editor of the NEJM, said: “The medical profession is being bought by the pharmaceutical industry, not only in terms of the practice of medicine, but also in terms of teaching and research. The academic institutions of this country are allowing themselves to be the paid agents of the pharmaceutical industry. I think it’s disgraceful.”

Dr Fung said: “Physicians and universities have allowed themselves to be bribed.” He went on to say the examples in medicine are everywhere. For instance, medical research is typically paid for by pharmaceutical companies. “Trials run by industry are 70% more likely than government funded trials to show a positive result.” Among the issues he described were: the selective publication of clinical trials, rigging the outcomes of those trials, publication bias and industry payments to medical journals and their editors.

Clinical trials with negative results are likely to be suppressed. Using the company Sanofi to illustrate the problem, Dr. Fung noted the company completed 92 studies in 2008, but only published the results of 14. He acknowledged how it would be financial suicide to publish data that would harm your company. “But knowing this, why do we still believe the evidence based medicine, when the evidence base is completely biased?”

With antidepressants, a review of the published literature published in the NEMJ suggested 94% of the trials conducted were positive. Among FDA-registered trials, 31% were not published and only 51% showed positive results. The authors said:

We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

Before the year 2000, pharmaceutical companies doing clinical trials did not have to declare beforehand what their primary outcomes would be. So they would “measure many different endpoints and simply figured out which one looked best and then declared the trial a success.” The government changed that requirement and after 2000, 8% of clinical trials showed good results when 57% of those before 2000 showed a positive result. Evidence of the evidence base was being corrupted by commercial interest.

If a journal publishes a positive article about a Pharma drug, the company would order several hundred thousand copies of the article to distribute to doctors in their marketing efforts. “It’s insanely profitable for journals to take money from Big Pharma.” The NEMJ gets 23% of its income from reprints; the Lancet gets 41%; and the American Medical Association gets 53%! “No wonder these journals are ready to sell their readers (ordinary physicians) down the river. It pays.” A cited study noted where 50.9% of the editors of prestigious medical journals received at least some payments from the industry, and in some cases “these payments were often large.”

We found that industry payments to journal editors are common and can be substantial. Moreover, many journals lack clear and transparent editorial conflicts of interest policies and disclosures. Given our findings, we would suggest that journals take several steps. Firstly, we would strongly argue that all journals should develop and implement a transparent, publicly accessible editorial conflicts of interest policy. Secondly, editors in chief should consider excluding those with considerable industry relations from editorial positions. While such a stance could be considered drastic, editors play a crucial role in research integrity; even an appearance of conflict can serve to undermine the clinical research enterprise.

In The Chronicle of Higher Education, Batt and Fugh-Berman noted where “Disclosing Corporate Funding Is Not Nearly Enough.” In the U.S. in 2015, industry spent $102.7 billion on health-related research, while federal agencies spent $35.9 billion. “The current administration attempted to further decrease NIH funding, but those efforts were unsuccessful.” They said reliance on industry money limits the scope of research; and “it weakens researchers’ ability to act as independent critics.” Pharmaceutical companies fund, publish and promote studies that that are favorable to their marketing goals and “suppress or attack research that threatens market share.”

Perhaps most troubling is that if the final results of a study do not support commercial goals, the full study may never be published. In general, industry-funded studies are less likely to be published than non-industry-funded ones. And contrary to expectations, the reason negative studies are unpublished is not because journals rejected them, but because they were never submitted for publication. Although many universities frown on agreements that give funders the right to suppress the publication of findings, policies regarding publishing are not uniform across colleges and universities. In any case, enforcement is nil: Colleges can’t force researchers to publish studies. Industry insiders tell us that when company representatives fail to prevent a researcher from publishing unfavorable results on a drug, they may attempt to persuade the researcher to “bury” the paper in an obscure journal. Or, under the guise of reviewing a manuscript for “accuracy,” a company may soften statements or insert subtle marketing messages into the article to mitigate harm to its marketing goals. We don’t know the extent to which industry funding distorts biomedical literature — and clinical decision-making — but a substantial body of evidence now shows that allowing industry to choose what scientific questions should be asked, and how findings should be analyzed, interpreted, and disseminated, has public-health costs. We need strategies to minimize industry influence on scientific questions, and the resulting impact on policies and medical practice.

Writing for Mad in America, Zenobia Morrill summarized a review article by three researchers, “Industry-corrupted psychiatric trials.” The authors quoted from Marcia Angell’s 2008 article for JAMA, “Industry-sponsored clinical research: A broken system,” where she said:

Over the past 2 decades, the pharmaceutical industry has gained unprecedented control over the evaluation of its own products. Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.”

Amstersdam, McHenry and Jureidini, the authors of “Industry-corrupted psychiatric trials,” noted it was common knowledge that pharmaceutical companies “laundered” their promotional efforts through medical communications companies that “ghostwrite articles and then pay academic consultants to sign on to the fraudulent articles.”

The firms set up advisory board meetings with key opinion leaders and marketing executives in advance of the clinical trials. Once a trial is complete, the medical ghostwriter who is employed by the medical communications firm produces a draft of a manuscript – from a summary of the Final Study Report of the clinical trial – and seeks feedback from the corporate sponsor. It is at this stage in the manuscript production that misrepresentation of the trial data frequently occurs, since the medical ghostwriter is under the direction of marketing executives to “spin” the data. The medical ghostwriter then revises a number of drafts with input from the external academic “authors” and internal industry scientists, and once the corporate sponsor is satisfied that the final manuscript draft is “on message,” it is submitted by a corporate-designated lead author to a medical journal for peer review. Once the manuscript is submitted, the medical ghostwriter disappears or is acknowledged in the fine print for “editorial assistance.”

As a result, ghostwriting by the pharmaceutical industry has become a major factor in the “crisis of credibility” in academic medicine. “The integrity of science depends on the trust placed in individual clinicians and researchers and in the peer-review system which is the foundation of a reliable body of knowledge.” If academics allow their names to appear on ghostwritten articles, “they betray this basic ethical responsibility and are guilty of academic misconduct,” according to Amstersdam, McHenry and Jureidini. Ghostwriting extends to include an academic façade for research “that has been designed, conducted and analyzed by industry.” Yet the vast majority of ghostwritten publications won’t be revealed as such.

Key opinion leaders (KOLs) or “thought leaders” are academic physicians who are carefully vetted by the industry on the basis of their receptivity to the sponsor’s products. Pharmaceutical companies say they have engaged these KOLs for expert evaluation and feedback on marketing strategy. However, they essentially are highly paid “product champions” or marketers. “Few physicians and psychiatrists can resist the flattering offer by industry to become KOLs.” Medical journals are noted to be part of the problem here as well.

Medical journals are part of the problem rather than the solution to the problem. Instead of demanding rigorous peer review of a submissions and an independent analysis of the data, medical journal editors are pressured to publish favorable articles of industry-sponsored trials and rarely publish critical deconstructions of ghostwritten clinical trials. As medical journals and their owners have become dependent upon pharmaceutical revenue, the journals fail to adhere to the standards of science. Thus the publication of “positive” studies showing drug safety and effectiveness means more pharmaceutical advertising and more orders of reprints for dissemination by the sales force. In contrast, a “negative” study showing poor tolerability or ineffectiveness results in no such revenue.

“Industry-corrupted psychiatric trials” then went on to deconstruct how three studies, “SmithKline Beecham Paroxetine Study 329,” “Forest Laboratory Citalopram Study CIT-MD-18” and “SmithKline Beecham Paroxetine Study 352” all manipulated or misrepresented outcome data. The first two to support the use of the SSRI antidepressants paroxetine (Paxil) and citalopram (Celexa) for the treatment of childhood and adolescent depression. The third study, “Paroxetine Study 352,” misrepresented and manipulated outcome data in adults diagnosed with bipolar affective disorder. Morrill said: “Misconduct of this study was revealed when academics filed complaints of plagiarism and research misconduct against KOLs at medical research universities across the U.S. as well as pharmaceutical company executives.”  Read the review article for further details on how these three research studies were deconstructed to reveal how they manipulated or misrepresented outcome data.

In closing, let me remind you again of the opinion of Marcia Angell, former editor of the NEMJ:

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. . . . Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.

06/4/14

Twentieth Century Snake Oil

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My wake up call to the deceptive practices of some pharmaceutical companies came when I read The Truth About Drug Companies by Marcia Angell in 2004. Angell speaks credibly to the issue since she is a former editor-in-chief of the prestigious The New England Journal of Medicine. One example that stayed with me over the years because of its sheer, incredible audacity was how Neurontin was made into a multi-billion dollar selling drug.

In 1994 Neurontin was approved by the FDA as a secondary treatment for epilepsy—to be used when patients failed to respond to other anti-seizure drugs. The patent was due to expire in 1998 (it eventually received a two year extension). So the company began to target doctors to prescribe it for unapproved, off-label uses, “mainly common but vague conditions like pain and anxiety, and also as the sole treatment for epilepsy.”

Although doctors are legally permitted to prescribe an FDA approved drug for any use whatsoever, it is illegal for a drug company to market a drug for off-label uses. According to Angell, what Parke-Davis did was to pay academic experts to put their names on flimsy research papers that showed the drug worked for certain off-label conditions. This “research” typically fell below the standard required by the FDA for an approval of the drug for a particular condition.

Angell said the studies were small and poorly designed. “Some of the articles contained no new data at all, just favorable comments about Neurontin.” Parke-Davis hired medical education and communication companies to prepare the articles and paid academic researchers to put their names on the articles as authors. Once the articles were published in academic journals, “medical liaisons” would visit doctor’s offices to answer questions about the research.

Parke-Davis also sponsored educational meetings and conferences. The “authors” of the papers would describe the positive results of the drug’s off-label uses. Not only were the speakers paid, “but often the doctors in the audience were paid” as consultants. This was to get around the anti-kickback laws. “Consultant meetings were sometimes little more than vacations for potential high prescribers of Neurontin.”

The result was Neurontin becoming a blockbuster drug, with over 2 billion in sales for 2003. “About 80 percent of prescriptions that year were for unapproved uses—conditions like bipolar disorder, post-traumatic stress, disorder, insomnia, restless legs syndrome, hot flashes, migraines, and tension headaches.” In fact, Neurontin became an all-purpose restorative for chronic discomfort. An internal company e-mail described Neurontin as “the ‘snake oil’ of the twentieth century.”

A generic version of Neurontin (gabapentin) went on sale in August of 2004. The website Drugs.com reported that Neurontin sales in 2004 were approximately $2 billion dollars. In 2005, sales dropped to $259.4 million. It dropped from the 10th best selling drug in 2004 to the 123rd best selling drug in 2005. By 2006, Neurontin had dropped out of the top 200 best selling drugs.

In May of 2004 the pharmaceutical manufacturer Warner-Lambert, of which Parke-Davis was then a division, agreed to pay $430 million to resolve criminal charges and civil liabilities in connection with its “illegal and fraudulent promotion of unapproved uses” for Neurontin. See the Department of Justice announcement here. Part of the global agreement was that Pfizer, Inc., the owner of Warner-Lambert since June of 2000, agreed to training and supervision of its marketing and sales staff to ensure that “any future off-label marketing conduct is detected and corrected on a timely basis.”

In December of 2013, the U.S. Supreme Court upheld a $142 million award to the Kaiser Foundation Health Plan by Pfizer for marketing Neurontin for unapproved uses. The court also allowed two other lawsuits against Pfizer to proceed. A key factor in the court’s decision apparently was an analysis by Meredith Rosenthal of the Harvard School of Public Health. “Her analysis found that marketing Neurontin for such unapproved uses as bipolar disorder, neuropathic pain and migraines caused physicians to write 43 million off-label prescriptions.” She further calculated that 99.4 percent of the prescriptions for bipolar disorder were caused by illegal marketing.

The two outstanding lawsuits noted above now seem be settled. In April of 2014 Pfizer agreed to pay $190 million to settle a lawsuit that was first filed in 2002.  The lawsuit claimed the pharmaceutical company took several steps to delay the entry of Neurontin into the generic drug market. According to a Reuters news article, along with other delay tactics, Pfizer allegedly filed “sham patent infringement lawsuits.” And just announced on May 30th, 2014 in this report by Bloomberg, Pfizer agreed to pay $325 million to settle a lawsuit brought by health-care providers claiming that Pfizer marketed Neurontin for unapproved uses. In both settlements, Pfizer did not admit to any wrongdoing.

So why does the history of unapproved marketing of Neurontin (gabapentin) rent so much space in my head and this blog? The Wall Street Journal recently ran an article titled “A Pill to Cure Addiction?” on “new medicines” that are being tested to help people quit drug and alcohol habits. The “new drug,” touted as a possible cure for addiction, is gabapentin.