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Denosumab (Prolia), for example, is often prescribed first-line for osteoporosis, but is no more effective than other osteoporosis drugs in preventing fractures and has a poor safety profile.6 For access to medicines, the gap between commercial pressures and health needs is widely recognised, with many lifesaving medicines not reaching those most in need, as occurred in the 1990s with human immunodeficiency virus (HIV) and/or acquired immune deficiency syndrome (AIDS) medicines, and recently with high-priced cancer medicines. A Spanish ISDB bulletin highlighted rofecoxib’s cardiovascular risks, referring to manipulation of the science, and was sued unsuccessfully by Merck.8 Similarly, although much has been done to improve clinical trial transparency, too often negative results remain hidden.9 Industry-sponsored continuing medical education has also been credited with fuelling the epidemic of opioid-related deaths in North America through inaccurate messages that newer opioids are nonaddictive, chronic pain is undertreated, and it is a ‘chronic disease’ for which long-term opioids use is appropriate.10 Commercial influence can also exaggerate drug benefits. A Cochrane systematic review found that industry-funded studies were 27% more likely (risk ratio [RR] 1.27; 95% confidence interval [CI] 1.17–1.37) to have efficacy results favourable to the tested products than non-industry-funded studies.11 Pharmaceutical industry influence has been called ‘the elephant in the room’ in medicine, omnipresent but never discussed, with around 60% of medical research globally funded by industry,12 most patient groups industry-funded,13 many doctors receiving industry payments14 and a strong influence on policy.15 What is the solution?

Between 1993 and 1998, the WHI randomized 16,608 women with an intact uterus to placebo or conjugated equine estrogen, 0.625 mg/day, combined with medroxyprogesterone, 2.5 mg/day, (to counter the risk of endometrial cancer) and randomized 10,739 women without a uterus to conjugated equine estrogen, 0.625 mg/day.14–16 Both arms of the WHI were stopped early (in 2002 and 2004) because of harm.15,16 Combined estrogen-progestin increased the risk of invasive breast cancer, pulmonary embolism, stroke, and a global index of harm.17 Estrogen-only treatment increased the risk of stroke but not breast cancer or pulmonary embolism.17 Menopausal hormone therapy use plummeted after the WHI results were reported, and breast cancer rates subsequently dropped dramatically in all countries with registries.18 The US Preventive Services Task Force report on hormone therapy for preventing chronic illness notes that combined menopausal hormone therapy is associated with 5 excess breast cancers per 1,000 women.19 Combined hormone therapy increased gallbladder disease and deaths from lung cancer and doubled the risk of probable dementia among women older than 65 years.20,21 Estrogen alone increased ovarian cancer incidence and mortality.22 Overall, the WHI found that an additional 1 in 500 women per year experienced serious harm with combined menopausal hormone therapy.15 The WHI study also found benefits of menopausal hormone therapy. Combined therapy reduced risks of hip fracture and endometrial cancer and slightly lowered the risk of diabetes.17,22,23 Estrogen alone decreased breast cancer incidence at 10- and 20-year follow-up and decreased fracture risk.17,24 Critics claim that women in the WHI were too old and too far from menopause, that harms occurred only in older women, and that the findings do not apply to current formulations.25 However, although the average age was 63 years, 8,833 (32%) of the 27,347 women randomized were in their 50s, making this the largest RCT of menopausal hormone therapy use among women in their 50s.25 Also, 7,135 (26%) of women were within 10 years of starting menopause.26 An analysis of outcomes in women aged 50 to 59 years found greater harm than benefit with combined and estrogen-only menopausal hormone therapy.17 Although younger women experienced fewer harms than older women, long-term use remained more harmful than beneficial. Menopausal hormone therapy is not recommended for long-term use or for chronic disease prevention because RCT evidence indicates that harms outweigh benefits (reduced risk of hip fracture and diabetes).17,20 The 2022 US Preventive Services Task Force statement on menopausal hormone therapy recommends against its use for primary prevention of chronic conditions because of a lack of net benefit.31 Menopause is a positive life experience for many women32 and should not be medicalized. ADRIANE FUGH-BERMAN, MD, Georgetown University Medical Center, Washington, District of Columbia BARBARA MINTZES, PhD, University of Sydney School of Pharmacy and Charles Perkins Centre, Faculty of Medicine and Health, New South Wales, Australia, and University of British Columbia School of Population and Public Health, Vancouver, Canada Author disclosure:

Semaglutide (▼Ozempic solution for injection, ▼Rybelsus tablets—Novo Nordisk) was initially granted market authorisation for the treatment of type 2 diabetes as an adjunct to diet and exercise. In 2021 and 2022, regulatory agencies in the USA and Europe licensed semaglutide (▼Wegovy solution for injection—Novo Nordisk) for the treatment of individuals who are obese, or overweight and who have at least one weight-related comorbidity. Manufacturer-sponsored randomised controlled trials have shown a loss of almost 12% of body weight over a 68-week period, however, once the medication is stopped people regain most of their pretreatment weight. Gastrointestinal adverse events occur commonly with semaglutide, and pancreatitis, diabetic retinopathy and severe allergic reactions have also been reported. Extensive hype in social and general media has resulted in increased demand for semaglutide leading to supply problems across the various licensed products including those used for treatment of diabetes. In the UK, the National Institute for Health and Care Excellence has recommended semaglutide as an option for weight management for a maximum treatment duration of 2 years. Further studies are underway to assess the effect of semaglutide on longer-term health benefits.

Background Systematic reviews, which assess the risk of bias in included studies, are increasingly used to develop environmental hazard assessments and public health guidelines. These research areas typically rely on evidence from human observational studies of exposures, yet there are currently no universally accepted standards for assessing risk of bias in such studies. The risk of bias in non-randomised studies of exposures (ROBINS-E) tool has been developed by building upon tools for risk of bias assessment of randomised trials, diagnostic test accuracy studies and observational studies of interventions. This paper reports our experience with the application of the ROBINS-E tool. Methods We applied ROBINS-E to 74 exposure studies (60 cohort studies, 14 case-control studies) in 3 areas: environmental risk, dietary exposure and drug harm. All investigators provided written feedback, and we documented verbal discussion of the tool. We inductively and iteratively classified the feedback into 7 themes based on commonalities and differences until all the feedback was accounted for in the themes. We present a description of each theme. Results We identified practical concerns with the premise that ROBINS-E is a structured comparison of the observational study being rated to the ‘ideal’ randomised controlled trial. ROBINS-E assesses 7 domains of bias, but relevant questions related to some critical sources of bias, such as exposure and funding source, are not assessed. ROBINS-E fails to discriminate between studies with a single risk of bias or multiple risks of bias. ROBINS-E is severely limited at determining whether confounders will bias study outcomes. The construct of co-exposures was difficult to distinguish from confounders. Applying ROBINS-E was time-consuming and confusing. Conclusions Our experience suggests that the ROBINS-E tool does not meet the need for an international standard for evaluating human observational studies for questions of harm relevant to public and environmental health. We propose that a simpler tool, based on empirical evidence of bias, would provide accurate measures of risk of bias and is more likely to meet the needs of the environmental and public health community.

Assessing the process used to synthesize the evidence in clinical practice guidelines enables users to determine the trustworthiness of the recommendations. Clinicians are increasingly dependent on guidelines to keep up with vast quantities of medical literature, and guidelines are followed to avoid malpractice suits. We aimed to assess whether systematic methods were used when synthesizing the evidence for guidelines; and to determine the type of review cited in support of recommendations. Guidelines published in 2017 and 2018 were retrieved from the TRIP and Epistemonikos databases. We randomly sorted and sequentially screened clinical guidelines on all topics to select the first 50 that met our inclusion criteria. Our primary outcomes were the number of guidelines using either a systematic or non-systematic process to gather, assess, and synthesise evidence; and the numbers of recommendations within guidelines based on different types of evidence synthesis (systematic or non-systematic reviews). If a review was cited, we looked for evidence that it was critically appraised, and recorded which quality assessment tool was used. Finally, we examined the relation between the use of the GRADE approach, systematic review process, and type of funder. Of the 50 guidelines, 17 (34%) systematically synthesised the evidence to inform recommendations. These 17 guidelines clearly reported their objectives and eligibility criteria, conducted comprehensive search strategies, and assessed the quality of the studies. Of the 29/50 guidelines that included reviews, 6 (21%) assessed the risk of bias of the review. The quality of primary studies was reported in 30/50 (60%) guidelines. High quality, systematic review products provide the best available evidence to inform guideline recommendations. Using non-systematic methods compromises the validity and reliability of the evidence used to inform guideline recommendations, leading to potentially misleading and untrustworthy results.

Many factors contribute to the inappropriate use of medicines, including not only a lack of information but also inaccurate and misleading promotional information. This review examines how the promotion of pharmaceuticals directly affects the prescribing and use of medicines. We define promotion broadly as all actions taken directly by pharmaceutical companies with the aim of enhancing product sales. We look in greater detail at promotion techniques aimed at prescribers, such as sales representatives, pharmaceutical advertisements in medical journals and use of key opinion leaders, along with the quality of information provided and the effects thereof. We also discuss promotion to the public, through direct-to-consumer advertising, and its effects. Finally, we consider initiatives to regulate promotion that come from industry, government and nongovernmental organizations.

BackgroundNo previous review has assessed the extent and effect of industry interactions on medical oncologists and haematologists specifically.MethodsA systematic review investigated interactions with the pharmaceutical industry and how these might affect the clinical practice, knowledge and beliefs of cancer physicians. MEDLINE, Embase, PsycINFO and Web of Science Core Collection databases were searched from inception to February 2021.ResultsTwenty-nine cross-sectional and two cohort studies met the inclusion criteria. These were classified into three categories of investigation: (1) extent of exposure to industry for cancer physicians as whole (n = 11); (2) financial ties among influential cancer physicians specifically (n = 11) and (3) associations between industry exposure and prescribing (n = 9). Cancer physicians frequently receive payments from or maintain financial ties with industry, at a prevalence of up to 63% in the United States (US) and 70.6% in Japan. Among influential clinicians, 86% of US and 78% of Japanese oncology guidelines authors receive payments. Payments were associated with either a neutral or negative influence on the quality of prescribing practice. Limited evidence suggests oncologists believe education by industry could lead to unconscious bias.ConclusionsThere is substantial evidence of frequent relationships between cancer physicians and the pharmaceutical industry in a range of high-income countries. More research is needed on clinical implications for patients and better management of these relationships.RegistrationPROSPERO identification number CRD42020143353.

Kim's overview of Food and Drug Administration (FDA) regulatory actions from 2005 to 2014 is a comprehensive analysis of the US regulatory experience with online direct-to-consumer advertising (DTCA) of prescription medicines. This experience is of relevance internationally as online DTCA reaches the English-speaking public globally, despite the illegality of DTCA in most countries. The most common violations were omissions or minimizations of risk information, overstatements of efficacy, unsubstantiated claims, and promotion of unapproved (\"off-label\") use. Nearly one fourth of violations involved cancer drugs, raising additional concerns about patient vulnerability, limited treatment advance, and high costs. Based on content analyses of online DTCA, these cases likely reflect a small proportion of unbalanced and misleading promotional information available on the web. The FDA is only able to review a small proportion of promotional materials submitted to them, due to limited staffing, and the delay between first posting and regulatory action means that many people may be exposed to messages that are found to be inaccurate and misleading. The sheer volume of online DTCA, combined with the ability for content to shift continually, poses unique regulatory challenges.

Background Each year, the French independent bulletin Prescrire publishes a list of medicines, “Drugs to avoid”, that should not be used in clinical practice as their risk-to-benefit ratio is unfavourable. This study assessed the market approval, reimbursement and use of these medicines in Australia. Methods The approval status of the medicines included in 2019 Prescrire “Drugs to avoid” list was assessed by searching the Australian Register of Therapeutic Goods website. Funding status was assessed on the Pharmaceutical Benefits Scheme (PBS) website, the Australian public insurance system. Use levels were determined by examining governmental reports on prescribing rates including the Australian Statistics on Medicines (ASM) reports, drug use reports released by the Drug Utilisation Sub Committee (DUSC) and PBS statistics. Results Of the 93 medicines included in the Prescrire 2019 “Drug to avoid” list included, 57 (61%) were approved in Australia in 2019 including 9 (16%) that were sold as over-the-counter medicines, 35 (38%) were listed on the PBS, 22 (24%) were registered but not listed on the PBS. Although most of these medicines were used infrequently, 16 (46%) had substantial use despite serious safety concerns. Dipeptidyl peptidase-4 (DPP-4) inhibitors were used by 22% of patients receiving a treatment for diabetes in 2016. More than 50,000 patients received an anti-dementia medicine in 2014, a 19% increase since 2009. Denosumab became the 8th medicine, in terms of total sales, funded by the Australian Government in 2017–2018. Conclusions Prescrire ’s assessments provide a reliable external benchmark to assess the current use of medicines in Australia. Sixteen “drugs to avoid”, judged to be more harmful than beneficial based on systematic, independent evidence reviews, are in substantial use in Australia. These results raise serious concerns about the awareness of Australian clinicians of medicine safety and efficacy. Medicines safety has become an Australian National Health Priority. Regulatory and reimbursement agencies should review the marketing and funding status of medicines which have not been shown to provide an efficacy and safety at least similar to alternative therapeutic options.

Most regulatory agencies, says Mintzes, fail to treat regulation of drug promotion as a public health concern. Unless this changes, she says, the public can expect more unfettered disease mongering.