Availability and Cost of Expensive and Common Generic Prescription Drugs: A Cross-sectional Analysis of Direct-to-Consumer Pharmacies.

BACKGROUND: Direct-to-consumer (DTC) pharmacies sell generic prescription drugs, often at lower prices than traditional retail pharmacies; however, not all drugs are available, and prices vary. OBJECTIVE: To determine the availability and cost of generic drugs at DTC pharmacies. DESIGN: Cross-sectional study. SETTING: Five national DTC pharmacies in April and May 2023. PARTICIPANTS: Each qualifying form of 100 generic drugs with the highest cost-per-patient (expensive) and the 50 generic drugs with the highest number of patients (common) in Medicare Part D in 2020 MAIN MEASURES: Availability of these drugs and the lowest DTC pharmacy price for a standardized drug strength and supply (e.g., 30 pills), compared to GoodRx retail pharmacy prices. KEY RESULTS: Of the 118 expensive generic dosage forms, 94 (80%) were available at 1 or more DTC pharmacies; out of 52 common generic dosage forms, 51 (98%) were available (p < 0.001). Of the 88 expensive generics available in comparable quantities and strengths across pharmacies, 42 (47%) had the lowest cost at Amazon, 23 (26%) at Mark Cuban Cost Plus Drug Company, 13 (14%) at Health Warehouse, and 12 (13%) at Costco; for 51 common generic formulations, 16 (31%) had the lowest cost at Costco, 14 (27%) at Amazon, 10 (20%) at Walmart, 6 (12%) at Health Warehouse, and 5 (10%) at Mark Cuban Cost Plus Drug Company. For the 77 expensive generics with available GoodRx retail pharmacy prices, the median cost savings at DTC pharmacies were $231 (95% CI, $129-$792) or 76% (IQR, 53-91%); for 51 common generics, savings were $19 (95% CI, $10-$34) or 75% (IQR, 67-83%). CONCLUSIONS: Many of the most expensive generic drugs are unavailable at direct-to-consumer pharmacies. Meanwhile, less expensive, commonly used generics are widely available, but drug prices vary by pharmacy and savings are modest, requiring patients to shop around for the lowest cost.

Inhibition of RAF dimers: it takes two to tango.

The RAS-regulated RAF-MEK1/2-ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I½ RAF inhibitors. Binding of type I or I½ RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed "paradox breakers" which interrupt BRAF dimerisation through disruption of the αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins.

Revision of Unicompartmental to Total Knee Arthroplasty: Does the Unicompartmental Implant (Metal-Backed vs All-Polyethylene) Impact the Total Knee Arthroplasty?

BACKGROUND: The aim of this study is to investigate differences in implant requirement, outcomes, and re-revision when total knee arthroplasty (TKA) was performed following unicompartmental knee arthroplasties (UKAs) with metal-backed (MB) compared to all-polyethylene (AP) tibial components. METHODS: Retrospective study of 60 UKAs converted to 60 TKAs at mean 7.3 years (0.1 to 17) after implantation in 55 patients (mean age, 64 [49-83]; 44% male): 44 MB and 16 AP. TKA implant requirement was investigated in addition to mode of failure, Oxford Knee Score, and TKA survival at mean 5.4 years (0.5 to 17). RESULTS: Progression of osteoarthritis was the commonest mode of failure in MB UKAs (P = .03) and unexplained pain in AP (P = .011) where revisions were performed earlier (4.8 ± 3.2 vs 8.2 ± 4.5, P = .012). In 56 of 60 (93%) cases, unconstrained TKA implants were used. The use of standard cruciate-retaining TKAs without augments or stems was less likely following MB UKA compared to AP (12 of 38 [32%] vs 10/14 [71%], P = .013). Specifically MB UKA implants were associated with more tibial stem use (P = .04) and more use of cruciate-substituting polyethylene (P = .05). There was no difference in the use of constrained implants. Multivariate analysis showed tibial resection depth to predict stem requirement. Seven were re-revised giving 7-year TKA survival: from MB UKA 70.3 (95% CI, 47.0 to 93.6) and from AP UKA 87.5 (95% CI, 64.6 to 100; P = .191). CONCLUSION: MB UKA implants increase the chances of a complex revision requiring tibial stems and cruciate substitution but reduce the chances of early revision compared to AP UKA which often fail early with pain.

Ten-year survival and patient-reported outcomes of a medial unicompartmental knee arthroplasty incorporating an all-polyethylene tibial component.

INTRODUCTION: Biomechanical studies have suggested that proximal tibial strain is elevated in UKAs incorporating all-polyethylene tibial components with concern that this leads to premature failure. This study reports minimum 10-year outcomes for a UKA incorporating an all-polyethylene tibial component to determine whether these concerns were realised. MATERIALS AND METHODS: 109 fixed bearing UKAs (97 patients, mean age 68 (range 48-87), 54/97 (56%) female) with all-polyethylene tibial components were followed up for ≥ 10 years with Oxford Knee Scores, Forgotten Joint Scores and Kaplan-Meier analysis. 106/109 implants were 7 mm, 3 were 9.5 mm. RESULTS: Ten-year survival was 85.5% (78.6-92.4 95% CI) with the end-point failure for any reason. Unexplained pain was the commonest mode of failure (6/17) followed by lateral compartment osteoarthritis (5/17) and tibial subsidence/loosening (4/17). Revision rate was highest at 2-5 years due to revisions for unexplained pain. Ten-year survival was worse in patients < 65 years old (p = 0.035), in those with BMI > 30 (p = 0.017) and in those with postoperative increases in medial tibial sclerosis (p < 0.001 log-rank). Implant malalignment was not significantly associated with failure. Radioisotope bone scans in 16 patients all remained "hot" at mean 6.1 years (range 2.1-11.5). Relative risk of failure in patients < 65 years was 2.9 (1.2-7.0 95% CI) and when BMI > 30 was 2.9 (1.2-6.9 95% CI). In those with intact UKAs at 10 years, mean Oxford Knee Score was 34.8 ± 10.7, Forgotten Joint Score was 37.9 ± 26.7 and 96% were satisfied with their knee. CONCLUSION: The high rate of early failure between 2 and 5 years in this all-polyethylene tibial component UKA did not persist in the long term. Though medial proximal tibial metabolic changes appear to persist they are not necessarily symptomatic. BMI > 30 and age < 65 years were significant risk factors for revision.

Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine.

A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine.

Changes in Bone Density in Metal-Backed and All-Polyethylene Medial Unicompartmental Knee Arthroplasty.

BACKGROUND: Proximal tibial strain in medial unicompartmental knee arthroplasty (UKA) may alter bone mineral density and cause pain. The aims of this retrospective cohort study were to quantify and compare changes in proximal tibial bone mineral density in metal-backed and all-polyethylene medial UKAs, correlating these with outcome, particularly ongoing pain. METHODS: Radiographs of 173 metal-backed and 82 all-polyethylene UKAs were analyzed using digital radiograph densitometry at 0, 1, 2, and 5 years. The mean grayscale of 4 proximal tibial regions was measured and converted to a ratio: the GSRb (grayscale ratio b), where GSRb>1 represents relative medial sclerosis. RESULTS: In both implants, GSRb reduced significantly to 1 year and stabilized with no differences between implants. Subgroup analysis showed less improvement in Oxford Knee Score in patients whose GSRb increased by more than 10% at 1 year (40/255) compared with patients whose GSRb reduced by more than 10% at both 1 years (8.2 vs 15.8, P=.002) and 5 years (9.6 vs 15.8, P=.022). Patients with persistently painful UKAs (17/255) showed no reduction in GSRb at 1 year compared with a 20% reduction in those without pain (P=.05). CONCLUSIONS: Bone mineral density changes under medial UKAs are independent of metal backing. Medial sclerosis appears to be associated with ongoing pain.

Trabecular Metal Use in Paprosky Type 2 and 3 Acetabular Defects: 5-Year Follow-Up.

BACKGROUND: The reconstructive challenge of achieving a stable acetabulum in revision total hip arthroplasties in the presence of major osteolytic lesions has led to debate about the most appropriate surgical strategy to minimize implant-related failures. Trabecular metal (TM) implants have become popular but ongoing surveillance of their performance is required. METHODS: We reviewed the clinical and radiological outcome of a consecutive series of 52 patients (55 hips) who had undergone revision total hip arthroplasty for Paprosky type 2 or 3 acetabular defects with TM revision acetabular shells between 2002 and 2008. RESULTS: Four implant failures occurred (2 infections and 2 dislocations). Eleven patients from this cohort died (representing 12 hips) before the 5-year follow-up period giving us a follow-up of 78.2%. Implant survival at 5 years was 92% (95% confidence interval: 80.2%-96.9%). There were no cases of radiological loosening. The mean Oxford hip score was 34 (range, 5-48) at a mean follow-up of 63 months (range, 34-105 months). CONCLUSIONS: We conclude that the use of TM revision shells for complex acetabular reconstruction yields satisfactory results.

Low-Power Fully Integrated 256-Channel Nanowire Electrode-on-Chip Neural Interface for Intracellular Electrophysiology.

Intracellular electrophysiology, a vital and versatile technique in cellular neuroscience, is typically conducted using the patch-clamp method. Despite its effectiveness, this method poses challenges due to its complexity and low throughput. The pursuit of multi-channel parallel neural intracellular recording has been a long-standing goal, yet achieving reliable and consistent scaling has been elusive because of several technological barriers. In this work, we introduce a micropower integrated circuit, optimized for scalable, high-throughput in vitro intrinsically intracellular electrophysiology. This system is capable of simultaneous recording and stimulation, implementing all essential functions such as signal amplification, acquisition, and control, with a direct interface to electrodes integrated on the chip. The electrophysiology system-on-chip (eSoC), fabricated in 180nm CMOS, measures 2.236 mm × 2.236 mm. It contains four 8 × 8 arrays of nanowire electrodes, each with a 50 µm pitch, placed over the top-metal layer on the chip surface, totaling 256 channels. Each channel has a power consumption of 0.47 µW, suitable for current stimulation and voltage recording, and covers 80 dB adjustable range at a sampling rate of 25 kHz. Experimental recordings with the eSoC from cultured neurons in vitro validate its functionality in accurately resolving chemically induced multi-unit intracellular electrical activity.

Federal Funding For Discovery And Development Of Costly HIV Drugs Was Far More Than Previously Estimated.

In July 2012, tenofovir disoproxil fumarate-emtricitabine (TDF-FTC, brand name Truvada) was approved by the Food and Drug Administration (FDA) to prevent HIV infection. To estimate the extent of the US government's direct financial contribution to the discovery and development of Truvada, we identified National Institutes of Health awards using FDA documents, peer-reviewed literature, patent records, court filings, and other publicly available materials. We classified seventy-three federal government awards to eleven researchers as being directly linked to the development and clinical testing of Truvada for prevention therapy, through which the US government spent an estimated $143 million. The substantial public funding raises questions about the high price charged by the drug's manufacturer, which reduced its affordability and limited its accessibility as HIV preventive therapy.

High Cost of Chimeric Antigen Receptor T-Cells: Challenges and Solutions.

Chimeric antigen receptor (CAR) T-cells are a cellular immunotherapy with remarkable efficacy in treating multiple hematologic malignancies but they are associated with extremely high prices that are, for many countries, prohibitively expensive. As their use increases both for hematologic malignancies and other indications, and large numbers of new cellular therapies are developed, novel approaches will be needed both to reduce the cost of therapy, and to pay for them. We review the many factors that lead to the high cost of CAR T-cells and offer proposals for reform.

High-Priced Sickle Cell Gene Therapies Threaten to Exacerbate US Health Disparities and Establish New Pricing Precedents for Molecular Medicine.

Gene therapies to treat sickle cell disease are in development and are expected to have high costs. The large eligible population size - by far, the largest for a gene therapy - poses daunting budget challenges and threatens to exacerbate health disparities for Black patients, who make up the vast majority of American sickle cell patients.

Sickle cell trait and multisystem trauma: an unaddressed urgent knowledge gap.

Sickle cell trait (SCT) has historically been considered a benign condition, but SCT-positive patients have increased baseline risk of venous thromboembolism and chronic kidney disease, as well as increased risk of sickled erythrocytes in settings of hypoxia, acidosis, and hypovolemia. Multisystem traumatic injuries are a common clinical scenario, in which hypoxia, acidosis, and hypovolemia occur; however, little is known about how SCT-positive status impacts outcomes in multisystem trauma. We conducted a scoping literature review to investigate what was known about SCT in the setting of multisystem trauma. In the 110+ years that sickle cell hemoglobinopathies have been known, only three studies have ever examined the relationship between SCT and multisystem traumas. All three articles were case reports. None of the articles intentionally measured the association between SCT and multisystem trauma outcomes; they only incidentally captured information on SCT. Our article then examines historical reasons why so little research has studied the pathophysiology of the multisystem trauma in patients with SCT. Among the reasons is that historical and logistical factors have long prevented patients from knowing their SCT-status: historical discriminations against SCT-positive patients in the 1960s and 1970s delayed federal mandating of SCT newborn screening until 2006, whereas difficulties communicating known SCT-status to afflicted children also contributed to lack of patient knowledge. In light of our findings, we offer specific calls to action for the trauma surgery research community: (1) consider testing for SCT in trauma patients that have unexpected complications, particularly venous thromboembolism, rhabdomyolysis, or renal failure and (2) support research to understand how SCT impacts multisystem trauma outcomes. We also offer specific guidelines about how to 'proceed with caution' in implementation of these goals in light of the troubled history of SCT testing and policy in the USA.

Public funding for transformative drugs: the case of sofosbuvir.

The approval of sofosbuvir (Sovaldi) in 2013 transformed chronic hepatitis C virus (HCV) care, but its high cost was criticized in part because of reports of substantial public involvement in its development. We developed a methodology to assess the public's contribution through the National Institutes of Health (NIH) in developing sofosbuvir. Using key terms from the timeline of sofosbuvir, we identified articles in PubMed; linked them to federal funding using the NIH RePORTER; reviewed the title, organization, and investigator of each resulting award for relatedness; and converted related awards to 2018 US dollars. Of 6043 unique awards, we identified 29 that were directly (US$7.7 million) and 110 that were indirectly (US$53.2 million) related awards made to major academic institutions and companies engaged in the development of the drug. These findings indicate that public funding had a key role in developing sofosbuvir, with an estimated US$60.9 million provided in NIH funding.

Diabetes Drugs: List Price Increases Were Not Always Reflected In Net Price; Impact Of Brand Competition Unclear.

List prices for brand-name drugs have risen steeply, often despite the introduction of competition from other brand-name drugs in the same therapeutic class. List prices, however, do not reflect any rebates that manufacturers provide payers. To understand how net prices (after rebates and other discounts) respond to competition, we compared changes in inflation-adjusted, revenue-weighted mean list and net prices of a one-month supply of three classes of diabetes drugs: glucagon-like peptide 1 (GLP1) agonists, dipeptidyl peptidase 4 (DPP4) inhibitors, and sodium glucose cotransporter 2 (SGLT2) inhibitors. These drug classes each had several brand-name products enter the market between 2005 and 2017. The annualized change in list price over this period was $75 (15 percent) for GLP1 agonists, $22 (8 percent) for DPP4 inhibitors, and $41 (11 percent) for SGLT2 inhibitors. In contrast, the annualized change in net price was $38 (10 percent) for GLP1 agonists, -$3 (-2 percent) for DPP4 inhibitors, and -$17 (-9 percent) for SGLT2 inhibitors, suggesting a variable impact of brand-name competition on net prices.

Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program.

INTRODUCTION: Risk evaluation and mitigation strategy (REMS) programs are intended to improve safe use of US Food and Drug Administration-approved drugs. However, controversy exists over whether they consistently accomplish this goal. OBJECTIVE: We aimed to assess how initiation of the erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin alfa changed following implementation and enforcement (following a 1-year post-implementation grace period) of a prominent REMS program warning physicians against use in cancer patients with hemoglobin above 10 g/dL. METHODS: Using claims data from a large US commercial insurance company, we conducted interrupted time-series analyses of darbepoetin alfa and epoetin alfa initiation among adult cancer patients in the 12 months before REMS program implementation, after REMS program implementation, and after REMS program enforcement. We also evaluated differences in inappropriate initiation (hemoglobin tests all above 10 g/dL in the prior month) between the periods. RESULTS: In total, we identified 3456 darbepoetin alfa initiators and 2632 epoetin alfa initiators. Over the study period, the monthly number of initiators per 100,000 patients with cancer fell from 119 to 32 for darbepoetin alfa and from 82 to 34 for epoetin alfa. However, non-significant post-REMS program implementation level and slope changes per 100,000 adult patients with cancer were observed for darbepoetin alfa (level 0.03 [95% confidence interval (CI) -14.98 to 15.05]; slope 1.94 [95% CI -0.22 to 4.10]) and epoetin alfa (level -4.10 [95% CI -16.85 to 8.65]; slope -0.52 [95% CI -2.35 to 1.32]). Non-significant post-REMS program enforcement level and slope changes were also seen for both drugs (darbepoetin alfa level 1.58 [95% CI -0.58 to 3.74, slope -0.28 [95% CI -15.29 to 14.73]; epoetin alfa level 1.58 (95% CI -0.26 to 3.42], slope 5.74 [95% CI -7.01 to 18.49]). Finally, non-significant changes in inappropriate darbepoetin alfa (60% vs. 53% vs. 57%, p = 0.68) and epoetin alfa (53% vs. 53% vs. 46%, p = 0.41) initiation were observed between the three study periods. CONCLUSION: REMS program implementation and enforcement were not associated with significant changes in ESA initiation, adding to concerns over the degree to which certain REMS programs enhance patient safety.

US Spending Associated With Transition From Daily to 3-Times-Weekly Glatiramer Acetate.

Importance: Market exclusivity for daily injections of glatiramer acetate, a disease-modifying therapy for multiple sclerosis, expired in 2015. In 2014, the manufacturer launched an alternate 3-times-weekly version that was widely adopted, sustaining market dominance of brand-name glatiramer until late 2017. Objective: To estimate excess US spending associated with the transition from daily to 3-times-weekly glatiramer. Design, Setting, and Participants: This economic evaluation estimated total US glatiramer spending from January 1, 2011, to June 30, 2019, using a national cohort from 3 data sources that collectively represent approximately 40% of the US glatiramer market: Medicare Part D, Medicaid, and a claims database of commercially insured and Medicare Advantage patients. Exposures: Calendar quarter. Main Outcomes and Measures: Outcomes were quarterly US glatiramer spending, estimated as price × use. Manufacturer list prices for generic products and estimates of net (postrebate) prices for brand-name products were used. Linear regression and interrupted time series models were used to compare spending trends in 3 periods: before generic competition (2011-2015), during generic competition for daily glatiramer (2015-2017), and during generic competition for daily and 3-times-weekly glatiramer (2017-2019). Results: From 2011 to 2015, US glatiramer spending increased to $962 million per quarter and did not decrease with generic competition of only daily glatiramer (2015-2017). After generic competition began for 3-times-weekly glatiramer in 2017, prices decreased by 47% to 64%, and spending decreased to $508 million per quarter in 2019 (P < .001 for slope). The delay in decreased spending from 2015 to 2017 was associated with excess spending of $4.3 billion to $6.5 billion. Conclusions and Relevance: These findings suggest that 2.5 years of delayed generic competition related to introduction of a new version of branded glatiramer acetate was associated with $4.3 billion to $6.5 billion in excess spending. Extended market exclusivity from introducing a new version of an existing brand-name drug can yield manufacturer returns out of proportion to the level of investment or risk involved; more limited incentives could encourage incremental innovations to existing drugs at a lower societal cost.

Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients.

A reduction in 5-hydroxyindoleacetic acid in cerebrospinal fluid was found in depressed and manic patients both while they were symptomatic and also after treatment. The concentration of homovanillic acid was initially reduced and then tended to increase after treatment.

Assessing the Justification, Funding, Success, and Survival Outcomes of Randomized Noninferiority Trials of Cancer Drugs: A Systematic Review and Pooled Analysis.

Importance: Noninferiority trials test whether a new intervention is not worse than the comparator by a given margin. Objectives: To study the characteristics of published randomized noninferiority trials in oncology with overall survival as an end point, to assess the association of justification and success in achieving noninferiority with the funding of these trials, and to evaluate the association of such trials with patient survival. Data Sources: A systematic search of PubMed and Google Scholar databases was conducted in March 2018, with no date restrictions. Study Selection: Randomized noninferiority trials of cancer drug therapies with overall survival as an end point were included. Trials of decision support, supportive care, and nondrug treatment in both arms were excluded. Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for meta-epidemiological studies. Studies were screened for eligibility criteria, and data on criteria for noninferiority, funding, success (achieving noninferiority), and hazard ratios with confidence intervals for overall survival were extracted. Hazard ratios for overall survival were pooled across trials using a random-effects model. Main Outcomes and Measures: Associations of the justification for using a noninferiority design and success in achieving noninferiority with the source of funding were assessed. Overall pooled hazard ratios and confidence intervals for overall survival were calculated. Results: Among 74 noninferiority trials of cancer drug therapies, 23 (31%; enrolling 21 437 patients) used overall survival as the primary end point. The noninferiority margins for the hazard ratio of overall survival ranged from 1.08 to 1.33. Noninferiority design was justified in 14 trials (61%) but not in 9 (39%). Overall, 18 trials (78%) concluded with a finding of noninferiority. Industry funding was associated with lack of justification for noninferiority design (P = .02, assessed using the Fisher exact test) but not with success in proving noninferiority (P = .80, assessed using the Fisher exact test). When the hazard ratios across the trials were pooled, there was no beneficial or detrimental association with overall survival, with a pooled hazard ratio of 0.97 (95% CI, 0.92-1.02). Conclusions and Relevance: The findings suggest that a substantial fraction of noninferiority trials in oncology, most of which are industry funded, lack justification for such a design. Greater attention to the use of noninferiority designs in randomized clinical trials of cancer drugs from local and national regulators is warranted.

Randomized Study of Providing Evidence Context to Mitigate Physician Misinterpretation Arising From Off-Label Drug Promotion.

BACKGROUND: Recent court decisions have thrown into question the Food and Drug Administration's rules limiting manufacturer promotion of prescription drugs for unapproved uses. We assessed how providing pro forma disclosures or more descriptive evidence context about the data supporting an off-label claim affected physicians' beliefs about drug efficacy. METHODS AND RESULTS: In online and mailed surveys, we randomized national samples of board-certified, clinically active cardiologists, internists, and endocrinologists to receive 1 of 3 information scenarios about a hypothetical drug derived verbatim from excerpts on the website for Vascepa, a prescription fish oil for which Food and Drug Administration specially permitted off-label promotion after a manufacturer lawsuit. The scenarios presented information about the approved on-label indication (severe hypertriglyceridemia), off-label claim + pro forma disclaimers (suggestive but not conclusive evidence for use as an add-on to a statin for patients reaching low-density lipoprotein goal but with persistent moderate hypertriglyceridemia), and off-label claim + evidence context (eg, reports on 3 trials failing to demonstrate cardiovascular benefit of other triglyceride-lowering drugs for such patients). Among 686 respondents (48% response rate), 29% reported receiving off-label information about Vascepa (ie, use as an add-on to a statin) from the manufacturer, and 16% had prescribed it off-label for this purpose. Off-label prescribing was 5 times higher among physicians who received such off-label information (38% versus 7%, P<0.001). For the hypothetical drug, the proportion of physicians endorsing the unproven claim that the drug reduced cardiovascular risk was similar among those randomized to the on-label and off-label claim + pro forma disclaimers scenarios (35% versus 37% [95% CI, -6% to 11%]), but substantially lower among those randomized to the off-label claim + evidence context scenario (21% [95% CI, -24% to 7%]). CONCLUSIONS: Physicians who received company information about the unapproved use of Vascepa were more likely to report prescribing it off-label. Supplementing off-label claims with evidence context improved the prescribers' knowledge and reduced enthusiasm for the unproven, off-label indication of reducing cardiovascular risk.