Program On Regulation, Therapeutics, And Law (PORTAL)
Literature Scan

Each month, the Program On Regulation, Therapeutics, And Law (PORTAL) in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital/Harvard Medical School reviews the peer-reviewed medical literature to identify interesting empirical studies, in-depth analyses, and thoughtful editorials on pharmaceutical law and policy.

Current and previous scans may be found below:

October 2016

September 2016

August 2016

July 2016

June 2016

May 2016

April 2016

March 2016

February 2016

Please visit the Archived PORTAL Scans to refer to scans dating back to August 2014.

October 2016

  1. Dafny LS, Ody CJ, Schmitt MA. Undermining Value-Based Purchasing – Lessons from the Pharmaceutical Industry. N Engl J Med. 2016 Oct. [Epub ahead of print]
  2. In 2015, the U.S. Department of Health and Human Services announced a goal of linking at least 50% of Medicare spending to value-based payment models such as accountable care organizations. Health care providers are now scrambling to reorganize in a way that delivers value while preserving or enhancing commercial success. Although it’s not yet clear how providers will respond to value-based payment models, an examination of pharmaceutical industry practices can provide insights into problems that may arise — and practices to avoid.

    Value-based plan design — a term that describes payers’ efforts to align consumer cost sharing with the value generated by a service or drug — may sound like a new development in health care, but it’s old news for prescription drugs. For years, insurers and pharmacy benefits managers have steered consumers toward generic and other high-value drugs by categorizing drugs into “tiers” and requiring lower copayments for preferred drugs. By 2000, roughly three quarters of consumers enrolled in employer-sponsored health plans had prescription plans with two or more drug tiers. Today, a similar proportion have plans with at least three tiers. Tiering not only encourages consumers to use high-value drugs, it also gives insurers leverage during price negotiations with manufacturers.

  3. Doshi P. Is this trial misreported? Truth seeking in the burgeoning age of trial transparency. BMJ. 2016;355:i5543.
  4. Glimpses inside SmithKline Beecham’s secret clinical trials programme for the antidepressant paroxetine began in the early 2000s. Amid a growing storm over the safety of selective serotonin reuptake inhibitors for children, a leaked memo revealed by the BBC’s Panorama programme depicted a company trying to manage the unfavourable results of two important trials. “It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine,” the memo read. A reviewer for the US Food and Drug Administration considered both trials as “failed.”

    But then there was the public face of the data. One of the two trials–Study 329–was published in the peer reviewed literature. The manufacturer told its sales representatives that the “landmark study … demonstrates REMARKABLE efficacy and safety.”

  5. Hwang TJ, Carpenter D, Lauffenburger JC, Wang B, Franklin JM, Kesselheim AS. Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results. JAMA Intern Med. 2016 Oct. [Epub ahead of print]
  6. Importance: Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research.
    Objective: To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results.
    Design, Setting, and Participants: Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product.
    Main Outcomes and Measures: For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval.
    Results: Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved.
    Conclusions and Relevance: Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.

  7. Kesselheim AS, Avorn J. Approving a Problematic Muscular Dystrophy Drug: Implications for FDA Policy. JAMA. 2016 Oct. [Epub ahead of print]
  8. In September 2016, the US Food and Drug Administration (FDA) approved eteplirsen (Exondys 51), a new drug for Duchenne muscular dystrophy (DMD), overruling the recommendations of both its scientific staff and its external advisory committee. Duchenne muscular dystrophy is a progressive and usually fatal X-linked genetic disease caused by mutations in a gene that produces the protein dystrophin that helps stabilize muscle fibers. No disease-modifying treatments are available.

    Eteplirsen was designed to offer a promising new therapeutic approach that would bypass a stop codon in a gene coding for dystrophin, allowing production of a truncated but functional version of the protein. In particular, eteplirsen targeted exon 51, the location of the stop codon in about 10% to 15% of patients with DMD (an estimated 2000-2500 cases in the United States). Despite this innovative mechanism, the development of eteplirsen was controversial, starting with its manufacturer-supported pivotal double-blind study, which involved only 12 patients: 8 were randomized to 2 different eteplirsen doses and 4 were randomized to placebo for 24 weeks. The latter were then switched to eteplirsen and all were to be followed for an additional 24 weeks. The sample size was substantially smaller than the study sample size in which a similar DMD drug, drisapersen, had been tested in 3 randomized trials that together enrolled 290 patients. The FDA declined to approve drisapersen in 2015 after these studies showed no clear benefit after 24 weeks in prespecified clinical end points, such as changes in a 6-minute walk test. Those trials also suggested the possibility of safety problems, including renal toxic effects and thrombocytopenia.

  9. Sommers BD, Blendon RJ, Orav EJ, Epstein AM. Changes in Utilization and Health Among Low-Income Adults After Medicaid Expansion or Expanded Private Insurance. JAMA Intern Med. 2016;176(10):1501-9.
  10. Importance: Under the Affordable Care Act (ACA), more than 30 states have expanded Medicaid, with some states choosing to expand private insurance instead (the “private option”). In addition, while coverage gains from the ACA’s Medicaid expansion are well documented, impacts on utilization and health are unclear.
    Objective: To assess changes in access to care, utilization, and self-reported health among low-income adults in 3 states taking alternative approaches to the ACA.
    Design, Setting, and Participants: Differences-in-differences analysis of survey data from November 2013 through December 2015 of US citizens ages 19 to 64 years with incomes below 138% of the federal poverty level in Kentucky, Arkansas, and Texas (n = 8676). Data analysis was conducted between January and May 2016.
    Exposures: Medicaid expansion in Kentucky and use of Medicaid funds to purchase private insurance for low-income adults in Arkansas (private option), compared with no expansion in Texas.
    Main Outcomes and Measures: Self-reported access to primary care, specialty care, and medications; affordability of care; outpatient, inpatient, and emergency utilization; receiving glucose and cholesterol testing, annual check-up, and care for chronic conditions; quality of care, depression score, and overall health.
    Results: Among the 3 states included in the study, Arkansas (n=2890), Kentucky (n=2898, and Texas (n=2888), there were no differences in sex, income, or marital status. Respondents from Texas were younger, more urban, and disproportionately Latino compared with those in Arkansas and Kentucky. Significant changes in coverage and access were more apparent in 2015 than in 2014. By 2015, expansion was associated with a 22.7 percentage-point reduction in the uninsured rate compared with nonexpansion (P < .001). Expansion was associated with significantly increased access to primary care (12.1 percentage points; P < .001), fewer skipped medications due to cost (-11.6 percentage points; P < .001), reduced out-of-pocket spending (-29.5%; P = .02), reduced likelihood of emergency department visits (-6.0 percentage points, P = .04), and increased outpatient visits (0.69 visits per year; P = .04). Screening for diabetes (6.3 percentage points; P = .05), glucose testing among patients with diabetes (10.7 percentage points; P = .03), and regular care for chronic conditions (12.0 percentage points; P = .008) all increased significantly after expansion. Quality of care ratings improved significantly (-7.1 percentage points with "fair/poor quality of care"; P = .03), as did the share of adults reporting excellent health (4.8 percentage points; P = .04). Comparisons of Arkansas vs Kentucky showed increased private coverage in the former (21.7 percentage points; P < .001), increased Medicaid in the latter (21.3 percentage points; P  < .001), and higher diabetic glucose testing rates in Kentucky (11.6 percentage points; P = .04), but no other statistically significant differences. Conclusions and Relevance: In the second year of expansion, Kentucky’s Medicaid program and Arkansas’s private option were associated with significant increases in outpatient utilization, preventive care, and improved health care quality; reductions in emergency department use; and improved self-reported health. Aside from the type of coverage obtained, outcomes were similar for nearly all other outcomes between the 2 states using alternative approaches to expansion.

  11. Tominaga T, Miyazaki S, Oniyama Y, Weber AD, Kondo T. The Japanese Postmarketing Adverse Event Relief System: A confluence of regulatory science, the legal system, and clinical pharmacology. Clin Pharmacol Ther. 2016 Oct. [Epub ahead of print]
  12. The Japanese Postmarketing Relief System provides for compensation to patients suffering adverse reactions, based on the acknowledgement that unpredicted adverse events occur inevitably once a drug is marketed. The system also provides new knowledge about the benefit-risk profile of a drug that may be incorporated into product labeling. The system relies on causality assessments that are based on sound clinical pharmacology principles. The system may serve as a model for other countries’ healthcare system.

  13. Wang C, Kane R, Levenson M, Kelman J, Wernecke M, Lee JY, Kozlowski S, Dekmezian C, Zhang Z, Thompson A, Smith K, Wu YT, Wei Y, Chillarige Y, Ryan Q, Worrall C, MaCurdy TE, Graham DJ. Association Between Changes in CMS Reimbursement Policy and Drug Labels for Erythrocyte-Stimulating Agents With Outcomes for Older Patients Undergoing Hemodialysis Covered by Fee-for-Service Medicare. JAMA Intern Med. 2016 Oct. [Epub ahead of print]
  14. Importance: In 2011, the US Centers for Medicare & Medicaid Services (CMS) changed its reimbursement policy for hemodialysis to a bundled comprehensive payment system that included the cost of erythrocyte-stimulating agents (ESAs). Also in 2011, the US Food and Drug Administration revised the drug label for ESAs, recommending more conservative dosing in patients with chronic kidney disease. In response to concerns that these measures could have adverse effects on patient care and outcomes, the CMS and the FDA initiated a collaboration to assess the effect.
    Objective: To assess the effects of the changes in reimbursement policy and the ESA drug label on patients who underwent incident hemodialysis.
    Design, Setting, and Participants: For this retrospective cohort study, patients 66 years or older who had undergone incident hemodialysis, and were enrolled in Medicare parts A, B, or D for at least 12 months prior to hemodialysis initiation between January 1, 2008, and December 31, 2013, were recruited from hemodialysis centers across the United States. Patients were divided into 2 cohorts based on their date of hemodialysis initiation and followed: January 1, 2008, to December 31, 2009, for the prepolicy cohort and July 1, 2011, to June 30, 2013, for the postpolicy cohort, with the exclusion of January 1, 2010, to June 30, 2011, as a transition period.
    Interventions: Changes in CMS reimbursement policy for dialysis and the FDA label for ESAs.
    Main Outcomes and Measures: Major adverse cardiovascular events (MACEs), including acute myocardial infarction (AMI), stroke, and all-cause mortality; hospitalized congestive heart failure (H-CHF); venous thromboembolism; and red blood cell transfusions. Secondary outcomes included evaluating effects on black and other patient subgroups.
    Results: Baseline characteristics of the 69 718 incident hemodialysis patients were similar between cohorts. Compared with the prepolicy period, the risk of MACE, death, H-CHF, and venous thromboembolism were similar in the postpolicy period, and the risk of stroke decreased (hazard ratio [HR], 0.77; 95% CI, 0.64-0.93; P = .01); the use of ESAs also decreased, and the rate of blood transfusions increased (HR, 1.09; 95% CI, 1.07-1.12; P < .001). In the post-postpolicy period, black patients had a significant reduction in risk of MACE (HR, 0.82; 95% CI, 0.73-0.92; P < .001) and all-cause mortality (HR, 0.82; 95% CI, 0.73-0.93; P = .002).
    Conclusions and Relevance: After the bundling policy and ESA labeling changes in 2011, the risks of MACE and death for patients 66 years or older and covered by fee-for-service Medicare who had undergone incident hemodialysis did not change; the risk of stroke was reduced, and the rate of blood transfusions modestly increased. Black patients had substantial reductions in the risks of MACE and death.

    September 2016

    1. Bouvy JC, Huinink L, De Bruin ML. Benefit-risk reassessment of medicines: a retrospective analysis of all safety-related referral procedures in Europe during 2001-2012. Pharmacoepidemiol Drug Saf. 2016;25(9):1004-14.
    2. PURPOSE: The aim of this study was to determine the outcomes and timing within the product life cycle of all benefit-risk reassessment procedures for marketed products that were completed by the committee for medicinal product for human use during 2001-2012.
      METHODS: A cohort of all referral procedures for benefit-risk reassessment (Article 20, Article 31, Article 36, Article 107 procedures) for which committee for medicinal product for human use issued an opinion between 1 January 2001 and 31 December 2012 was created. The European Medicines Agency website and the Dutch Medicines Evaluation Board website were used to collect all data.
      RESULTS: There were a total of 73 benefit-risk reassessments during the study period; 61 reassessments for a single product and 12 reassessments for multiple products or an entire product class. Nineteen reassessments resulted in the recommendation to remove the product from the market. On average, a benefit-risk reassessment was performed 18.7 years after the product was first marketed. Seventeen products were marketed 5 years or less when the reassessment procedure was completed; six of these products were subsequently removed from the market.
      CONCLUSIONS: The majority of all benefit-risk reassessments that were performed during the study period did not result in removing the product from the market, but rather, in confirming the positive benefit-risk of the product, conditional to changes to the product’s marketing authorisation. About half of all products that were removed from the market during the 2000s had been marketed for more than 20 years.

    3. Gupta R, Kesselheim AS, Downing N, Greene J, Ross JS. Generic Drug Approvals Since the 1984 Hatch-Waxman Act. JAMA Intern Med. 2016;176(9):1391-3.
    4. The Hatch-Waxman Act of 1984 catalyzed the generic drug market, which now constitutes over 85% of US prescriptions. The number of generic alternatives to a brand-name drug affects prices; availability of at least 4 generic drugs has been associated with brand-name price reductions of approximately 60% when compared with fewer or no generics. Recently, prices for several generic drugs have increased 100-fold or more, in part because of limited competition. We characterized the number of generic versions for all brand-name drugs approved by the US Food and Drug Administration (FDA), along with associations between the number of generics and characteristics of brand-name drugs.

    5. Kister I, Corboy JR. Reducing costs while enhancing quality of care in MS. Neurology. 2016 Sep 2. [Epub ahead of print]
    6. The rapid escalation in prices of disease-modifying therapies (DMTs) for multiple sclerosis (MS) over the past decade has resulted in a dramatic overall increase in the costs of MS-related care. In this article, we outline various approaches whereby neurologists can contribute to responsible cost containment while maintaining, and even enhancing, the quality of MS care. The premise of the article is that clinicians are uniquely positioned to introduce innovative management strategies that are both medically sound and cost-efficient. We describe our “top 5” recommendations, including strategies for customizing relapse treatment; developing alternative dosing schedules for Food and Drug Administration-approved MS DMTs; using off-label therapies for relapse suppression; and limiting the use of DMTs to those who clearly fulfill diagnostic criteria, and who might benefit from continued use over time. These suggestions are well-grounded in the literature and our personal experience, but are not always supported with rigorous Class I evidence as yet. We advocate for neurologists to take a greater role in shaping clinical research agendas and helping to establish cost-effective approaches on a firm empiric basis.

    7. Kleijnen S, Lipska I, Leonardo Alves T, Meijboom K, Elsada A, Vervölgyi V, d’Andon A, Timoney A, Leufkens HG, De Boer A, Goettsch WG. Relative effectiveness assessments of oncology medicines for pricing and reimbursement decisions in European countries. Ann Oncol. 2016;27(9):1768-75.
    8. BACKGROUND: There is a debate on the added clinical value of new, expensive, anticancer treatments. Among European decision makers, the relevance of commonly used end points in trials, especially overall survival (OS), progression-free survival (PFS) and quality of life (QoL), varies, leading to the available evidence being valued differently. This research studies the extent to which the value of end points for cancer medicines differs among European decision makers.
      METHODS: We compared guidelines and relative effectiveness assessments (REAs) of medicines for pricing or reimbursement decisions in England, France, Germany, The Netherlands, Poland, and Scotland. Anticancer medicines that received marketing authorization in Europe between 2011 and 2013 with at least four available national REAs were evaluated. A total of 79 REAs were included.
      RESULTS: Health technology assessment (HTA) guidelines indicate a preference for clinically and patient relevant end points such as OS and QoL above surrogate end points. Most guidelines do not specify whether PFS is considered a surrogate or patient-relevant end point. The number of REAs included per jurisdiction varied between 7 (The Netherlands) and 18 (Germany). OS data were included in all REAs and were the preferred end point by HTA agencies, but these data were not always mature or robust. QoL data are included in only 54% of the REAs, with a limited impact on the recommendations. PFS data are included in 70% of the REAs, but the extent to which HTA agencies find PFS relevant varies.
      CONCLUSIONS: European decision-making on relative effectiveness of anticancer medicines is affected by a gap in requested versus available clinical evidence, mainly because the regulator is willing to accept some degree of clinical uncertainty. A multi-stakeholder debate would be essential to align concrete robust evidence requirements in oncology and a collectively shared definition for relevant clinical benefit, which will benefit patients and society in general.

    9. Lin D, Lucas E, Murimi IB, Jackson K, Baier M, Frattaroli S, Gielen A, Moyo P, Simoni-Wastilla L, Alexander GC. Physician attitudes and experiences with Maryland’s prescription drug monitoring program (PDMP). Addiction. 2016. [Epub ahead of print]
    10. AIMS: Physicians’ use of Prescription Drug Monitoring Programs (PDMPs) varies by state. Among Maryland physicians, we sought to (1) estimate the PDMP impact on changes in opioid prescribing, (2) approximate the scope of PDMP utility and (3) determine the barriers to PDMP use after its 2013 implementation.
      DESIGN: Cross-sectional postal survey linking responses to state records of PDMP registration and use; randomly sampling physicians within specialty and registration strata.
      SETTING: Maryland, USA.
      PARTICIPANTS: 1,000 surveyed primary care, pain, and emergency medicine physicians stratified into three subpopulations: PDMP non-registrants, PDMP registrants who were non-users and PDMP users. 405 respondents (44%) of 916 eligible physicians were analyzed.
      MEASUREMENTS: Primary outcome measure was PDMP use. Key predictors were clinic characteristics, including type of practice and number of patients prescribed opioids.
      FINDINGS: No response-wave bias was identified. Seventy percent of physicians believed PDMP access decreased their amount and increased their comfort level in prescribing opioids. Three-fourths (74) of PDMP users reported the data very useful for informing opioid prescribing, though one-fifth (20%) reported difficulty accessing the data. Commonly reported barriers to PDMP use were lack of knowledge regarding its existence and registration process. In multivariable analysis after adjusting for key clinic characteristics, practicing at a managed care organization was associated with lower PDMP use (Incidence Rate Ratio [IRR] 0.19, 95% CI 0.05-0.73). Conversely, physicians who prescribed opioids for more than 50 patients accessed the PDMP three times as often as those prescribing opioids for fewer than 10 patients monthly (IRR: 3.00, 95% CI 1.07-8.43).
      CONCLUSIONS: In this survey of Maryland USA physicians, most participants reported that Prescription Drug Monitoring Programs (PDMP) improved their opioid prescribing by decreasing prescription amounts and increasing comfort with prescribing opioids. Common barriers to PDMP use included not knowing about the program, registration difficulties, and data access difficulties.

    11. Oye KA, Eichler HG, Hoos A, Mori Y, Mullin TM, Pearson M. Pharmaceuticals Licensing and Reimbursement in the European Union, United States and Japan. Clin Pharamcol Ther. 2016. [Epub ahead of print]
    12. This paper describes recent developments in licensing and reimbursement policies in the EU, US and Japan, examines causes of changes, compares differences and projects trends. With respect to licensing, the EMA, FDA and PMDA are committed to rigorous evaluation of pharmaceuticals in advance of market access with feedback from post-market experience. The EMA is exploring integrated adaptive pathways for licensing, with formal pilot tests to provide a practical proof of concept. The FDA is augmenting traditional licensing procedures through reforms including Breakthrough Product Designation. The PMDA is implementing reforms to foster innovation and earlier patient access through its Sakigaki strategy and licensing reforms on regenerative medicines. With respect to reimbursement, several generalizations emerge. Relative to US counterparts, EU payers typically set higher standards for evidence of effectiveness as a condition of reimbursement, impose tougher limits on reimbursement by indication, and drive harder deals in negotiations over price.

    13. Mailankody S, Prasad V. Thinking Systematically About the Off-Label Use of Cancer Drugs and Combinations for Patients Who Have Exhausted Proven Therapies. Oncologist. 2016;21(9):1031-2.
    14. Debates surrounding the appropriateness of expanded access programs and right-to-try laws center on the question of under what circumstances should cancer patients be able to receive drugs or combinations that have not fully completed the stages of drug development (not completed testing in phase I, II, or III). The commonality here is that the agent in question has not been approved for any use in the U.S. A path to the drug thus requires special logistics. However, the fundamental question raised by expanded access is a broader one. Given that many cancer drugs are approved for one indication but, once approved, can be used alone or in combination for many others, the core question of expanded access is: Under what circumstances should providers and patients be able to attempt drugs or combinations for indications for which we still lack formal clinical trials?

    15. Sanders GD, Neumann PJ, Basu A, Brock DW, Feeny D, Krahn M, Kuntz KM, Meltzer DO, Owens DK, Prosser LA, Salomon JA, Sculpher MJ, Trikalinos TA, Russell LB, Siegel JE, Ganiats TG. Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine. JAMA. 2016;316(10):1093-103.
    16. IMPORTANCE: Since publication of the report by the Panel on Cost-Effectiveness in Health and Medicine in 1996, researchers have advanced the methods of cost-effectiveness analysis, and policy makers have experimented with its application. The need to deliver health care efficiently and the importance of using analytic techniques to understand the clinical and economic consequences of strategies to improve health have increased in recent years.
      OBJECTIVE: To review the state of the field and provide recommendations to improve the quality of cost-effectiveness analyses. The intended audiences include researchers, government policy makers, public health officials, healthcare administrators, payers, businesses, clinicians, patients, and consumers.
      DESIGN: In 2012, the Second Panel on Cost-Effectiveness in Health and Medicine was formed and included 2 co-chairs, 13 members, and 3 additional members of a leadership group. These members were selected on the basis of their experience in the field to provide broad expertise in the design, conduct, and use of cost-effectiveness analyses. Over the next 3.5 years, the panel developed recommendations by consensus. These recommendations were then reviewed by invited external reviewers and through a public posting process.
      FINDINGS: The concept of a “reference case” and a set of standard methodological practices that all cost-effectiveness analyses should follow to improve quality and comparability are recommended. All cost-effectiveness analyses should report 2 reference case analyses: one based on a health care sector perspective and another based on a societal perspective. The use of an “impact inventory,” which is a structured table that contains consequences (both inside and outside the formal health care sector), intended to clarify the scope and boundaries of the 2 reference case analyses is also recommended. This special communication reviews these recommendations and others concerning the estimation of the consequences of interventions, the valuation of health outcomes, and the reporting of cost-effectiveness analyses.
      CONCLUSIONS AND RELEVANCE: The Second Panel reviewed the current status of the field of cost-effectiveness analysis and developed a new set of recommendations. Major changes include the recommendation to perform analyses from 2 reference case perspectives and to provide an impact inventory to clarify included consequences.

    17. Xu J, Gill R, Cruz M, Staffa J, Lurie P. Effect of US Food and Drug Administration-Approved Pediatric Labeling on Dispensing of Extended Release Oxycodone in the Outpatient Retail Setting. JAMA Pediatr. 2016. [Epub ahead of print]
    18. For years, extended-release (ER) oxycodone has been prescribed to children for management of pain. In August 2015, based on studies conducted under the Best Pharmaceuticals for Children Act that are designed to better inform pediatric prescribing, the US Food and Drug Administration approved the use of OxyContin (Purdue Pharma) for management of pain requiring treatment with an ER/long-acting opioid in children 11 years and older who are already tolerating a daily opioid dose equivalent to at least 20 mg of oxycodone, as described in the labeling. The new labeling was not intended to expand pediatric use of ER opioids, but rather to help clinicians use OxyContin safely in pediatric patients.

      Following the label change, some voiced concerns regarding the potential for increased prescribing and misuse of OxyContin in children. To understand the effect of the pediatric labeling for OxyContin on dispensing of all oxycodone ER products (OxyContin and authorized generics) in the pediatric population, we examined national data on dispensed prescriptions for oxycodone ER in outpatient retail pharmacies before and after the label change.

      August 2016

      1. Chang HY, Lyapustina T, Rutkow L, Daubresse M, Richey M, Faul M, Stuart EA, Alexander GC. Impact of prescription drug monitoring programs and pill mill laws on high-risk opioid prescribers: A comparative interrupted time series analysis. Drug Alcohol Depend. 2016;165:1-8.
      2. BACKGROUND: Prescription drug monitoring programs (PDMPs) and pill mill laws were implemented to reduce opioid-related injuries/deaths. We evaluated their effects on high-risk prescribers in Florida.
        METHODS: We used IMS Health’s LRx Lifelink database between July 2010 and September 2012 to identify opioid-prescribing prescribers in Florida (intervention state, N: 38,465) and Georgia (control state, N: 18,566). The pre-intervention, intervention, and post-intervention periods were: July 2010-June 2011, July 2011-September 2011, and October 2011-September 2012. High-risk prescribers were those in the top 5th percentile of opioid volume during four consecutive calendar quarters. We applied comparative interrupted time series models to evaluate policy effects on clinical practices and monthly prescribing measures for low-risk/high-risk prescribers.
        RESULTS: We identified 1526 (4.0%) high-risk prescribers in Florida, accounting for 67% of total opioid volume and 40% of total opioid prescriptions. Relative to their lower risk counterparts, they wrote sixteen times more monthly opioid prescriptions (79 vs. 5, p<0.01), and had more prescription-filling patients receiving opioids (47% vs. 19%, p<0.01). Following policy implementation, Florida's high-risk providers experienced large relative reductions in opioid patients and opioid prescriptions (-536 patients/month, 95% confidence intervals [CI] -829 to -243; -847 prescriptions/month, CI -1498 to -197), morphine equivalent dose (-0.88mg/month, CI -1.13 to -0.62), and total opioid volume (-3.88kg/month, CI -5.14 to -2.62). Low-risk providers did not experience statistically significantly relative reductions, nor did policy implementation affect the status of being high- vs. low- risk prescribers.
        CONCLUSIONS: High-risk prescribers are disproportionately responsive to state policies. However, opioids-prescribing remains highly concentrated among high-risk providers.

      3. Chambers JD, Rane PB, Neumann PJ. The impact of formulary drug exclusion policies on patients and healthcare costs. Am J Manag Care. 2016;22(8):524-31.
      4. OBJECTIVES: In an attempt to increase the efficiency of their drug benefit policies, insurers are increasingly excluding drugs from their formularies that they deem to be of low value. Our objective was to identify and review empirical evaluations of drug exclusion policies and examine how they affected patients and healthcare costs.
        STUDY DESIGN: Literature review.
        METHODS: We performed a literature search to identify empirical studies that evaluated drug exclusion policies. We reviewed each study to determine how the policy impacted patients (ie, if disease control or frequency, or severity of symptoms, were affected) and if healthcare costs (eg, drug expenditures and costs associated with physician office visits, hospitalizations, laboratory tests) changed.
        RESULTS: We included 26 studies pertaining to 27 drug exclusion policies. Twenty studies reported the impact of 21 drug exclusion policies on patients: 6 (28.6%) policies were reported to have had a positive impact, 6 (28.6%) to have had a negative impact, and 9 (42.8%) to not have impacted patients. Eighteen studies reported the impact of 19 drug exclusion policies on overall healthcare costs: 14 (73.7%) policies were reported to have reduced costs, 1 (5.3%) to have had a neutral impact on costs, and 4 (21.1%) to have increased costs.
        CONCLUSIONS: Although there were important exceptions, most studies found that drug exclusion policies reduced costs and did not negatively impact patients.

      5. Doshi JA, Lim R, Li P, Young PP, Lawnicki VF, State JJ, Troxel AB, Volpp KG. A Synchronized Prescription Refill Program Improved Medication Adherence. Health Aff. 2016;35(8):1504-12.
      6. Synchronizing medication refills-renewing all medications at the same time from the same pharmacy-is an increasingly popular strategy to improve adherence to medication regimens, but there has been little research regarding its effectiveness. In light of increasing policy interest, we evaluated the impact of a pilot refill synchronization program implemented by a large national insurer. A random sample of Medicare Advantage patients receiving mail-order refills for common maintenance medications (antihypertensive, lipid-lowering, or antidiabetic agents) were invited to join the program and followed for twelve months. On average, the absolute increase in the proportion of patients deemed adherent during follow-up was 3-10 percentage points for the intervention group, compared to 1-5 percentage points for the control group. Patients with poorer baseline adherence showed larger increases in the absolute proportion deemed adherent in intervention (23-26 percentage points) compared to a control group (13-15 percentage points). Synchronizing refills might be a promising intervention to improve adherence to maintenance medications, especially among Medicare patients with low baseline adherence.

      7. Fleischman W, Agrawal S, King M, Venkatesh AK, Krumholz HM, McKee D, Brown D, Ross JS. Association between payments from manufacturers of pharmaceuticals to physicians and regional prescribing: cross sectional ecological study. BMJ. 2016;354:i4189.
      8. OBJECTIVE: To examine the association between payments made by the manufacturers of pharmaceuticals to physicians and prescribing by physicians within hospital referral regions.
        DESIGN: Cross sectional analysis of 2013 and 2014 Open Payments and Medicare Part D prescribing data for two classes of commonly prescribed, commonly marketed drugs: oral anticoagulants and non-insulin diabetes drugs, overall and stratified by physician and payment type. SETTING: 306 hospital referral regions, United States.
        PARTICIPANTS: 45 949 454 Medicare Part D prescriptions written by 623 886 physicians to 10 513 173 patients for two drug classes: oral anticoagulants and non-insulin diabetes drugs.
        MAIN OUTCOME MEASURES: Proportion, or market share, of marketed oral anticoagulants and non-insulin diabetes drugs prescribed by physicians among all drugs in each class and within hospital referral regions.
        RESULTS: Among 306 hospital referral regions, there were 977 407 payments to physicians totaling $61 026 140 (£46 174 600; €54 632 500) related to oral anticoagulants, and 1 787 884 payments totaling $108 417 616 related to non-insulin diabetes drugs. The median market share of the hospital referral regions was 21.6% for marketed oral anticoagulants and 12.6% for marketed non-insulin diabetes drugs. Among hospital referral regions, one additional payment (median value $13, interquartile range, $10-$18) was associated with 94 (95% confidence interval 76 to 112) additional days filled of marketed oral anticoagulants and 107 (89 to 125) additional days filled of marketed non-insulin diabetes drugs (P<0.001). Payments to specialists were associated with greater prescribing of marketed drugs than payments to non-specialists (212 v 100 additional days filled per payment of marketed oral anticoagulants, 331 v 114 for marketed non-insulin diabetes drugs, P<0.001). Payments for speaker and consulting fees for non-insulin diabetes drugs were associated with greater prescribing of marketed drugs than payments for food and beverages or educational materials (484 v 110, P<0.001).

        CONCLUSIONS AND STUDY LIMITATIONS: Payments by the manufacturers of pharmaceuticals to physicians were associated with greater regional prescribing of marketed drugs among Medicare Part D beneficiaries. Payments to specialists and payments for speaker and consulting fees were predominantly associated with greater regional prescribing of marketed drugs than payments to non-specialists or payments for food and beverages, gifts, or educational materials. As a cross sectional, ecological study, we cannot prove causation between payments to physicians and increased prescribing. Furthermore, our findings should be interpreted only at the regional level. Our study is limited to prescribing by physicians and the two drug classes studied.

      9. Green AK, Wood WA, Basch EM. Time to Reassess the Cancer Compendia for Off-label Drug Coverage in Oncology. JAMA. 2016 Aug. [Epub ahead of print]
      10. Use of cancer therapies for indications not approved by the US Food and Drug Administration (FDA), also known as “off-label” use, is widely practiced in oncology care.1 Examples include bevacizumab in metastatic esophageal cancer or cetuximab in metastatic prostate cancer. In the United States, off-label use of 10 common cancer drugs accounted for nearly $5 billion in costs in 2010, an amount that likely substantially underrepresents current off-label spending given the escalation in oncology drug pricing and number of available products, but recent comprehensive estimates have not been published.

      11. Hey SP, Kesselheim AS. The FDA, Juno Therapeutics, and the ethical imperative of transparency. BMJ. 2016;354:i4435.
      12. Despite deaths, investigational new drugs are still protected trade secrets of the manufacturer.

      13. Kesselheim AS, Avorn J, Sarpatwari A. The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform. JAMA. 2016;316(8):858-71.
      14. IMPORTANCE: The increasing cost of prescription drugs in the United States has become a source of concern for patients, prescribers, payers, and policy makers.
        OBJECTIVES: To review the origins and effects of high drug prices in the US market and to consider policy options that could contain the cost of prescription drugs.
        EVIDENCE: We reviewed the peer-reviewed medical and health policy literature from January 2005 to July 2016 for articles addressing the sources of drug prices in the United States, the justifications and consequences of high prices, and possible solutions.
        FINDINGS: Per capita prescription drug spending in the United States exceeds that in all other countries, largely driven by brand-name drug prices that have been increasing in recent years at rates far beyond the consumer price index. In 2013, per capita spending on prescription drugs was $858 compared with an average of $400 for 19 other industrialized nations. In the United States, prescription medications now comprise an estimated 17% of overall personal health care services. The most important factor that allows manufacturers to set high drug prices is market exclusivity, protected by monopoly rights awarded upon Food and Drug Administration approval and by patents. The availability of generic drugs after this exclusivity period is the main means of reducing prices in the United States, but access to them may be delayed by numerous business and legal strategies. The primary counterweight against excessive pricing during market exclusivity is the negotiating power of the payer, which is currently constrained by several factors, including the requirement that most government drug payment plans cover nearly all products. Another key contributor to drug spending is physician prescribing choices when comparable alternatives are available at different costs. Although prices are often justified by the high cost of drug development, there is no evidence of an association between research and development costs and prices; rather, prescription drugs are priced in the United States primarily on the basis of what the market will bear.
        CONCLUSIONS AND RELEVANCE: High drug prices are the result of the approach the United States has taken to granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits. The most realistic short-term strategies to address high prices include enforcing more stringent requirements for the award and extension of exclusivity rights; enhancing competition by ensuring timely generic drug availability; providing greater opportunities for meaningful price negotiation by governmental payers; generating more evidence about comparative cost-effectiveness of therapeutic alternatives; and more effectively educating patients, prescribers, payers, and policy makers about these choices.

      15. Sarpatwari A, Gagne JJ. Balancing benefits and harms: privacy protection policies.Pharmacoepidemiol Drug Saf. 2016;25(8):969-71.
      16. While the goals of patient privacy protections are indisputable, the comparative effectiveness of more versus less stringent policies is uncertain. As we continue to discover the adverse effects of privacy protections, more research is needed to understand the relative benefits of these policies and regulations in order to find a system that optimizes patient privacy protection while minimizing hindrance on research. After all, while privacy protection is in the interest of patients, so too are the results of rigorous, efficient, and timely healthcare research.

      17. Wolf MS, Davis TC, Curtis LM, Bailey SC, Knox JP, Bergeron A, Abbet M, Shrank WH, Parker RM, Wood AJ. A Patient-Centered Prescription Drug Label to Promote Appropriate Medication Use and Adherence.J Gen Intern Med. 2016 Aug. [Epub ahead of print]
      18. BACKGROUNDv: Patient misunderstanding of prescription drug label instructions is a common cause of unintentional misuse of medication and adverse health outcomes. Those with limited literacy and English proficiency are at greater risk.
        OBJECTIVE: To test the effectiveness of a patient-centered drug label strategy, including a Universal Medication Schedule (UMS), to improve proper regimen use and adherence compared to a current standard.
        DESIGN: Two-arm, multi-site patient-randomized pragmatic trial.
        PARTICIPANTS: English- and Spanish-speaking patients from eight community health centers in northern Virginia who received prescriptions from a central-fill pharmacy and who were 1) ≥30 years of age, 2) diagnosed with type 2 diabetes and/or hypertension, and 3) taking ≥2 oral medications.
        INTERVENTION: A patient-centered label (PCL) strategy that incorporated evidence-based practices for format and content, including prioritized information, larger font size, and increased white space. Most notably, instructions were conveyed with the UMS, which uses standard intervals for expressing when to take medicine (morning, noon, evening, bedtime).
        MAIN MEASURES: Demonstrated proper use of a multi-drug regimen; medication adherence measured by self-report and pill count at 3 and 9 months.
        KEY RESULTS: A total of 845 patients participated in the study (85.6 % cooperation rate). Patients receiving the PCL demonstrated slightly better proper use of their drug regimens at first exposure (76.9 % vs. 70.1 %, p = 0.06) and at 9 months (85.9 % vs. 77.4 %, p = 0.03). The effect of the PCL was significant for English-speaking patients (OR 2.21, 95 % CI 1.13-4.31) but not for Spanish speakers (OR 1.19, 95 % CI 0.63-2.24). Overall, the intervention did not improve medication adherence. However, significant benefits from the PCL were found among patients with limited literacy (OR 5.08, 95 % CI 1.15-22.37) and for those with medications to be taken ≥2 times a day (OR 2.77, 95 % CI 1.17-6.53).
        CONCLUSIONS: A simple modification to pharmacy-generated labeling, with minimal investment required, can offer modest improvements to regimen use and adherence, mostly among patients with limited literacy and more complex regimens.

        July 2016

        1. Gabler NB, Duan N, Raneses E, Suttner L, Ciarametaro M, Cooney E, Dubois RW, Halpern SD, Kravitz RL. No improvement in the reporting of clinical trial subgroup effects in high-impact general medical journals. Trials. 2016 Jul 16;17(1):320.
        2. BACKGROUND: When subgroup analyses are not correctly analyzed and reported, incorrect conclusions may be drawn, and inappropriate treatments provided. Despite the increased recognition of the importance of subgroup analysis, little information exists regarding the prevalence, appropriateness, and study characteristics that influence subgroup analysis. The objective of this study is to determine (1) if the use of subgroup analyses and multivariable risk indices has increased, (2) whether statistical methodology has improved over time, and (3) which study characteristics predict subgroup analysis.
          METHODS: We randomly selected randomized controlled trials (RCTs) from five high-impact general medical journals during three time periods. Data from these articles were abstracted in duplicate using standard forms and a standard protocol. Subgroup analysis was defined as reporting any subgroup effect. Appropriate methods for subgroup analysis included a formal test for heterogeneity or interaction across treatment-by-covariate groups. We used logistic regression to determine the variables significantly associated with any subgroup analysis or, among RCTs reporting subgroup analyses, using appropriate methodology.
          RESULTS: The final sample of 416 articles reported 437 RCTs, of which 270 (62 %) reported subgroup analysis. Among these, 185 (69 %) used appropriate methods to conduct such analyses. Subgroup analysis was reported in 62, 55, and 67 % of the articles from 2007, 2010, and 2013, respectively. The percentage using appropriate methods decreased over the three time points from 77 % in 2007 to 63 % in 2013 (p < 0.05). Significant predictors of reporting subgroup analysis included industry funding (OR 1.94 (95 % CI 1.17, 3.21)), sample size (OR 1.98 per quintile (1.64, 2.40), and a significant primary outcome (OR 0.55 (0.33, 0.92)). The use of appropriate methods to conduct subgroup analysis decreased by year (OR 0.88 (0.76, 1.00)) and was less common with industry funding (OR 0.35 (0.18, 0.70)). Only 33 (18 %) of the RCTs examined subgroup effects using a multivariable risk index.
          CONCLUSIONS: While we found no significant increase in the reporting of subgroup analysis over time, our results show a significant decrease in the reporting of subgroup analyses using appropriate methods during recent years. Industry-sponsored trials may more commonly report subgroup analyses, but without utilizing appropriate methods. Suboptimal reporting of subgroup effects may impact optimal physician-patient decision-making.

        3. Gagne JJ, Han X, Hennessy S, Leonard CE, Chrischilles EA, Carnahan RM, Wang SV, Fuller C, Iyer A, Katcoff H, Woodworth TS, Archdeacon P, Meyer TE, Schneeweiss S, Toh S. Successful comparison of US Food and Drug Administration Sentinel analysis tools to traditional approaches in quantifying a known drug-adverse event association. Clin Pharmacol Ther. 2016 Jul 14. [Epub ahead of print].
        4. The US Food and Drug Administration’s Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semi-automated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81 to 3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors versus beta-blockers. Using data from 13 Data Partners between January 1, 2008 and September 30, 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced a HR of 3.14 (95% CI, 2.86 to 3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment.

        5. Gupta R, Kesselheim AS, Downing N, Greene J, Ross JS. Generic Drug Approvals Since the 1984 Hatch-Waxman Act. JAMA Intern Med. 2016 Jul 18. 2016.3411. [Epub ahead of print].
        6. This study uses US Food and Drug Administration data to identify approved generic drugs manufactured between September 30, 1984, and January 11, 2016 and compares the effects of number of generic drugs associated with brand-name drugs.

          The Hatch-Waxman Act of 1984 catalyzed the generic drug market, which now constitutes over 85% of US prescriptions. The number of generic alternatives to a brand-name drug affects prices; availability of at least 4 generic drugs has been associated with brand-name price reductions of approximately 60% when compared with fewer or no generics. Recently, prices for several generic drugs have increased 100-fold or more, in part because of limited competition. We characterized the number of generic versions for all brand-name drugs approved by the US Food and Drug Administration (FDA), along with associations between the number of generics and characteristics of brand-name drugs.

        7. Haffner ME. The history of orphan drug regulation – US and Beyond. Clin Pharmacol Ther. 2016 Jul 9. [Epub ahead of print] .
        8. The US Orphan Drug Act, passed in 1982, was the first orphan drug legislation in the world. It is a law based on economic incentives making it financially possible for pharmaceutical firms to develop products for small patient populations. Since passage, many additional countries have developed orphan drug programs and many pharmaceutical firms have developed around the orphan program. Today, more than 500 drugs for rare diseases have been developed in the US.

        9. Hoekman J, Klamer TT, Mantel-Teeuwisse AK, Leufkens HG, De Bruin ML. Protecting Pharmaceutical Patents and Test Data: How the Trans-Pacific Partnership Agreement Could Affect Access to Medicines in the US and Abroad. AMA J Ethics. 2016 Jul 1;18(7):727-35.
        10. The Trans-Pacific Partnership (TPP) Agreement is a proposed free trade agreement between the US and 11 other countries in Asia and South America covering many consumer goods, including prescription medicines. This review describes how the TPP could affect international laws governing intellectual property rights for prescription drugs, focusing on patents and exclusivity protections for test data, including their effect on reimbursement decisions by national health care authorities responsible for health priority setting. We conclude that the TPP could affect low-income patients’ access to medicines in signatory countries.

        11. Luo J, Kesselheim AS. Protecting Pharmaceutical Patents and Test Data: How the Trans-Pacific Partnership Agreement Could Affect Access to Medicines in the US and Abroad. AMA J Ethics. 2016 Jul 1;18(7):727-35.
        12. The Trans-Pacific Partnership (TPP) Agreement is a proposed free trade agreement between the US and 11 other countries in Asia and South America covering many consumer goods, including prescription medicines. This review describes how the TPP could affect international laws governing intellectual property rights for prescription drugs, focusing on patents and exclusivity protections for test data, including their effect on reimbursement decisions by national health care authorities responsible for health priority setting. We conclude that the TPP could affect low-income patients’ access to medicines in signatory countries.

        13. Mailankody S, Prasad V. Implications of Proposed Medicare Reforms to Counteract High Cancer Drug Prices. JAMA. 2016 Jul 19;316(3):271-2.
        14. This Viewpoint describes 6 pilot programs from the Centers for Medicare & Medicaid Services aimed at lowering Part B drug costs by discussing their application to cancer treatments.

        15. van Staa TP, Goldacre B, Buchan I, Smeeth L. Big health data: the need to earn public trust. BMJ. 2016 Jul 14;354:i3636.
        16. Better use of large scale health data has the potential to benefit patient care, public health, and research. The handling of such data, however, raises concerns about patient privacy, even when the risks of disclosure are extremely small.

          The problems are illustrated by recent English initiatives trying to aggregate and improve the accessibility of routinely collected healthcare and related records, sometimes loosely referred to as “big data.” One such initiative, care.data, was set to link and provide access to health and social care information from different settings, including primary care, to facilitate the planning and provision of healthcare and to advance health science.1 Data were to be extracted from all primary care practices in England. A related initiative, the Clinical Practice Research Datalink (CPRD), evolved from the General Practice Research Database (GPRD). CPRD was intended to build on GPRD by linking patients’ primary care records to hospital data, around 50 disease registries and clinical audits, genetic information from UK Biobank, and even the loyalty cards of a large supermarket chain, creating an integrated data repository and linked services for all of England that could be sold to universities, drug companies, and non-healthcare industries. Care.data has now been abandoned and CPRD has stalled. The flawed implementation of care.data plus earlier examples of data mismanagement have made privacy issues a mainstream public concern. We look at what went wrong and how future initiatives might gain public support.

          June 2016

          1. Bothwell LE, Greene JA, Podolsky SH, Jones DS. Assessing the Gold Standard–Lessons from the History of RCTs. N Engl J Med. 2016;374(22):2175-81.
          2. Over the past 70 years, randomized, controlled trials (RCTs) have reshaped medical knowledge and practice. Popularized by mid-20th-century clinical researchers and statisticians aiming to reduce bias and enhance the accuracy of clinical experimentation, RCTs have often functioned well in that role. Yet the past seven decades also bear witness to many limitations of this new “gold standard.” The scientific and political history of RCTs offers lessons regarding the complexity of medicine and disease and the economic and political forces that shape the production and circulation of medical knowledge.

          3. Gellad WF, Good CB. Prescription of Brand-Name Medications When Generic Alternatives Are Available-Patently Unfair. JAMA Intern Med. 2016 Jun 27. [Epub ahead of print]
          4. In December 1996, 8 days before Christmas, the US Food and Drug Administration (FDA) approved Lipitor (atorvastatin; Pfizer) for the treatment of hyperlipidemia. Lipitor would become one of the most profitable prescription drugs in history, bringing in $130 billion in sales during its lifetime as a brand-name product and peaking at nearly $13 billion in sales in 2006 alone. Lipitor was far from the first statin in its class (simvastatin, pravastatin, and fluvastatin were already on the market), but 1996 was also the year that the FDA began allowing direct-to-consumer broadcast advertising. Lipitor was aggressively marketed based on its more potent lowering of cholesterol levels compared with other statins.
            The story of Lipitor’s exit from the market—its loss of patent exclusivity—is as well-known as the story of its entry. The first generic version of atorvastatin was delayed owing to litigation and finally launched in November 2011. The generic received 6 months of market exclusivity, limiting the number of generic drugs that could compete until May 2012, when multiple other generics entered the market and the price dropped dramatically. Notably, Pfizer aggressively defended its sales territory during the 6 months between limited and full generic competition, providing incentives for insurers to keep Lipitor on their formularies and launching its own generic competitor. In a comprehensive analysis after the loss of Lipitor’s patent exclusivity, researchers with the National Bureau of Economic Research (NBER) used IMS Health sales data to document the modest change in price when generic atorvastatin entered the market and the dramatic reduction in price 6 months later.

          5. Hwang TJ, Sokolov E, Franklin JM, Kesselheim AS. Comparison of rates of safety issues and reporting of trial outcomes for medical devices approved in the European Union and United States: cohort study. BMJ. 2016;353:i3323.
          6. Objective: To evaluate safety alerts and recalls, publication of key trial outcomes, and subsequent US approval of high profile medical devices introduced in the European Union.
            Design: Cohort study.
            Setting: Novel cardiovascular, orthopedic, and neurologic devices approved in the EU through Conformité Européenne marking between 2005 and 2010.
            Data Sources: Public and commercial databases searched up to January 2016 for press releases and announcements of approvals; public Food and Drug Administration and European regulatory authority databases for US approvals and safety alerts and recalls; and Medline, Embase, and Web of Science for peer reviewed publications.
            Main Outcome Measures: We categorized the novelty of the devices in the study sample as a “major innovation” or an “other change,” and extracted descriptive data about the devices and information on any safety alerts and withdrawals. Linear regression models examined factors associated with differential EU and US approvals. Cox proportional hazards regression models were used to evaluate factors associated with safety alerts and recalls and the publication of trial outcomes for devices categorized as major innovations. Models controlled for time, therapeutic category, regulatory pathway, size of sponsoring company, and indicator variables for devices approved first in the EU and devices approved only in the EU.
            Results: 67% (206/309) of devices identified were approved in both the US and the EU, of which 63% (129/206) were approved first in the EU. The unadjusted rate of safety alerts and recalls for devices approved first in the EU was 27% (62/232) compared with 14% (11/77) for devices approved first in the US. The adjusted hazard ratio for safety alerts and recalls was 2.9 (95% confidence interval 1.4 to 6.2) for devices approved first in the EU. The results of pivotal trials were published for 49% (37/75) of devices categorized as major innovations, with an overall publication rate of 37% five years after approval.
            Conclusions: Devices approved first in the EU are associated with an increased risk of post-marketing safety alerts and recalls. Poor trial publication rates mean that patients and clinicians need greater regulatory transparency to make informed decisions about treatment.

          7. Ioannidis JP. Why Most Clinical Research Is Not Useful. PLoS Med. 2016;13(6):e1002049.
          8. John Ioannidis argues that problem base, context placement, information gain, pragmatism, patient centeredness, value for money, feasibility, and transparency define useful clinical research. He suggests most clinical research is not useful and reform is overdue.

          9. Kesselheim AS, Gagne JJ, Eddings W, Franklin JM, Ross KM, Fulchino LA, Campbell EG. Prevalence and Predictors of Generic Drug Skepticism Among Physicians: Results of a National Survey. JAMA Intern Med. 2016;176(6):845-7.
          10. Generic drugs are low-cost, therapeutically equivalent versions of brand-name drugs. Use of generic drugs increases patient adherence and improves health outcomes. However, a 2009 survey of physicians showed that 23% disagreed that generic drugs were as effective as brand-name drugs and 50% reported quality concerns, leading more than one-quarter not to recommend generic drugs as first-line therapy.
            Because generic drugs now make up more than 85% of prescriptions, we reassessed physicians’ perceptions and determined how professional or demographic characteristics predict physicians’ support of generic drug prescribing.

          11. Kesselheim AS, Gagne JJ, Franklin JM, Eddings W, Fulchino LA, Avorn J, Campbell EG. Variations in Patients’ Perceptions and Use of Generic Drugs: Results of a National Survey. J Gen Intern Med. 2016;31(6):609-14.
          12. Background: Over 84 % of all prescriptions in the US are filled as generic drugs, though in prior surveys, patients reported concerns about their quality.
            Objective: We aimed to survey patients’ perceptions and use of generic drugs.
            Design: Our survey (administered August 2014) assessed patients’ skepticism about generic drug safety and effectiveness and how often they requested brand-name drugs. Chi-square tests and two-sample t-tests assessed associations between patient demographics and the outcomes.
            Participants: Our sample frame was the CVS Advisor Panel, a national database of 124,621 CVS customers. We randomly selected 1450 patients with self-reported chronic conditions who filled at least one prescription in the prior 3 months.
            Main Measures: We assessed how often patients reported asking their physicians to prescribe a brand-name over a generic drug in the last year, and “generic skepticism,” defined as not believing generic drugs were as safe, effective, had the same side effects, and contained the same active ingredients as brand-name drugs.
            Key Results: Of the 1,442 patients with valid addresses, 933 responded (65 % response rate) and 753 took the full survey. A vast majority (83 %) agreed that physicians should prescribe generic drugs when available, and 54 % said they had not asked their physicians to prescribe a brand-name drug over a generic in the past year. Most respondents considered generic drugs to be as effective (87 %) and safe (88 %) as their brand-name counterparts, and to have the same side effects (80 %) and active ingredients (84 %). Non-Caucasians were more likely than Caucasians to request a brand-name drug over a generic (56 % vs. 43 %, p < 0.01), and were also more skeptical of generic drugs' clinical equivalence (43 % vs. 29 %, p < 0.01).
            Conclusions: We found a substantial shift towards more patients having positive views of generic drugs, but lingering negative perceptions will have to be overcome to ensure continued cost-savings and improved patient outcomes from generic drugs.

          13. Luo J, Seeger JD, Donneyong M, Gagne JJ, Avorn J, Kesselheim AS. Effect of Generic Competition on Atorvastatin Prescribing and Patients’ Out-of-Pocket Spending. JAMA Intern Med. 2016 Jun 27. [Epub ahead of print]
          14. Importance: In November 2011, the cholesterol level-lowering medication atorvastatin calcium became available in the United States as a generic drug. However, only a single generic form (from a manufacturer that qualified for market exclusivity by challenging several of Pfizer’s patents) and an authorized generic form (a brand-name drug sold as a generic) were available for the first 180 days.
            Objective: To describe trends in the prescribing of generic atorvastatin after expiration of market exclusivity for the brand-name medication and the effect on patients’ out-of-pocket spending.
            Design, Setting, and Participants: A US population-based study used commercial claims data from the Optum Clinformatics research database (UnitedHealth Group) from December 1, 2010, to May 31, 2013. Participants were 1 968 709 adults with commercial insurance who had been prescribed 1 or more statins (13 285 223 statin prescriptions). An interrupted times series model was used to examine the effect of limited and full generic competition on brand-name and generic atorvastatin prescriptions. Data were analyzed from December 1, 2010, to May 31, 2013.
            Exposures: Prescription of brand-name atorvastatin, generic atorvastatin, and authorized generic atorvastatin were distinguished using National Drug Codes.
            Main Outcome and Measures: Total number of prescriptions dispensed per month and out-of-pocket expenditures for a typical 30-day supply of 20-mg atorvastatin during the periods of brand-name availability only, limited generic competition (lasting 180 days after market exclusivity ended), and full generic competition.
            Results: Of the 1 968 709 beneficiaries, 1 483 066 (58.8% male and 41.2% female; mean [SD] age, 55.6 [10.2] years) received a prescription for a single statin and were included in the analysis. The introduction of the first generic competitor was associated with a reduction in monthly brand-name atorvastatin fills by 20 896 prescriptions (level change, P = .001), an 18.1% change compared with the month preceding loss of exclusivity. Full generic competition reduced brand-name fills by 54 944 prescriptions (level change, P < .001), a 47.6% change relative to the month preceding loss of exclusivity. During the first 180 days of generic competition, no meaningful difference in monthly out-of-pocket spending was found between brand-name (median, $16.98; interquartile range [IQR], $8.76-$48.66) and generic (median, $19.98; IQR, $7.50-$54.90) atorvastatin. After full generic competition, estimated monthly out-of-pocket spending for generic atorvastatin (median $5.10; IQR, $3.36-$19.98) or authorized generic atorvastatin (median, $5.52; IQR, $3.48-$19.98) was substantially lower than that for brand-name atorvastatin (median, $30.00; IQR, $15.00-$91.38).
            Conclusions and Relevance: Among patients with commercial health insurance, delays in generic uptake and high levels of out-of-pocket spending during the first 180 days after atorvastatin lost market exclusivity slowed changes in drug prescribing and decreases in patients’ out-of-pocket costs.

          15. Moore TJ, Furberg CD, Mattison DR, Cohen MR. Completeness of serious adverse drug event reports received by the US Food and Drug Administration in 2014. Pharmacoepidemiol Drug Saf. 2016 Jun;25(6):713-8.
          16. Purpose: Adverse drug event reports to the US Food and Drug Administration (FDA) remain the primary tool for identifying serious drug adverse effects without adequate existing warnings. We assessed the completeness of reports the FDA received in 2014.
            Methods: Serious adverse drug event reports were evaluated for whether they included age, gender, event date, and at least one medical term describing the event in computer excerpts. Report sources were direct reports to the FDA, manufacturer expedited reports about events without adequate warnings, and manufacturer periodic reports about events with existing warnings.
            Results: In 2014, the FDA received 528,192 new case reports indicating a serious or fatal outcome, 25,038 (4.7%) directly from health professionals and consumers, and 503,154 (95.3%) from drug manufacturers. Overall, 21,595 (86.2%) of serious reports submitted directly to the FDA provided data for all four completeness variables, compared with 271,022 (40.4%) of manufacturer expedited reports and 24,988 (51.3%) of periodic reports. Among manufacturer serious reports, 37.9% lacked age and 46.9% had no event date. Performance by 25 manufacturers submitting 5000 or more reports varied from 24.4% complete on all variables to 67% complete. Patient death cases had the lowest completeness scores in all categories.
            Conclusions: By these measures, report completeness from drug manufacturers was poor compared with direct submissions to the agency. The FDA needs to update reporting requirements and compliance policies to help industry capture better adverse event information from new forms of manufacturer interactions with health professionals and consumers.

          17. Quesada O, Yang E, Redberg RF. Availability and Dissemination of Results From US Food and Drug Administration-Mandated Postapproval Studies for Medical Devices. JAMA Intern Med. 2016 Jun 27. [Epub ahead of print]
          18. Medical devices present unique challenges to the US Food and Drug Administration (FDA) approval process owing to their complexity, the learning curve associated with adopting new technology, and short market life compared with drugs. In 2011 the Institute of Medicine recommended a lifecycle approach highlighting the importance of postapproval studies (PAS). In its efforts to speed patient access to potentially life-saving medical devices, the FDA has been shifting priorities from premarket to postmarket data collection. Thus, it is important to understand how well PAS are doing at achieving the agency’s goals of assessing safety and effectiveness. Publication is the best method for dissemination of results to inform clinical practice and provide data transparency. We evaluated the availability of results of completed PAS, including publication in peer-reviewed journals, labeling, or posting on company websites.

          19. Sarpatwari A, Kesselheim AS. Navigating the Dermatological Drug Cost Curve. JAMA. 2016;315(24):2724-5.
          20. Increasing costs of brand-name prescription drugs are causing concern for patients, physicians, and policy makers alike.1 What should be done? Some in the pharmaceutical industry suggest that concerns are overblown because overall retail spending on prescription drugs has remained less than 12% of overall health care spending over the past 30 years. But this perspective overlooks the fact that the use of lower-cost generic drugs has increased from 20% to more than 85% of all prescriptions dispensed during that time.3 In addition, spiraling brand-name drug prices are substantially affecting the economy and patient care. Retail drug spending now accounts for19% of employer-provided insurance benefits, and nearly a quarter of respondents to a national survey currently taking a prescription drug reported that they or a family member did not fill a prescription in the last year due to cost.

          21. Sarpatwari A, Avorn J, Kesselheim AS. State Initiatives to Control Medication Costs–Can Transparency Legislation Help? N Engl J Med. 2016;374(24):2301-4.
          22. Spending on prescription drugs has risen sharply in the United States over the past 2 years. Although thousandfold price increases for a few generic products in limited use have attracted much attention, overall spending growth has been driven more by the widespread use of costly new agents such as sofosbuvir (Sovaldi) and cumulative markups in prices of common brand-name drugs such as rosuvastatin (Crestor), imatinib (Gleevec), and etanercept (Enbrel). Coverage of these products has strained payers’ budgets, forcing difficult funding choices.
            With little relief coming from federal legislation, states have started experimenting with their own novel approaches to the problem. One tactic has been to tighten eligibility requirements for some high-cost drugs. In the case of the hepatitis C drug sofosbuvir, for example, most state Medicaid programs have limited coverage to patients who already have liver damage. Similarly, several states have required publicly funded recipients of these drugs to abstain from drug and alcohol use. Such coverage restrictions have come under fire for being non–evidence-based and discriminatory, and particularly problematic when used to limit access to highly effective drugs. In an alternative strategy, some states have contracted with nonprofit “academic detailing” organizations to assess the most current evidence about medications and educate prescribers about the relative efficacy, safety, and cost-effectiveness of their therapeutic choices.

          23. Schwartz LM, Woloshin S, Zheng E, Tse T, Zarin DA. ClinicalTrials.gov and Drugs@FDA: A Comparison of Results Reporting for New Drug Approval Trials. Ann Intern Med. 2016 Jun 14. [Epub ahead of print]
          24. Background: Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear.
            Purpose: To validate results posted on ClinicalTrials.gov against publicly available U.S. Food and Drug Administration (FDA) reviews on Drugs@FDA.
            Data Sources: ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical and statistical reviews).
            Study Selection: 100 parallel-group, randomized trials for new drug approvals (January 2013 to July 2014) with results posted on ClinicalTrials.gov (15 March 2015).
            Data Extraction: 2 assessors extracted, and another verified, the trial design, primary and secondary outcomes, adverse events, and deaths.
            Results: Most trials were phase 3 (90%), double-blind (92%), and placebo-controlled (73%) and involved 32 drugs from 24 companies. Of 137 primary outcomes identified from ClinicalTrials.gov, 134 (98%) had corresponding data at Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results. Most differences were nominal (that is, relative difference <10%). Primary outcome results in 14 trials could not be validated. Of 1927 secondary outcomes from ClinicalTrials.gov, Drugs@FDA mentioned 1061 (55%) and included results data for 367 (19%). Of 96 trials with 1 or more serious adverse events in either source, 14 could be compared and 7 had discordant numbers of persons experiencing the adverse events. Of 62 trials with 1 or more deaths in either source, 25 could be compared and 17 were discordant.
            Limitation: Unknown generalizability to uncontrolled or crossover trial results.
            Conclusion: Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half the secondary outcomes, as well as serious events and deaths, could not be validated because Drugs@FDA includes only “key outcomes” for regulatory decision making and frequently includes only adverse event results aggregated across multiple trials.

            May 2016

            1. Deak D, Outterson K, Powers JH, Kesselheim AS. Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration-Approved Antibiotics, 2010-2015. Ann Intern Med. 2016 May 31. doi: 10.7326/M16-0291. [Epub ahead of print]
            2. A weak antibiotic pipeline and the increase in drug-resistant pathogens have led to calls for more new antibiotics. Eight new antibiotics were approved by the U.S. Food and Drug Administration (FDA) between January 2010 and December 2015: ceftaroline, fidaxomicin, bedaquiline, dalbavancin, tedizolid, oritavancin, ceftolozane-tazobactam, and ceftazidime-avibactam. This study evaluates the development course and pivotal trials of these antibiotics for their innovativeness, development process, documented patient outcomes, and cost. Data sources were FDA approval packages and databases (January 2010 to December 2015); the Red Book (Truven Health Analytics); Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (FDA); and supplementary information from company filings, press releases, and media reports. Four antibiotics were approved for acute bacterial skin and skin-structure infection. Seven had similar mechanisms of action to those of previously approved drugs. Six were initially developed by small to midsized companies, and 7 are currently marketed by 1 of 3 large companies. The drugs spent a median of 6.2 years in clinical trials (interquartile range [IQR], 5.4 to 8.8 years) and 8 months in FDA review (IQR, 7.5 to 8 months). The median number of patients enrolled in the pivotal trials was 666 (IQR, 553 to 739 patients; full range, 44 to 1005 patients), and median trial duration was 18 months (IQR, 15 to 22 months). Seven drugs were approved on the basis of pivotal trials evaluating noninferiority. One drug demonstrated superiority on an exploratory secondary end point, 2 showed decreased efficacy in patients with renal insufficiency, and 1 showed increased mortality compared with older drugs. Seven of the drugs are substantially more expensive than their trial comparators. Limitations are that future research may show benefit to patients; new drugs from older classes may show superior effectiveness in specific patient populations; and initial U.S. prices for each new antibiotic were obtained from public sources. Recently marketed antibiotics are more expensive but have been approved without evidence of clinical superiority.

            3. Eichler HG, Hurts H, Broich K, Rasi G. Drug Regulation and Pricing–Can Regulators Influence Affordability? New Engl J Med. 2016 May 12;374(19):1807-9.
            4. Public debate in the 1990s over drugs’ clinical toxicity has given way to concerns about their financial toxicity. Although drug regulators aren’t supposed to be concerned with pricing, they’ve been drawn into an acrimonious debate over the cost of medicines. At the European Medicines Agency (EMA), we often hear conflicting arguments: high and inflexible regulatory standards drive up the cost of pharmaceutical research and development (R&D), thereby increasing drug prices; regulators license products even when the data are insufficient for assessing their value and allow drug makers to overcharge; more generics, biosimilars, and me-too drugs are needed to create a dynamic market that will keep prices down; me-too drugs should be discouraged, since they offer no added benefit to patients and lead to overutilization and higher spending; and regulators shouldn’t allow drugs on the market that no one can afford.

            5. Hey SP, Weijer C. What questions can a placebo answer? Monash Bioeth Rev. 2016 May 17. [Epub ahead of print]
            6. The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of clinical equipoise have put forward alleged counter-examples to this restriction-describing instances of ethical placebo-controlled trials that apparently violate clinical equipoise. In this essay, we respond to these examples and show that clinical equipoise is not as restrictive of placebos as these authors assume. We argue that a subtler appreciation for clinical equipoise-in particular the distinction between de facto and de jure interpretations of the concept-allows the concept to explain when and why a placebo control may be necessary to answer a question of clinical importance.

            7. Kapczynski A, Kesselheim AS. ‘Government Patent Use’: A Legal Approach To Reducing Drug Spending. Health Aff (Millwood). 2016 May 1;35(5):791-7.
            8. The high cost of patent-protected brand-name drugs can strain budgets and curb the widespread use of new medicines. An example is the case of direct-acting antiviral drugs for the treatment of hepatitis C. While prices for these drugs have come down in recent months, they still create barriers to treatment. Additionally, prescribing restrictions imposed by insurers put patients at increased risk of medical complications and contribute to transmission of the hepatitis C virus. We propose that the federal government invoke its power under an existing “government patent use” law to reduce excessive prices for important patent-protected medicines. Using this law would permit the government to procure generic versions of patented drugs and in exchange pay the patent-holding companies reasonable royalties to compensate them for research and development. This would allow patients in federal programs, and perhaps beyond, to be treated with inexpensive generic medicines according to clinical need-meaning that many more patients could be reached for no more, and perhaps far less, money than is currently spent. Another benefit would be a reduction in the opportunity for companies to extract monopoly profits that far exceed their risk-adjusted costs of research and development.

            9. Kim C, Prasad V. Strength of Validation for Surrogate End Points Used in the US Food and Drug Administration’s Approval of Oncology Drugs. Mayo Clin Proc. 2016 May 10. [Epub ahead of print]
            10. Objective: To determine the strength of the surrogate-survival correlation for cancer drug approvals based on a surrogate.
              Participants and Methods: We performed a retrospective study of the US Food and Drug Administration (FDA) database, with focused searches of MEDLINE and Google Scholar. Among cancer drugs approved based on a surrogate end point, we examined previous publications assessing the strength of the surrogate-survival correlation. Specifically, we identified the percentage of surrogate approvals lacking any formal analysis of the strength of the surrogate-survival correlation, and when conducted, the strength of such correlations.
              Results: Between January 1, 2009, and December 31, 2014, the FDA approved marketing applications for 55 indications based on a surrogate, of which 25 were accelerated approvals and 30 were traditional approvals. We could not find any formal analyses of the strength of the surrogate-survival correlation in 14 out of 25 accelerated approvals (56%) and 11 out of 30 traditional approvals (37%). For accelerated approvals, just 4 approvals (16%) were made where a level 1 analysis (the most robust way to validate a surrogate) had been performed, with all 4 studies reporting low correlation (r≤0.7). For traditional approvals, a level 1 analysis had been performed for 15 approvals (50%): 8 (53%) reported low correlation (r≤0.7), 4 (27%) medium correlation (r>0.7 to r<0.85), and 3 (20%) high correlation (r≥0.85) with survival.
              Conclusions: The use of surrogate end points for drug approval often lacks formal empirical verification of the strength of the surrogate-survival association.

            11. Outterson K, McDonnell A. Funding Antibiotic Innovation With Vouchers: Recommendations On How To Strengthen A Flawed Incentive Policy. Health Aff (Millwood). 2016 May 1;35(5):784-90.
            12. A serious need to spur antibiotic innovation has arisen because of the lack of antibiotics to combat certain conditions and the overuse of other antibiotics leading to greater antibiotic resistance. In response to this need, proposals have been made to Congress to fund antibiotic research through a voucher program for new antibiotics, which would delay generic entry for any drug, even potential blockbuster lifesaving generics. We find this proposal to be inefficient, in part because of the mismatch between the private value of the voucher and the public value of the antibiotic innovation. However, vouchers have the political advantage in the United States of being able to raise sufficient amounts of money without annual appropriations from Congress. We propose that if antibiotic vouchers are to be considered, the design should include dollar and time caps to limit their volatility, sufficient advance notice to protect generic manufacturers, and market-based linkages between the value of the voucher and the value of the antibiotic innovation. We also explore a second option: The federal government could auction vouchers to the highest bidders and use the money to create an antibiotics innovation fund.

            13. Patel MS, Day SC, Halpern SD, Hanson CW, Martinez JR, Honeywell S Jr, Volpp KG. Generic Medication Prescription Rates After Health System-Wide Redesign of Default Options Within the Electronic Health Record. JAMA Intern Med. 2016 May 9. [Epub ahead of print]
            14. The growing adoption of the electronic health record (EHR) brings new opportunities to improve physician decision making toward higher-value care. Default options, or the conditions that are set into place unless an alternative is actively chosen, have been shown to influence decisions in many contexts. However, the effectiveness of different ways of implementing defaults has not been systematically examined in health care, and many people may assume that changing defaults is a one size fits all intervention that will always have the same effect. In prior work, changing the design of EHR medication display defaults for internal medicine physicians increased generic prescribing rates by 5.4 percentage points. In that intervention, the process of searching for a brand-name medication changed from displaying a list of brand-name options followed by their generic equivalents to displaying only generic-equivalent options. To view brand names, a physician had to click on another tab. In November 2014, the University of Pennsylvania Health System implemented a different change in EHR defaults among all specialties across the entire health system. Instead of changing EHR display defaults, an opt-out checkbox labeled “dispense as written” was added to the prescription screen, and if left unchecked the generic-equivalent medication was prescribed. The objective of this study was to evaluate the effect of this intervention on physician prescribing behaviors.

            15. Yeh JS, Franklin JM, Avorn J, Landon J, Kesselheim AS. Association of Industry Payments to Physicians With the Prescribing of Brand-name Statins in Massachusetts. JAMA Intern Med. 2016 May 9. [Epub ahead of print]
            16. Importance: Pharmaceutical industry payments to physicians may affect prescribing practices and increase costs if more expensive medications are prescribed.
              Objective: Determine the association between industry payments to physicians and the prescribing of brand-name as compared with generic statins for lowering cholesterol.
              Design, Setting, and Participants: Cross-sectional linkage of the Part D Medicare prescriptions claims data with the Massachusetts physicians payment database including all licensed Massachusetts physicians who wrote prescriptions for statins paid for under the Medicare drug benefit in 2011.
              Main Outcomes and Measures: The exposure variable was a physician’s industry payments as listed in the Massachusetts database. The outcome was the physician’s rate of prescribing brand-name statins. We used linear regression to analyze the association between the intensity of physicians’ industry relationships (as measured by total payments) and their prescribing practices, as well as the effects of specific types of payments.
              Results: Among the 2444 Massachusetts physicians in the Medicare prescribing database in 2011, 899 (36.8%) received industry payments. The most frequent payment was for company-sponsored meals (n = 639 [71.1%]). Statins accounted for 1 559 003 prescription claims; 356 807 (22.8%) were for brand-name drugs. For physicians with no industry payments listed, the median brand-name statin prescribing rate was 17.8% (95% CI, 17.2%-18.4%). For every $1000 in total payments received, the brand-name statin prescribing rate increased by 0.1% (95% CI, 0.06%-0.13%; P < .001). Payments for educational training were associated with a 4.8% increase in the rate of brand-name prescribing (P = .004); other forms of payments were not.
              Conclusions and Relevance: Industry payments to physicians are associated with higher rates of prescribing brand-name statins. As the United States seeks to reign in the costs of prescription drugs and make them less expensive for patients, our findings are concerning.

              April 2016

              1. Califf RM, Woodcock J, Ostroff S. A Proactive Response to Prescription Opioid Abuse. N Engl J Med. 2016 Apr 14;374(15):1480-5.
              2. We at the Food and Drug Administration (FDA) continue to be deeply concerned about the growing epidemic of opioid abuse, addiction, and overdose — an epidemic directly related to the increasingly widespread misuse of powerful opioid pain medications. As the federal agency charged with ensuring that the drugs used by the U.S. public are both effective and safe, we are committed to working in partnership with other government agencies, health care providers, the medical products industry and, most important, patients and their families to deal proactively with this unfolding public health crisis, which has already profoundly affected individuals, families, and communities throughout our country. We will do so while also safeguarding appropriate access to vitally important pain medications for the patients who need them.

              3. Goldacre B, Gray J. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials. 2016 Apr 8;17(1):164.
              4. OpenTrials is a collaborative and open database for all available structured data and documents on all clinical trials, threaded together by individual trial. With a versatile and expandable data schema, it is initially designed to host and match the following documents and data for each trial: registry entries; links, abstracts, or texts of academic journal papers; portions of regulatory documents describing individual trials; structured data on methods and results extracted by systematic reviewers or other researchers; clinical study reports; and additional documents such as blank consent forms, blank case report forms, and protocols. The intention is to create an open, freely re-usable index of all such information and to increase discoverability, facilitate research, identify inconsistent data, enable audits on the availability and completeness of this information, support advocacy for better data and drive up standards around open data in evidence-based medicine. The project has phase I funding. This will allow us to create a practical data schema and populate the database initially through web-scraping, basic record linkage techniques, crowd-sourced curation around selected drug areas, and import of existing sources of structured and documents. It will also allow us to create user-friendly web interfaces onto the data and conduct user engagement workshops to optimise the database and interface designs. Where other projects have set out to manually and perfectly curate a narrow range of information on a smaller number of trials, we aim to use a broader range of techniques and attempt to match a very large quantity of information on all trials. We are currently seeking feedback and additional sources of structured data.

              5. Kesselheim AS, Woloshin S, Eddings W, Franklin JM, Ross KM, Schwartz LM. Physicians’ Knowledge About FDA Approval Standards and Perceptions of the “Breakthrough Therapy” Designation. JAMA. 2016 Apr 12;315(14):1516-8.
              6. Before US patients can use new prescription drugs, the US Food and Drug Administration (FDA) reviews the clinical trial results to confirm that benefits outweigh harms for the indication. Approval may involve superiority to placebo, not to an active comparator or standard of care (although approval can be based on uncontrolled or historically controlled studies). Numerous pathways expedite drug development and approval for serious or life-threatening conditions. For example, since 2012, the FDA can designate a drug as a “breakthrough therapy” if preliminary clinical evidence—such as an improvement in a pharmacodynamic biomarker—suggests an advantage over existing options. Through April 2015, the FDA designated 76 “breakthrough” drugs, and the term is routinely used in press releases and prescribing resources.
                Although the term breakthrough leads consumers to overly optimistic beliefs about drug effectiveness, it is not known how physicians understand this term—or more generally, what FDA approval means.

              7. Rex JH, Outterson K. Antibiotic reimbursement in a model delinked from sales: a benchmark-based worldwide approach. Lancet Infect Dis. 2016 Apr;16(4):500-5.
              8. Despite the life-saving ability of antibiotics and their importance as a key enabler of all of modern health care, their effectiveness is now threatened by a rising tide of resistance. Unfortunately, the antibiotic pipeline does not match health needs because of challenges in discovery and development, as well as the poor economics of antibiotics. Discovery and development are being addressed by a range of public-private partnerships; however, correcting the poor economics of antibiotics will need an overhaul of the present business model on a worldwide scale. Discussions are now converging on delinking reward from antibiotic sales through prizes, milestone payments, or insurance-like models in which innovation is rewarded with a fixed series of payments of a predictable size. Rewarding all drugs with the same payments could create perverse incentives to produce drugs that provide the least possible innovation. Thus, we propose a payment model using a graded array of benchmarked rewards designed to encourage the development of antibiotics with the greatest societal value, together with appropriate worldwide access to antibiotics to maximise human health.

              9. Woloshin S, Schwartz LM. US Food and Drug Administration Approval of Flibanserin: Even the Score Does Not Add Up. JAMA Intern Med. 2016 Apr 1;176(4):439-42.
              10. Flibanserin (Addyi), the new female libido pill, is about desire, arousal, and satisfaction. The manufacturer, Sprout Pharmaceuticals (a division of Valeant Pharmaceuticals North America LLC), clearly had desire. They purchased the rights to the drug even after its initial rejection by the US Food and Drug Administration (FDA) and persisted through 2 contentious review cycles. Sprout worked hard to arouse support for the drug, helping create and fund “Even the Score,” an advocacy campaign pushing the message that sexism—not legitimate scientific questions—motivated the drug’s rejection. And within 48 hours of FDA approval, flibanserin was sold to Valeant Pharmaceuticals for about $1 billion in cash.
                Very satisfying for Sprout, but what about the women who take flibanserin? What happens to their desire, arousal, and satisfaction? Very little, according to the meta-analysis by Jaspers et al in this issue. Premenopausal and postmenopausal women taking the approved dose—compared with placebo—experienced 0.5 more satisfying sexual encounters a month and scored 0.3 points higher on a 5-point sexual desire scale. Jaspers et al concluded that these modest benefits did not outweigh harms. According to the FDA, about 10% more premenopausal women taking the approved dose (100 mg) of flibanserin had a meaningful benefit (ie, were “much” or “very much” improved), but flibanserin increased somonolence, sedation, or fatigue compared with placebo: 21% vs 8%. Perhaps most importantly, combining flibanserin with alcohol (and other common drugs) can cause dangerous hypotension and syncope—problems so serious that the FDA put a black box warning, its most serious safety alert, on the label.

                March 2016

                1. Hey SP, Kesselheim AS. An Uninformative Truth: The Logic of Amarin’s Off-Label Promotion. PLoS Med. 2016 Mar 15;13(3):e1001978.
                2. The United States Food and Drug Administration (FDA) generally does not permit pharmaceutical manufacturers to promote their products for non-FDA-approved (“off-label”) indications. A lawsuit filed by Amarin Pharmaceutical in May 2015 sought permission to distribute off-label statements relating to its product Vascepa, because it argued that those statements were “truthful and non-misleading” and that the First Amendment’s protection of commercial speech gave it the right to make those statements. In August 2015, a federal court agreed with Amarin. We argue that Amarin’s argument is faulty, because the so-called “truthful and nonmisleading” statement is a tautology—that is, it is only truthful because of its logical construction—not because it is consistent with the state of scientific evidence. Since the off-label marketing statement is actually misleading when viewed from this perspective, the federal court’s conclusion was incorrect. We propose that informativeness in asserting scientific facts, rather than truthfulness, ought to be the gold standard for evaluating commercial speech about pharmaceuticals.

                3. Hoekman J, Klamer TT, Mantel-Teeuwisse AK, Leufkens HG, De Bruin ML. Characteristics and follow-up of post-marketing studies of conditionally authorised medicines in the EU. Br J Clin Pharmacol. 2016 Mar 18. [Epub ahead of print].
                4. Aims: To provide insight in the characteristics and follow-up of post-marketing studies for medicines that were conditionally authorised in the EU.
                  Methods: We compiled a list of all post-marketing studies attached as specific obligations to the license of medicines that were granted conditional marketing authorisation (MA) from January 2006 to April 2014. Studies were characterised based on their objective, design, status upon MA and due data set by authorities. They were linked to online study registrations (Clinicaltrials.gov, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines and determined whether studies were completed in time.
                  Results: A total of 59 post-marketing studies were requested for 21 conditionally authorised medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting post-marketing studies were ‘long-term follow-up’ and ‘increase data on subpopulations’. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed in time. Actual completion time took a median (IQR) of 274 (-121 – 556) days longer than expected.
                  Conclusions: Our results indicate that most post-marketing studies attached to a conditional marketing authorisation were eventually completed, but half were completed with a substantial delay. The observations suggest caution when broadening the use of post-marketing studies for resolving uncertainties about benefits and risks after MA.

                5. Kapczynski A. Free Speech and Pharmaceutical Regulation-Fishy Business. JAMA Intern Med. 2016 Mar 1;176(3):295-6.
                6. This Viewpoint discusses the implications of recent circuit court decisions regarding commercial speech and off-label marketing of prescription drugs. Recent research has not been kind to fish oil salesmen, or the value of ω-3 fatty acid supplements for the secondary prevention of cardiovascular disease. Amarin Corporation, in particular, has been hit hard. The company’s only approved product is icosapent ethyl (Vascepa), a prescription-based derivative of fish oil. In 2012, the US Food and Drug Administration (FDA) approved the drug to treat patients with very high triglyceride levels, but the company has long wanted to promote its use in a much larger group of patients: those with lower triglyceride levels and cardiovascular disease who were already being treated with statins. In 2013, an FDA advisory committee voted 9 to 2 against approval for this use, in part because several recent studies of other drugs with similar effects on blood lipids showed no clinical benefit when they were added to statins. Amarin’s stock price plummeted, and investors brought suit claiming that they had been misled about the promise of the drug.

                7. Massey PR, Wang R, Prasad V, Bates SE, Fojo T. Assessing the Eventual Publication of Clinical Trial Abstracts Submitted to a Large Annual Oncology Meeting. Oncologist. 2016 Mar;21(3):261-8.
                8. Background: Despite the ethical imperative to publish clinical trials when human subjects are involved, such data frequently remain unpublished. The objectives were to tabulate the rate and ascertain factors associated with eventual publication of clinical trial results reported as abstracts in the Proceedings of the American Society of Clinical Oncology (American Society of Clinical Oncology).
                  Materials and Methods: Abstracts describing clinical trials for patients with breast, lung, colorectal, ovarian, and prostate cancer from 2009 to 2011 were identified by using a comprehensive online database (http://meetinglibrary.asco.org/abstracts). Abstracts included reported results of a treatment or intervention assessed in a discrete, prospective clinical trial. Publication status at 4-6 years was determined by using a standardized search of PubMed. Primary outcomes were the rate of publication for abstracts of randomized and nonrandomized clinical trials. Secondary outcomes included factors influencing the publication of results.
                  Results: A total of 1,075 abstracts describing 378 randomized and 697 nonrandomized clinical trials were evaluated. Across all years, 75% of randomized and 54% of nonrandomized trials were published, with an overall publication rate of 61%. Sample size was a statistically significant predictor of publication for both randomized and nonrandomized trials (odds ratio [OR] per increase of 100 participants = 1.23 [1.11-1.36], p < .001; and 1.64 [1.15-2.34], p = .006, respectively). Among randomized studies, an industry coauthor or involvement of a cooperative group increased the likelihood of publication (OR 2.37, p = .013; and 2.21, p = .01, respectively). Among nonrandomized studies, phase II trials were more likely to be published than phase I (p < .001). Use of an experimental agent was not a predictor of publication in randomized (OR 0.76 [0.38-1.52]; p = .441) or nonrandomized trials (OR 0.89 [0.61-1.29]; p = .532).
                  Conclusion: This is the largest reported study examining why oncology trials are not published. The data show that 4-6 years after appearing as abstracts, 39% of oncology clinical trials remain unpublished. Larger sample size and advanced trial phase were associated with eventual publication; among randomized trials, an industry-affiliated author or a cooperative group increased likelihood of publication. Unfortunately, we found that, despite widespread recognition of the problem and the creation of central data repositories, timely publishing of oncology clinical trials results remains unsatisfactory.
                  Implications for Practice: The Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects notes the ethical obligation to report clinical trial data, whether positive or negative. This obligation is listed alongside requirements for risk minimization, access, confidentiality, and informed consent, all bedrocks of the clinical trial system, yet clinical trials are often not published, particularly if negative or difficult to complete. This study found that among American Society for Clinical Oncology (ASCO) Annual Meeting abstracts, 2009-2011, only 61% were published 4-6 years later: 75% of randomized trials and 54% of nonrandomized trials. Clinicians need to insist that every study in which they participate is published.

                9. Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC. Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011. JAMA Intern Med. 2016 Mar 21. [Epub ahead of print]
                10. Importance: Prescription and over-the-counter medicines and dietary supplements are commonly used, alone and together, among older adults. However, the effect of recent regulatory and market forces on these patterns is not known.
                  Objectives: To characterize changes in the prevalence of medication use, including concurrent use of prescription and over-the-counter medications and dietary supplements, and to quantify the frequency and types of potential major drug-drug interactions.
                  Design, Setting, and Participants: Descriptive analyses of a longitudinal, nationally representative sample of community-dwelling older adults 62 to 85 years old. In-home interviews with direct medication inspection were conducted in 2005-2006 and again in 2010-2011. The dates of the analysis were March to November 2015. We defined medication use as the use of at least 1 prescription or over-the-counter medication or dietary supplement at least daily or weekly and defined concurrent use as the regular use of at least 2 medications. We used Micromedex to identify potential major drug-drug interactions.
                  Main Outcomes and Measures: Population estimates of the prevalence of medication use (in aggregate and by therapeutic class), concurrent use, and major drug-drug interactions.
                  Results: The study cohort comprised 2351 participants in 2005-2006 and 2206 in 2010-2011. Their mean age was 70.9 years in 2005-2006 and 71.4 years in 2010-2011. Fifty-three percent of participants were female in 2005-2006, and 51.6% were female in 2010-2011. The use of at least 1 prescription medication slightly increased from 84.1% in 2005-2006 to 87.7% in 2010-2011 (P = .003). Concurrent use of at least 5 prescription medications increased from 30.6% to 35.8% (P = .02). While the use of over-the-counter medications declined from 44.4% to 37.9%, the use of dietary supplements increased from 51.8% to 63.7% (P < .001 for both). There were clinically significant increases in the use of statins (33.8% to 46.2%), antiplatelets (32.8% to 43.0%), and omega-3 fish oils (4.7% to 18.6%) (P < .05 for all). In 2010-2011, approximately 15.1% of older adults were at risk for a potential major drug-drug interaction compared with an estimated 8.4% in 2005-2006 (P < .001). Most of these interacting regimens involved medications and dietary supplements increasingly used in 2010-2011.
                  Conclusions and Relevance: In this study, the use of prescription medications and dietary supplements, and concurrent use of interacting medications, has increased since 2005, with 15% of older adults potentially at risk for a major drug-drug interaction. Improving safety with the use of multiple medications has the potential to reduce preventable adverse drug events associated with medications commonly used among older adults.

                11. Yeh JS, Sarpatwari A, Kesselheim AS. Ethical and Practical Considerations in Removing Black Box Warnings from Drug Labels. Drug Saf. 2016 Mar 21. [Epub ahead of print]
                12. Boxed warnings-also known as “black box” warnings-can be a powerful tool in communicating drug risks to physicians and patients. The overall number of boxed warnings has grown in recent years as the US Food and Drug Administration (FDA) has approved more drugs on the basis of limited pre-marketing information and as new safety issues for marketed drugs have been identified. Two recent manufacturers’ petitions to remove boxed warnings on the drugs rosiglitazone (Avandia) and varenicline (Chantix) have led to divergent FDA decisions and revealed different considerations involved in boxed warning imposition and removal. For ethical and practical reasons, the FDA is justified in applying a higher standard for boxed warning removal than for imposition, as removal of a boxed warning may have unintended effects on physician and patient behavior. However, no guidelines on boxed warning removal currently exist. To promote safe use of approved prescription drugs, the FDA should adopt a uniform and transparent process governing decisions to impose or remove boxed warnings.

                  February 2016

                  1. Chen R, Desai NR, Ross JS, Zhang W, Chau KH, Wayda B, Murugiah K, Lu DY, Mittal A, Krumholz HM. Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers. BMJ. 2016 Feb 17;352:i637.
                  2. Objective: To determine rates of publication and reporting of results within two years for all completed clinical trials registered in ClinicalTrials.gov across leading academic medical centers in the United States.
                    Design: Cross sectional analysis.
                    Setting: Academic medical centers in the United States.
                    Participants: Academic medical centers with 40 or more completed interventional trials registered on ClinicalTrials.gov.
                    Methods: Using the Aggregate Analysis of ClinicalTrials.gov database and manual review, we identified all interventional clinical trials registered on ClinicalTrials.gov with a primary completion date between October 2007 and September 2010 and with a lead investigator affiliated with an academic medical center.
                    Main Outcome Measures: The proportion of trials that disseminated results, defined as publication or reporting of results on ClinicalTrials.gov, overall and within 24 months of study completion.
                    Results: We identified 4347 interventional clinical trials across 51 academic medical centers. Among the trials, 1005 (23%) enrolled more than 100 patients, 1216 (28%) were double blind, and 2169 (50%) were phase II through IV. Overall, academic medical centers disseminated results for 2892 (66%) trials, with 1560 (35.9%) achieving this within 24 months of study completion. The proportion of clinical trials with results disseminated within 24 months of study completion ranged from 16.2% (6/37) to 55.3% (57/103) across academic medical centers. The proportion of clinical trials published within 24 months of study completion ranged from 10.8% (4/37) to 40.3% (31/77) across academic medical centers, whereas results reporting on ClinicalTrials.gov ranged from 1.6% (2/122) to 40.7% (72/177).
                    Conclusions: Despite the ethical mandate and expressed values and mission of academic institutions, there is poor performance and noticeable variation in the dissemination of clinical trial results across leading academic medical centers.

                  3. Doshi P, Jefferson T. Open data 5 years on: a case series of 12 freedom of information requests for regulatory data to the European Medicines Agency. Trials. 2016 Feb 11;17(1):78.
                  4. Background: Clinical trial (and other) data from the European Medicines Agency (EMA) offers the best available opportunity to address the extensive reporting bias in pharmaceutical trial literature. Data are requested via freedom of information requests, but 5 years on, little is known about how the system is working.
                    Methods: Case series of 12 requests for regulatory data (clinical study reports and other regulatory data) relating to 29 different compounds. We logged start and end dates for correspondence with and data releases from the EMA, the need for additional correspondence and appeal of initial negative decisions, and inspected data releases for redaction. We measured: time from initial request to first substantive response from the EMA, to final decision from the EMA (in case of appeal), to initial receipt of documents, and to completion of request; number of data transmission batches generated; number of pages received for each request; average number of pages per batch over time (for releases in multiple batches); judgment as to whether the request was satisfied.
                    Results: We found great variability in time to receive an initial decision from the EMA (1 to 13 weeks). Additional correspondence with the EMA was necessary in 10 of 12 requests. Four of 12 were initially refused but 3 of 4 were allowed on appeal after 3 to 33 additional weeks. One request was denied despite appeal. Time to final decision was 1 to 43 weeks. We received data for 11 of 12 requests in 98 batches. While two requests remain outstanding as at June 2015 the remaining nine requests took a median 43 weeks to completion (range: 17 to 186 weeks). Despite redaction in 10 of 11 releases (mainly of researcher and participant identifying information), 8 requested were wholly satisfied.
                    Conclusions: The EMA is the only regulator in the world that is routinely releasing original clinical trial data, but release can take considerable time to occur and often only after a lengthy correspondence. Given its importance for research and significance for transparency we suggest ways in which the process could be made more efficient.

                  5. Hwang TJ, Kesselheim AS. Vaccine Pipeline Has Grown During The Past Two Decades With More Early-Stage Trials From Small And Medium-Size Companies. Health Aff (Millwood). 2016 Feb 1;35(2):219-26.
                  6. Many serious diseases lack safe and effective vaccines. Using a large commercial database, we examined trends in global vaccine research and development and found that the proportion of new vaccine candidates entering all stages of clinical development increased by 3-5 percentage points over the past two decades. Small and medium-size companies accounted for nearly twice as many new Phase I vaccine trials compared to large companies, but late-stage (Phase III) vaccine trials were dominated by large companies. There were no significant differences between vaccines and drugs in the probability of success in clinical trials or in profitability. Small and medium-size companies, including spin-outs from academic research centers, play an important role in innovative research and discovery. Our findings suggest that policy making targeted at smaller companies, such as prizes or opportunities for public-private partnerships, could support the development of new vaccines, particularly those targeting unmet medical needs and emerging public health threats.

                  7. Kesselheim AS, Gagne JJ Franklin JM, Eddings W, Fulchino LA, Avorn J, Campbell EG. Variations in Patients’ Perceptions and Use of Generic Drugs: Results of a National Survey. J Gen Intern Med. 2016 Feb 16. [Epub ahead of print]
                  8. Background: Over 84 % of all prescriptions in the US are filled as generic drugs, though in prior surveys, patients reported concerns about their quality.
                    Objective: We aimed to survey patients’ perceptions and use of generic drugs.
                    Design: Our survey (administered August 2014) assessed patients’ skepticism about generic drug safety and effectiveness and how often they requested brand-name drugs. Chi-square tests and two-sample t-tests assessed associations between patient demographics and the outcomes.
                    Participants: Our sample frame was the CVS Advisor Panel, a national database of 124,621 CVS customers. We randomly selected 1450 patients with self-reported chronic conditions who filled at least one prescription in the prior 3 months.
                    Main Measures: We assessed how often patients reported asking their physicians to prescribe a brand-name over a generic drug in the last year, and “generic skepticism,” defined as not believing generic drugs were as safe, effective, had the same side effects, and contained the same active ingredients as brand-name drugs.
                    Key Results: Of the 1,442 patients with valid addresses, 933 responded (65 % response rate) and 753 took the full survey. A vast majority (83 %) agreed that physicians should prescribe generic drugs when available, and 54 % said they had not asked their physicians to prescribe a brand-name drug over a generic in the past year. Most respondents considered generic drugs to be as effective (87 %) and safe (88 %) as their brand-name counterparts, and to have the same side effects (80 %) and active ingredients (84 %). Non-Caucasians were more likely than Caucasians to request a brand-name drug over a generic (56 % vs. 43 %, p < 0.01), and were also more skeptical of generic drugs' clinical equivalence (43 % vs. 29 %, p < 0.01).
                    Conclusions: We found a substantial shift towards more patients having positive views of generic drugs, but lingering negative perceptions will have to be overcome to ensure continued cost-savings and improved patient outcomes from generic drugs.

                  9. Lyapustina T, Rutkow L, Chang HY, Daubresse M, Ramji AF, Faul M, Stuart EA, Alexander GC. Effect of a “pill mill” law on opioid prescribing and utilization: The case of Texas. Drug Alcohol Depend. 2016 Feb 1;159:190-7.
                  10. Background: States have attempted to reduce prescription opioid abuse through strengthening the regulation of pain management clinics; however, the effect of such measures remains unclear. We quantified the impact of Texas’s September 2010 “pill mill” law on opioid prescribing and utilization.
                    Methods: We used the IMS Health LRx LifeLink database to examine anonymized, patient-level pharmacy claims for a closed cohort of individuals filling prescription opioids in Texas between September 2009 and August 2011. Our primary outcomes were derived at a monthly level and included: (1) average morphine equivalent dose (MED) per transaction; (2) aggregate opioid volume; (3) number of opioid prescriptions; and (4) quantity of opioid pills dispensed. We compared observed values with the counterfactual, which we estimated from pre-intervention levels and trends.
                    Results: Texas’s pill mill law was associated with declines in average MED per transaction (-0.57mg/month, 95% confidence interval [CI] -1.09, -0.057), monthly opioid volume (-9.99kg/month, CI -12.86, -7.11), monthly number of opioid prescriptions (-12,200 prescriptions/month, CI -15,300, -9,150) and monthly quantity of opioid pills dispensed (-714,000 pills/month, CI -877,000, -550,000). These reductions reflected decreases of 8.1-24.3% across the outcomes at one year compared with the counterfactual, and they were concentrated among prescribers and patients with the highest opioid prescribing and utilization at baseline.
                    Conclusions: Following the implementation of Texas’s 2010 pill mill law, there were clinically significant reductions in opioid dose, volume, prescriptions and pills dispensed within the state, which were limited to individuals with higher levels of baseline opioid prescribing and utilization.

                  11. Moore TJ, Furberg CD, Mattison DR, Cohen MR. Completeness of serious adverse drug event reports received by the US Food and Drug Administration in 2014. Pharmacoepidemiol Drug Saf. 2016 Feb 10. [Epub ahead of print]
                  12. Purpose: Adverse drug event reports to the US Food and Drug Administration (FDA) remain the primary tool for identifying serious drug adverse effects without adequate existing warnings. We assessed the completeness of reports the FDA received in 2014.
                    Methods: Serious adverse drug event reports were evaluated for whether they included age, gender, event date, and at least one medical term describing the event in computer excerpts. Report sources were direct reports to the FDA, manufacturer expedited reports about events without adequate warnings, and manufacturer periodic reports about events with existing warnings.
                    Results: In 2014, the FDA received 528,192 new case reports indicating a serious or fatal outcome, 25,038 (4.7%) directly from health professionals and consumers, and 503,154 (95.3%) from drug manufacturers. Overall, 21,595 (86.2%) of serious reports submitted directly to the FDA provided data for all four completeness variables, compared with 271,022 (40.4%) of manufacturer expedited reports and 24,988 (51.3%) of periodic reports. Among manufacturer serious reports, 37.9% lacked age and 46.9% had no event date. Performance by 25 manufacturers submitting 5000 or more reports varied from 24.4% complete on all variables to 67% complete. Patient death cases had the lowest completeness scores in all categories.
                    Conclusions: By these measures, report completeness from drug manufacturers was poor compared with direct submissions to the agency. The FDA needs to update reporting requirements and compliance policies to help industry capture better adverse event information from new forms of manufacturer interactions with health professionals and consumers.

                  13. Phillips AT, Rathi VK, Ross JS. Publication of Clinical Studies Supporting FDA Premarket Approval for High-Risk Cardiovascular Devices Between 2011 and 2013: A Cross-sectional Study. JAMA Intern Med. 2016 Feb 22. [Epub ahead of print]
                  14. This study examines the publication and reporting of studies supporting novel high-risk cardiovascular devices approved by the US Food and Drug Administration. Selective publication of clinical studies supporting US Food and Drug Administration (FDA) approval of novel drugs and devices prevents patients and physicians from making informed decisions about these products. Among 149 novel therapeutics approved by the FDA between January 2005 and December 2011, a total of 326 of 380 (85.8%) supporting pivotal studies were published. In contrast, less than half of all studies supporting FDA Premarket Approval (PMA) of novel, high-risk cardiovascular devices between January 2000 and December 2010 were published, and more than one-fourth of these presented results in a manner discrepant with FDA reviews. It remains unknown whether contemporary practices of disseminating medical device research have improved in the wake of the 2007 FDA Amendment Act, which expanded the registration and reporting requirements on ClinicalTrials.gov to explicitly include medical devices. We therefore examined the publication and reporting of studies supporting novel, high-risk cardiovascular devices approved by the FDA between January 2011 and December 2013, which account for approximately half of all FDA PMAs, along with potential predictors of publication, including study, device, and company characteristics.

                  15. Sarpatwari A, Kesselheim AS. The Case for Reforming Drug Naming: Should Brand Name Trademark Protections Expire upon Generic Entry? PLoS Med. 2016 Feb 9;13(2):e1001955.
                  16. Ameet Sarpatwari and Aaron Kesselheim explore whether stripping branded drugs of trademark protection would improve the efficiency and fairness of health care.
                    Prozac, Lipitor, Viagra, and numerous other brand names for prescription drugs have entered the common vernacular in the United States (US). This is for good reason, since pharmaceutical manufacturers spend at least US$30 billion annually on marketing brand awareness to US physicians and patients [1]. Globally, the use of brand names in such advertising has persisted largely unquestioned as a means for manufacturers to distinguish innovator drugs from each other and from their generic equivalents. However, use of brand names also means that each new prescription drug automatically receives two names—its brand name and generic name—and perhaps even more, as brand names can vary from country to country (Prozac is also called Erocap, Lorien, Lovan, and Zactin outside the US). While prescription drug brand names can increase medication name recognition by patients and help differentiate products, they can also confuse patients and reduce appropriate use of generic drugs. Given increased pressure to reduce drug costs and use medicines safely and effectively, can the prescription drug naming system be improved?

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