Author: Jackie Werner

Hot Topics: Many Drugs Face Safety Issues After FDA Approval

Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010

Downing NS, Shah ND, Aminawung JA, et al. Postmarket safety events among novel therapeutics approved by the US food and drug administration between 2001 and 2010. JAMA. 2017;317(18):1854-1863. doi: 10.1001/jama.2017.5150.

Importance  Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.

Objectives  To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk.

Design and Setting  Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.

Exposures  Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time.

Main Outcomes and Measures  A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications.

Results  From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02).

Conclusions and Relevance  Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.

Posted in Front Page, Hot Topics in Research, Pharmaceutical Sciences

Hot Topics: Severe Epilepsy Eased by Compound in Cannabis

Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. N Engl J Med. 2017;376(21):2011-2020.


The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.


In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.


The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsiveseizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.


Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; number, NCT02091375.)

Posted in Front Page, Hot Topics in Research, Neurology

Hot Topics: Steroid Shots Ineffective For Arthritic Knee Pain

Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial

McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA. 2017;317(19):1967-1975.

Importance  Synovitis is common and is associated with progression of structural characteristics of knee osteoarthritis. Intra-articular corticosteroids could reduce cartilage damage associated with synovitis but might have adverse effects on cartilage and periarticular bone.

Objective  To determine the effects of intra-articular injection of 40 mg of triamcinolone acetonide every 3 months on progression of cartilage loss and knee pain.

Design, Setting, and Participants  Two-year, randomized, placebo-controlled, double-blind trial of intra-articular triamcinolone vs saline for symptomatic knee osteoarthritis with ultrasonic features of synovitis in 140 patients. Mixed-effects regression models with a random intercept were used to analyze the longitudinal repeated outcome measures. Patients fulfilling the American College of Rheumatology criteria for symptomatic knee osteoarthritis, Kellgren-Lawrence grades 2 or 3, were enrolled at Tufts Medical Center beginning February 11, 2013; all patients completed the study by January 1, 2015.

Interventions  Intra-articular triamcinolone (n = 70) or saline (n = 70) every 12 weeks for 2 years.

Main Outcomes and Measures  Annual knee magnetic resonance imaging for quantitative evaluation of cartilage volume (minimal clinically important difference not yet defined), and Western Ontario and McMaster Universities Osteoarthritis index collected every 3 months (Likert pain subscale range, 0 [no pain] to 20 [extreme pain]; minimal clinically important improvement, 3.94).

Results  Among 140 randomized patients (mean age, 58 [SD, 8] years, 75 women [54%]), 119 (85%) completed the study. Intra-articular triamcinolone resulted in significantly greater cartilage volume loss than did saline for a mean change in index compartment cartilage thickness of −0.21 mm vs −0.10 mm (between-group difference, −0.11 mm; 95% CI, −0.20 to −0.03 mm); and no significant difference in pain (−1.2 vs −1.9; between-group difference, −0.6; 95% CI, −1.6 to 0.3). The saline group had 3 treatment-related adverse events compared with 5 in the triamcinolone group and had a small increase in hemoglobin A1c levels (between-group difference, −0.2%; 95% CI, −0.5% to −0.007%).

Conclusions and Relevance  Among patients with symptomatic knee osteoarthritis, 2 years of intra-articular triamcinolone, compared with intra-articular saline, resulted in significantly greater cartilage volume loss and no significant difference in knee pain. These findings do not support this treatment for patients with symptomatic knee osteoarthritis.

Posted in Geriatrics, Hot Topics in Research, Rheumatology

Hot Topics: Marketing Restrictions Change Prescribing Patterns

Association Between Academic Medical Center Pharmaceutical Detailing Policies and Physician Prescribing

Larkin I, Ang D, Steinhart J, Chao M, Patterson M, Sah S, Wu T, Schoenbaum M, Hutchins D, Brennan T, Loewenstein G. Association Between Academic Medical Center Pharmaceutical Detailing Policies and Physician Prescribing. JAMA. 2017;317(17):1785-1795. doi:10.1001/jama.2017.4039

Importance  In an effort to regulate physician conflicts of interest, some US academic medical centers (AMCs) enacted policies restricting pharmaceutical representative sales visits to physicians (known as detailing) between 2006 and 2012. Little is known about the effect of these policies on physician prescribing.

Objective  To analyze the association between detailing policies enacted at AMCs and physician prescribing of actively detailed and not detailed drugs.

Design, Setting, and Participants  The study used a difference-in-differences multivariable regression analysis to compare changes in prescribing by physicians before and after implementation of detailing policies at AMCs in 5 states (California, Illinois, Massachusetts, Pennsylvania, and New York) that made up the intervention group with changes in prescribing by a matched control group of similar physicians not subject to a detailing policy.

Exposures  Academic medical center implementation of policies regulating pharmaceutical salesperson visits to attending physicians.

Main Outcomes and Measures  The monthly within-drug class market share of prescriptions written by an individual physician for detailed and nondetailed drugs in 8 drug classes (lipid-lowering drugs, gastroesophageal reflux disease drugs, diabetes drugs, antihypertensive drugs, hypnotic drugs approved for the treatment of insomnia [sleep aids], attention-deficit/hyperactivity disorder drugs, antidepressant drugs, and antipsychotic drugs) comparing the 10- to 36-month period before implementation of the detailing policies with the 12- to 36-month period after implementation, depending on data availability.

Results  The analysis included 16 121 483 prescriptions written between January 2006 and June 2012 by 2126 attending physicians at the 19 intervention group AMCs and by 24 593 matched control group physicians. The sample mean market share at the physician-drug-month level for detailed and nondetailed drugs prior to enactment of policies was 19.3% and 14.2%, respectively. Exposure to an AMC detailing policy was associated with a decrease in the market share of detailed drugs of 1.67 percentage points (95% CI, −2.18 to −1.18 percentage points; P < .001) and an increase in the market share of nondetailed drugs of 0.84 percentage points (95% CI, 0.54 to 1.14 percentage points; P < .001). Associations were statistically significant for 6 of 8 study drug classes for detailed drugs (lipid-lowering drugs, gastroesophageal reflux disease drugs, antihypertensive drugs, sleep aids, attention-deficit/hyperactivity disorder drugs, and antidepressant drugs) and for 9 of the 19 AMCs that implemented policies. Eleven of the 19 AMCs regulated salesperson gifts to physicians, restricted salesperson access to facilities, and incorporated explicit enforcement mechanisms. For 8 of these 11 AMCs, there was a significant change in prescribing. In contrast, there was a significant change at only 1 of 8 AMCs that did not enact policies in all 3 areas.

Conclusions and Relevance  Implementation of policies at AMCs that restricted pharmaceutical detailing between 2006 and 2012 was associated with modest but significant reductions in prescribing of detailed drugs across 6 of 8 major drug classes; however, changes were not seen in all of the AMCs that enacted policies.

Posted in Ethics, Hot Topics in Research

Hot Topics: Most Pediatric Flu Deaths Could Be Prevented With Flu Shot

Influenza vaccine effectiveness against pediatric deaths: 2010–2014

Flannery B, Reynolds SB, Blanton L, et al. Influenza vaccine effectiveness against pediatric deaths: 2010–2014. Pediatrics. 2017;139(5). doi: 10.1542/peds.2016-4244.

BACKGROUND AND OBJECTIVES: Surveillance for laboratory-confirmed influenza-associated pediatric deaths since 2004 has shown that most deaths occur in unvaccinated children. We assessed whether influenza vaccination reduced the risk of influenza-associated death in children and adolescents.

METHODS: We conducted a case–cohort analysis comparing vaccination uptake among laboratory-confirmed influenza-associated pediatric deaths with estimated vaccination coverage among pediatric cohorts in the United States. Case vaccination and high-risk status were determined by case investigation. Influenza vaccination coverage estimates were obtained from national survey data or a national insurance claims database. We estimated odds ratios from logistic regression comparing odds of vaccination among cases with odds of vaccination in comparison cohorts. We used Bayesian methods to compute 95% credible intervals (CIs) for vaccine effectiveness (VE), calculated as (1 − odds ratio) × 100.

RESULTS: From July 2010 through June 2014, 358 laboratory-confirmed influenza-associated pediatric deaths were reported among children aged 6 months through 17 years. Vaccination status was determined for 291 deaths; 75 (26%) received vaccine before illness onset. Average vaccination coverage in survey cohorts was 48%. Overall VE against death was 65% (95% CI, 54% to 74%). Among 153 deaths in children with underlying high-risk medical conditions, 47 (31%) were vaccinated. VE among children with high-risk conditions was 51% (95% CI, 31% to 67%), compared with 65% (95% CI, 47% to 78%) among children without high-risk conditions.

CONCLUSIONS: Influenza vaccination was associated with reduced risk of laboratory-confirmed influenza-associated pediatric death. Increasing influenza vaccination could prevent influenza-associated deaths among children and adolescents.

Posted in Hot Topics in Research, Infectious Disease

Hot Topics: PTSD in Women Strongly Linked to Genetics

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

Duncan L,E., Ratanatharathorn A, Aiello A,E., et al. Largest GWAS of PTSD (N=20thinsp]070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry. 2017.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ~10000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Posted in Anxiety Disorders, Hot Topics in Research, Psychology and Psychiatry

Hot Topics: First Tardive Dyskinesia Drug Approved by FDA

FDA approves first drug to treat tardive dyskinesia

Food and Drug Administration, U.S. Department of Health and Human Services. (2017). FDA approves first drug to treat tardive dyskinesia. Retrieved from

The U.S. Food and Drug Administration today [April 11, 2017] approved Ingrezza (valbenazine) capsules to treat adults with tardive dyskinesia. This is the first drug approved by the FDA for this condition.

Tardive dyskinesia is a neurological disorder characterized by repetitive involuntary movements, usually of the jaw, lips and tongue, such as grimacing, sticking out the tongue and smacking the lips. Some affected people also experience involuntary movement of the extremities or difficulty breathing.

Posted in Hot Topics in Research, Neurology, Psychology and Psychiatry

Hot Topics: Visual Abstracts Increase Reach of Research

Graphic showing findings of Visual Abstracts Increase Article Dissemination study

Credit Andrew Ibrahim, University of Michigan/Annals of Surgery

Visual Abstracts to Disseminate Research on Social Media: A Prospective, Case-control Crossover Study

Ibrahim AM, Lillemoe KD, Klingensmith ME, Dimick JB. Visual abstracts to disseminate research on social media: A prospective, case-control crossover study. Ann Surg. 2017. doi: 10.1097/SLA.0000000000002277.

Nearly all major academic research journals have adopted social media platforms, such as Twitter, to disseminate their publications and make them more accessible to readers. One recent study suggested that articles featured on Twitter may be 3 times more likely to be read versus those that were not. Despite the widespread adoption of Twitter by academic journals, the extent to which the social media platforms and strategies can influence practical outcomes, such as number of article reads, remain understudied.

In July of 2016, Annals of Surgery adopted the use of ‘‘visual abstracts’’ as a novel strategy to improve dissemination of the journal’s publications. A visual abstract is simply a visual representation of the key findings typically found in the abstract portion of an article. They are produced by the journal after an article is accepted. Examples can be found in Figure 1. As of March 2017, more than 15 journals have utilized visual abstracts in their social media dissemination strategy, yet no data exist describing how their use impacts dissemination of publications.

In this context, a case-control crossover study was conducted to compare tweets that included only the title of the article versus tweets that contain the title and a visual abstract. Such information would be valuable to help journals and authors understand the impact of different dissemination strategies for their publications.

Posted in Hot Topics in Research, Research and Scholarly Communication

Hot Topics: FDA Approves First Drug For Severe Multiple Sclerosis

FDA approves new drug to treat multiple sclerosis

Food and Drug Administration, U.S. Department of Health and Human Services. (2017). FDA approves new drug to treat multiple sclerosis. Retrieved from

On March 28, the U.S. Food and Drug Administration approved Ocrevus (ocrelizumab) to treat adult patients with relapsing forms of multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS). This is the first drug approved by the FDA for PPMS. Ocrevus is an intravenous infusion given by a health care professional.

“Multiple sclerosis can have a profound impact on a person’s life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy not only provides another treatment option for those with relapsing MS, but for the first time provides an approved therapy for those with primary progressive MS.”

Posted in Central Nervous System Disorders, Hot Topics in Research

Hot Topics: Training Medical Students to Organize Needle Exchange Programs

Students as effective harm reductionists and needle exchange organizers

Barbour K, McQuade M, Brown B. Students as effective harm reductionists and needle exchange organizers. Substance Abuse Treatment, Prevention, and Policy. 2017;12(15).

Needle exchange programs are safe, highly effective programs for promoting health among people who inject drugs. However, they remain poorly funded, and often illegal, in many places worldwide due to fear and stigma surrounding drug use. Continued advocacy, education, and implementation of new needle exchanges are thus essential to improve public health and reduce structural inequality.

We argue that students, and especially professional and graduate students, have the potential to play an important role in advancing harm reduction. Students benefit from the respect given to the professions they are training to enter, which gives them leverage to navigate the political hurdles often faced by needle exchange organizers, especially in areas that presently lack services. In addition, due to their relative simplicity, needle exchanges do not require much of the licensing, clinical knowledge, and infrastructure associated with more traditional student programs, such as student-run free medical clinics. Students are capable of learning harm reduction cultural approaches and techniques if they remain humble, open-minded, and seek the help of the harm reduction community. Consequently, students can generate tremendous benefits to their community without performing beyond their appropriate clinical limitations.

Students benefit from organizing needle exchanges by gaining applied experience in advocacy, organization-building, and political finesse. Working in a needle exchange significantly helps erode stigma against multiple marginalized populations. Students in health-related professions additionally learn clinically-relevant knowledge that is often lacking from their formal training, such as an understanding of structural violence and inequality, root causes of substance use, client-centered approaches to health services, and interacting with clients as peers, rather than through the standard hierarchical medical interaction.

We therefore encourage students to learn about and consider organizing needle exchanges during their training. Our experience is that students can be successful in developing sustainable programs which benefit their clients, the broader harm reduction movement, and themselves alike.


Posted in Hot Topics in Research, Substance Use Disorders