A Ray of Sunshine: Transparency in Physician-Industry Relationships Is Not Enough.

Gifts from pharmaceutical and medical device companies to physicians in the United States have been reported since 2014, through the Physician Payments Sunshine Act. Although researchers have utilized these data to publish many studies on conflicts of interest (COIs) and prescribing behavior, there is no evidence that physician behavior regarding COI has changed, or that employers, meeting organizers, or medical journals are excluding physicians based on conflicts of interest. Disclosure is necessary but not sufficient to address the damage that industry relationships causes to medical knowledge and public health.

Testosterone and sexual function.

PURPOSE OF REVIEW: Testosterone therapy has been advocated in the treatment of symptoms that may represent normal aging. We briefly review randomized clinical trials on the effects of testosterone therapy on sexual function. RECENT FINDINGS: About half of clinical trials showed no benefit of testosterone therapy on any aspect of sexual function. In those studies showing a benefit on some aspect of sexual function, most sexual function domains were not improved. Testosterone therapy has been disappointing in the treatment of erectile dysfunction. Potential risks of therapy include an increase in thromboembolic and other cardiovascular diseases. SUMMARY: The limited and inconsistent benefits of testosterone therapy for sexual function argue against use of this therapy in aging men, including those with 'low testosterone'.

Direct-to-consumer Marketing to People with Hemophilia.

Adriane Fugh-Berman and colleagues describe how strategies similar to those used to market drugs to physicians are directed towards people with hemophilia.

Hypoactive sexual desire disorder: inventing a disease to sell low libido.

Condition branding is a marketing technique in which companies develop conditions concurrently with developing drugs; examples include gastro-oesophageal reflux disease, premenstrual dysphoric disorder, social anxiety disorder, erectile dysfunction and hypoactive sexual desire disorder. Although it is illegal for pharmaceutical companies to market drugs prior to regulatory approval, there are no restrictions on marketing diseases, and industry seeks to establish a disease state in the minds of clinicians years before an expected drug launch. Continuing medical education (CME) courses are an important part of promotion prior to drug approval and have become a key marketing tool for increasing clinician receptivity to new products. We systematically identified 14 free, internet-based, industry-funded, accredited CME modules on hypoactive sexual desire disorder in women which came out before a new drug, flibanserin, was being considered for regulatory approval in the USA. Common themes in these modules included the following: (1) Hypoactive sexual desire disorder is common, underdiagnosed and can have a profound effect on quality of life. (2) Women may not be aware that they are sick or distressed. (3) Simple questionnaires can assist clinicians in diagnosing the disorder. (4) It is problematic that there are medicines available to treat sexual problems for men but not women. In fact, there is no scientifically established norm for sexual activity, feelings or desire, and there is no evidence that hypoactive sexual desire disorder is a medical condition. Hypoactive sexual desire disorder is a typical example of a condition that was sponsored by industry to prepare the market for a specific treatment.

Parkinson's Disease Psychosis and the Marketing of Pimavanserin.

In 2016, Nuplazid (pimavanserin) became the first FDA-approved treatment for Parkinson's Disease Psychosis (PDP). We explored the possibility that PDP was a term created to market Nuplazid. We examined trends in perceptions of psychosis in Parkinson's disease from the 1990s to 2020 through MEDLINE search term frequency, neurology textbooks, guidance from professional societies, Acadia annual reports, sponsored websites, and a sponsored meeting held by the National Institutes of Health (NIH). We analyzed continuing medical education (CME) activities on PDP and analyzed the connection between payments by the manufacturer of pimavanserin and prescriptions. Our analysis of nine sponsored CME activities reveals misleading themes, including: PDP is common, progressive, and not always drug-induced; there is no such thing as a benign hallucination, and psychotic symptoms always worsen; PDP increases mortality; and competing treatments are ineffective or dangerous while pimavanserin is safe and effective for treating PDP. Industry-sponsored CME was used to disseminate inaccurate and misleading marketing messages on psychosis related to Parkinson's disease. Some professional societies and some textbooks also resisted the PDP label. Reframing PDP as a unique condition is a typical example of condition branding. The establishment of PDP expanded the use of pimavanserin and is likely to have resulted in many avoidable deaths.

Ethics and eplerenone.

The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies.

Evergreened drugs or evergreened profits?

BACKGROUND: Branded drugs contribute disproportionately to high prescription drug spending. Pharmaceutical companies utilize patent extension "evergreening" techniques that contribute to high drug costs. AIMS: This article describes various patent extension techniques and analyzes the tactic of combining generic drugs with branded drugs, using metformin combinations for diabetes treatment as a case study. It examines the argument that FDCs enhance adherence and compares the cost of several branded fixed-dose combinations with the cost of their individual constituents. MATERIALS & METHODS: We reviewed literature on patent extension techniques in both medical and marketing literature, supplemented by our own extensive files. We performed a price analysis of several branded pharmaceuticals and generically available equivalents. Prescription drug prices were determined using GoodRx.com, and prices of over-the-counter products were established based on the prices of two chain wholesalers. Patent and formulation information was taken from the FDA Orange Book: Approved Drugs with Therapeutic Equivalence Evaluations database. RESULTS: "Evergreening" patent extension tactics include the sequential release of different formulations, minor dosing changes, and fixed-dose combinations (FDCs). A "new use" provides an opportunity for a company to re-patent, rebrand, and remarket one drug for multiple indications. It is unclear whether or not FDCs enhance adherence. Branded fixed-dose combinations generally cost far more than their individual constituents. FDCs that combine metformin with other drugs are an exception, often costing the same as the non-metformin component. DISCUSSION: Patent extension tactics increase drug costs while providing little additional benefit to patients. Minor alterations in formulations or dosing may provide no clinical benefits. Many FDCs are expensive and fail to provide cost-justified improvements in clinical outcomes, compared to equivalent generic drugs that would save money while delivering an equal standard of care. Combining newer hypoglycemic drugs with metformin, a gold-standard, generic, inexpensive drug, does not appear to cost more than individual constituents but offers no clinical advantage over metformin alone. CONCLUSION: Evergreening tactics should be reined in, as they represent significant cost to the healthcare system and to patients. Physicians and other prescribers should avoid prescribing FDCs, or slightly tweaked "new" drugs. Patented drug combinations generate profit without innovation.

Pharmaceutical marketing: the example of drug samples.

Branded drug samples are one of the most important promotional tools that pharmaceutical manufactures employ. Pharmaceutical sales representatives ("drug reps") use samples to gain access to physicians and other prescribers. Sample provision is closely intertwined with visits by drug reps; detailing visits convince physicians to try new products, while sampling maintains the flow of prescriptions. Only drugs with the highest profit margins are sampled. Although physicians believe that samples save patients money, patients who receive samples have higher overall out-of-pocket costs. Most studies have found that patients in financial need are least likely to receive samples. Pharmaceutical marketers pitch samples as a low-risk way to deal with diagnostic uncertainty. In fact, there is no evidence that samples aid diagnosis. Sample availability may compromise patient safety by reducing compliance with guidelines and steering patients towards newer drugs, for which adverse effects have not been well-delineated. Although physicians believe that samples improve adherence for low-income patients, branded samples do not improve access or adherence Samples are not a charitable activity, but are instead a highly effective form of drug marketing. Sampling of branded drugs increase drug costs for everyone. Only a cohesive effort by clinicians, legislators and policymakers can end this practice. Evidence supports a ban on sample distribution of branded products.

Survey of opioid prescribing among dentists indicates need for more effective education regarding pain management.

BACKGROUND: Dentists commonly prescribe opioids and are the highest prescribers of opioids to patients 18 years and younger. Little is known about dentists' beliefs regarding opioids and other analgesics. METHODS: The authors conducted a national survey of dentists about their opioid prescribing habits, perceptions regarding opioid effectiveness, beliefs about patient behaviors, and relationships with drug and equipment manufacturers. RESULTS: The authors received 291 responses from 30 states and 2 territories and analyzed 269 completed surveys. Although 84% of respondents reported believing that nonsteroidal anti-inflammatory drug (NSAID)-acetaminophen combinations are equally as effective or more effective than opioids, 43% of respondents also reported regularly prescribing opioid medications. Of those who reported prescribing opioids, 9 of 10 reported they were less likely to prescribe opioids to adolescents aged 11 through 18 years, but only 48% reported they were less likely to prescribe opioids to young adults aged 19 through 25 years. One-half of those who reported prescribing opioids reported prescribing in amounts that would result in unused medication, and 69% reported having had patients divert or misuse opioids. Few dentists reported industry interactions. CONCLUSIONS: The continued prescription of opioids contradicts mounting evidence about the superiority of NSAIDs over opioids in dentistry. Continuing dental education, increased use of prescription drug monitoring programs, and the development of national guidelines are necessary to align clinical practice with current evidence. PRACTICAL IMPLICATIONS: Dentists should seek to minimize opioid prescribing and pill counts and instead opt for safer, more effective NSAID-acetaminophen combinations. Dentists also should refrain from prescribing opioids to patients younger than 25 years because of the high risk of experiencing addiction in this population.

Making the Case for Accelerated Withdrawal of Aducanumab.

The controversial approval in June 2021 by the Food and Drug Administration (FDA) of aducanumab (marketed as Aduhelm), Biogen's monoclonal antibody for patients with Alzheimer's disease, raises significant concerns for the dementia field and drug approval process, considering its lack of adequate evidence for clinical efficacy, safety issues, and cost. On 15 December 2021, an international group of clinicians, basic science experts, psychological and social science researchers, lay people with lived experience of dementia, and advocates for public health met to discuss making a recommendation for whether aducanumab's approval should be withdrawn. Attendees considered arguments both in favor of and in opposition to withdrawal and voted unanimously to recommend that the FDA withdraw its approval for aducanumab and to support the Right Care Alliance's filing of a formal Citizen Petition to this effect.

Promotional tone in reviews of menopausal hormone therapy after the Women's Health Initiative: an analysis of published articles.

BACKGROUND: Even after the Women's Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women's health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy. METHODS AND FINDINGS: We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ=0.57) and substantial agreement for promotional tone (κ=0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p=0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49-4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles. CONCLUSION: There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy.

Changing Pharmaceutical Industry Interaction in US Family Medicine Residencies: A CERA Study.

BACKGROUND: Pharmaceutical interaction in US residencies is common. This study explores the extent and type of learner interactions in US family medicine residencies with the pharmaceutical industry and compares interactions from 2008, 2013, and 2019. METHODS: We surveyed program directors of 628 family medicine residencies with 8 questions using the 2019 Council of Academic Family Medicine Educational Research Alliance Survey and compared the responses to 2008 and 2013 results. RESULTS: The survey response rate was 39%; 81% of responding residencies did not allow food or gifts, 86% did not allow drug samples, 84% did not allow industry to interact with medical students or residents, and 81% did not allow industry-sponsored residency activities. These numbers were statistically significantly higher than both 2008 and 2013. In 2019, 151 responding programs (64%) were pharma-free, that is, they answered "No" to all 4 questions about interactions. Pharma-free residencies were increased in 2019 compared with 26% in 2008% and 49% in 2013. University-based family medicine programs were more likely to be pharma-free. Only 21% of responding programs had a formal curriculum that explores the interaction between physicians and the pharmaceutical industry. Factors cited for decreasing interaction included: institutional policy, ethical concerns, faculty input, and local response to national legislation. CONCLUSIONS: Interaction between trainees in US family medicine residencies and the pharmaceutical industry continued to decrease. A changing national legislative landscape combined with institutional policies and concerns about industry influence on prescribing habits may be important factors driving the limiting of interactions.

Increase your Confidence in Opioid Prescribing: Marketing Messages in Continuing Medical Education Activities on ER/LA Opioids.

BACKGROUND: Overprescription of opioids has fueled an epidemic of addiction and overdose deaths. The FDA required manufacturers of extended-release/long-acting (ER/LA) opioids to fund continuing medical education (CME) on opioids as part of a Risk Evaluation and Mitigation Strategy (REMS). OBJECTIVES: We sought to determine whether industry-funded REMS on long-acting opioids were consistent with the FDA's goal to reduce serious, adverse outcomes resulting from inappropriate prescribing, misuse, and abuse. STUDY DESIGN: In 2018, we analyzed all internet-based REMS CME activities funded by the REMS Program Companies (RPC), a consortium of ER/LA opioid manufacturers. METHODS: We utilized systematic narrative thematic analysis, an inductive approach that allows for mapping of concepts and meanings across a body of data by identifying, recording, analyzing, and refining key narrative points, called "themes". Authors viewed all REMS activities multiple times. RESULTS: Ten themes were identified, all of which were at least somewhat incongruent with federal guidelines and their goals: 1. Chronic pain is a common, under-treated problem. 2.Chronic pain is a chronic disease.3.Opioids are an appropriate treatment for chronic pain. 4.LAs are more appropriate than immediate-release (IR) opioids for chronic pain. 5.Tolerance is normal, expected, and beneficial. 6. Opioid rotation" can maximize analgesia and minimize adverse effects.7. There is no population for whom opioids are absolutely contraindicated or inappropriate. 8. Screening and monitoring tools are effective for preventing opioid-related problems. 9. Opioid related adverse effects, such as respiratory depression and addiction, are due only to misuse and abuse. Addiction, overdose, and death are due to street drugs such as heroin and fentanyl, not prescription opioids.Themes and statements repeated in these activities were inconsistent with current medical knowledge, evidence-based federal guidelines, and FDA goals. LIMITATIONS: We evaluated only online, not live, CME. We also did not evaluate individual conflicts of interest of faculty. CONCLUSIONS: Industry-funded REMS-compliant CME on opioids contain messages that misrepresent scientific evidence and may foster overprescribing of opioids.

The haunting of medical journals: how ghostwriting sold "HRT".

Adriane Fugh-Berman examines documents unsealed in recent litigation to investigate how pharmaceutical companies promoted hormone therapy drugs, including the use of medical writing companies to produce ghostwritten manuscripts and place them into medical journals.

Marketing Messages in Continuing Medical Education (CME) Modules on Binge-Eating Disorder (BED).

BACKGROUND: In 2015, Vyvanse (lisdexamfetamine) became the first Food and Drug Administration (FDA)-approved treatment for binge-eating disorder (BED), a condition first recognized by the DSM-V in 2013. Because pharmaceutical companies use continuing medical education (CME) to help sell drugs, we explored possible bias in CME modules on BED. METHODS: We utilized a qualitative thematic analysis research approach to identify and classify patterns in CME activities focusing on BED. RESULTS: We identified 27 online CME activities on BED in 2015. All were funded by Shire, which manufactures lisdexamfetamine. Seven of 16 presenters disclosed financial ties with Shire. Twenty-nine slides recurred in at least 2 CME modules, and 12 slides were repeated in 5 or more modules. Diagnosis-related themes included: BED is a real, treatable disease; BED is highly prevalent but often missed; BED can occur in anyone; BED results in poor quality of life; many patients with BED are obese; and BED makes losing weight difficult. Treatment-related themes included: lisdexamfetamine is highly effective; topiramate is limited by substantial adverse effects; and other therapeutic options for BED are inferior to lisdexamfetamine because they do not cause weight loss. Although amphetamines can cause addiction, myocardial infarction, stroke, and death, no module mentioned these serious adverse effects. CONCLUSIONS: It seems that CME is being used to promote lisdexamfetamine for weight loss (a contraindicated use) and to highlight benefits of lisdexamfetamine while underplaying the risks.

Pharmaceutical Ethics and Grassroots Activism in the United States: A Social History Perspective.

Women's health activists laid the groundwork for passage of the law that created the U.S. Food and Drug Administration in 1906. The pharmaceutical and food industries fought regulatory reforms then and continue to do so now. We examine public health activism in the Progressive Era, the postwar era and the present day. The women's health movement began in the 1960s, and criticized both the pharmaceutical industry and the medical establishment. In the 1990s, patient advocacy groups began accepting industry funds; thousands of commercially-funded groups now dominate the advocacy landscape. As pharma funding became normalized, concerns arose regarding a) the lack of transparency and public accountability regarding funding, b) the distortion of groups' agendas, and c) the ability of pharma-funded groups to dominate the discourse and override less well-resourced patient and health advocacy groups. Although industry-funded groups argue that funding allows them to provide useful services, the trade-off in health risks, exorbitant prices and distorted information is far too high. Sincerity is beside the point; patients and the industry have differing interests when it comes to drug safety and efficacy, drug information and drug prices. A growing resistance movement is asserting the values of its activist predecessors and opposing the prevailing culture of pharma-funded advocacy.