Approval of cancer drugs with uncertain therapeutic value: a comparison of regulatory decisions in Europe and the United States

Policy Points Regulatory agencies may have limited evidence on the clinical benefits and harms of new drugs when deciding whether new therapeutic agents are allowed to enter the market and under which conditions, including whether approval is granted under special regulatory pathways and obligations to address knowledge gaps through postmarketing studies are imposed. In a matched comparison of marketing applications for cancer drugs of uncertain therapeutic value reviewed by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), we found frequent discordance between the two agencies on regulatory outcomes and the use of special regulatory pathways. Both agencies often granted regular approval, even when the other agency judged there to be substantial uncertainty about drug benefits and risks that needed to be resolved through additional studies in the postmarketing period. Postmarketing studies imposed by regulators under special approval pathways to address remaining questions of efficacy and safety may not be suited to deliver timely, confirmatory evidence due to shortcomings in study design and delays, raising questions over the suitability of the FDA's Accelerated Approval and the EMA's Conditional Marketing Authorization as tools for allowing early market access for cancer drugs while maintaining rigorous regulatory standards. Context: Regulatory agencies are increasingly required to make market approval decisions for new drugs on the basis of limited clinical evidence, a situation commonly encountered in cancer. We aimed to investigate how regulators manage uncertainty in the benefit-risk profiles of new cancer drugs by comparing decisions for the world's two largest regulatory bodies—the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)—over a 5-year period. Methods: We systematically identified a set of cancer drug-indication pairs for which data on efficacy and safety was less complete than that required for regular approval at time of market entry from 2009 to 2013, as determined by the FDA's use of Accelerated Approval (AA) or the EMA's use of Conditional Marketing Authorization (CMA) pathways, and matched these across the two agencies. Using publicly available information, we compared regulatory pathways and outcomes, final approved indications, and postmarketing obligations imposed by the agencies. Findings: We identified 21 cancer drug-indication pairs that received FDA AA, EMA CMA, or both. Although most applications relied on identical pivotal trials across the FDA and the EMA, regulatory pathways often differed; 57% of indications received either FDA AA or EMA CMA, and regular approval by the other agency. After approval, the EMA more often accepted single-arm studies to confirm clinical benefit compared to the FDA (75% vs. 29% of indications), and the FDA more commonly requested randomized controlled trials (85% vs. 50%). Forty-one percent of confirmatory trials after FDA AA were conducted in different populations than the approved indication, compared to 13% after EMA CMA. Both agencies relied primarily on surrogate measures of patient benefit for postmarketing obligations. After a median follow-up of 7.25 years, 40% of FDA and 61% of EMA postmarketing obligations after AA and CMA, respectively, were delayed. Conclusions: US and European regulators often deemed early and less complete evidence on benefit-risk profiles of cancer drugs sufficient to grant regular approval, raising questions over regulatory standards for the approval of new medicines. Even when imposing confirmatory studies in the postmarketing period through special approval pathways, meaningful evidence may not materialize due to shortcomings in study design and delays in conducting required studies with due diligence

Evolution of Self-Care Education

During the past 15 years, the curriculum content for nonprescription medication and self-care therapeutics has expanded significantly. Self-care courses ranging from stand-alone, required courses to therapeutic content and skills laboratories, have evolved in colleges and schools of pharmacy to accommodate rapid changes related to nonprescription medications and to meet the needs of students. The design of and content delivery methods used in self-care courses vary among institutions. Teaching innovations such as team-based learning, role playing/vignettes, videos, and social media, as well as interdisciplinary learning have enhanced delivery of this content. Given that faculty members train future pharmacists, they should be familiar with the new paradigms of Nonprescription Safe Use Regulatory Expansion (NSURE) Initiative, nonprescription medications for chronic diseases, and the growing trends of health and wellness in advancing patient-care initiatives. This paper reviews the significant changes that may be impacting self-care curriculums in the United States

Risk in CNS drug discovery: focus on treatment of Alzheimer's Disease

Despite rapid progress in our understanding of disease mechanisms and an exploding list of new targets for therapeutic intervention, drug discovery and development remains a highly risky business. Understanding the risk involved requires appreciation of the differing perspectives of risk held by the various stakeholders involved in drug research. Risk can be reduced by thoughtful management of drug candidate selection, careful planning and program execution by a team of engaged experts, and disciplined decision making. Drug development is particularly challenging for treatments of neurodegenerative diseases such as Alzheimer's disease, in which translation from animal models of efficacy to human success is poor or unknown, the timelines for clinical study are long, and the markers of efficacy are still evolving. Despite this there are several therapies in clinical development that hold the promise of influencing this disease through novel and possibly synergistic mechanisms

Systematic derivation of an Australian standard for Tall Man lettering to distinguish similar drug names

Rationale, aims and objectives - Confusion between similar drug names can cause harmful medication errors. Similar drug names can be visually differentiated using a typographical technique known as Tall Man lettering. While international conventions exist to derive Tall Man representation for drug names, there has been no national standard developed in Australia. This paper describes the derivation of a risk-based, standardized approach for use of Tall Man lettering in Australia, and known as National Tall Man Lettering. Method - A three-stage approach was applied. An Australian list of similar drug names was systematically compiled from the literature and clinical error reports. Secondly, drug name pairs were prioritized using a risk matrix based on the likelihood of name confusion (a four-component score) vs. consensus ratings of the potential severity of the confusion by 31 expert reviewers. The mid-type Tall Man convention was then applied to derive the typography for the highest priority drug pair names. Results - Of 250 pairs of confusable Australian drug names, comprising 341 discrete names, 35 pairs were identified by the matrix as an ‘extreme’ risk if confused. The mid-type Tall Man convention was successfully applied to the majority of the prioritized drugs; some adaption of the convention was required. Conclusion - This systematic process for identification of confusable drug names and associated risk, followed by application of a convention for Tall Man lettering, has produced a standard now endorsed for use in clinical settings in Australia. Periodic updating is recommended to accommodate new drug names and error reports

Exploring the Influence of Family on Adolescents’ Seafood Consumption Choices

Seafood in the adolescent diet has many benefits, yet a number of adolescents do not consume the recommended levels. Despite this the consumption of seafood by younger consumers has received scant attention in the extant literature. Previous studies on adolescents’ food-related behaviour tend to focus on general choice mechanisms or perceptions of food and mainly relate to fruit and vegetable intake. The present study seeks to address this gap through investigating the impact of family upon the consumption of seafood by younger consumers through exploring adolescents’ attitudes and behaviour in regard to eating seafood. Utilising an exploratory qualitative methodology, seven focus groups of adolescents aged 13–19 years were conducted at two schools in South-West England. Discussions covered a range of issues related to adolescent seafood consumption. The use of thematic content analysis found that the family, and parents in particular, exert high levels of influence over adolescents’ consumption of seafood both at home and when dining out. The parent who does the shopping and cooking has the greatest role. Sibling preferences and dietary choices also influence whether seafood is served in the home. Of value to researchers and management are the insights gleaned into the influences on adolescents’ attitudes toward and behaviour in regard to eating seafood. In particular encouraging seafood consumption will rely upon interventions aimed at both parents and children and need to take into account adolescents’ diet and lifestyle preferences, while also acknowledging the influence of peers and the school food environment

Examining the Psychometric Properties of the CEAC (Comparing e-Cigarette and Cigarette) Questionnaire and Its Usefulness as a Predictor of e-Cigarette Use

Background: Electronic cigarette (e-cigarette) use continues to rise, while there is conflicting evidence about the health effects of its use. As such, research is needed to better determine risks factors for e-cigarette use. Accumulating evidence suggests that attitudes toward e-cigarette use could be a potential risk factor for e-cigarette use. Objectives: This study sought to examine the psychometric properties of the Comparing E-cigarette And Cigarette questionnaire (CEAC), and to replicate a structural model of the relationship between impulsive-related personality traits and e-cigarette use mediated by positive attitudes toward e-cigarettes. Methods: Participants were 525 adults (mean age = 33.42, SD = 11.27) who completed the CEAC and UPPS-P (trait impulsivity) questionnaires online. Results: Confirmatory factor analysis of the CEAC replicated the a priori factor structure of the questionnaire reasonably well (χ2(df = 32) =172.85, CFI = 0.94, TLI = 0.91, RMSEA = 0.09 (0.08–0.11, 90% Confidence Interval, SRMR = 0.06). Structural path analysis showed that deficits in conscientiousness was significantly negatively related to e-cigarette attitudes (β = –0.20, p = .01), while urgency (β = 0.19, p = .018) showed a significant positive relationship to e-cigarette attitudes. E-cigarette users showed significantly more positive attitudes toward e-cigarettes than nonusers (β = 0.59, p < .001). No significant direct effects were found between impulsivity-related traits and e-cigarette use. Conclusions: The present study suggests that impulsivity-related traits and attitudes toward e-cigarettes are likely to be important risk factors for e-cigarette use. Future prospective and experimental studies should test if the causal model described in this study predicts risk for e-cigarette use, and whether this model could therefore be used to guide strategies for reducing risk for e-cigarette use

Reasons for non-vaccination against HPV and future vaccination intentions among 19-26 year-old women

<p>Abstract</p> <p>Background</p> <p>Despite CDC recommendations regarding universal catch-up vaccination against human papillomavirus (HPV), only about ten percent of young adult women in the United States have been vaccinated. The purpose of this study was to better understand reasons for non-vaccination among insured 19-26 year-old women and to evaluate future vaccination intentions.</p> <p>Methods</p> <p>We used an administrative claims database from a large US managed care plan to identify women aged 19-26 for receipt of a mailed survey. From a sample of 1,375 women with no evidence of HPV vaccination from June 1, 2006 through April 30, 2007, 222 completed surveys were received, of which 185 were eligible for this analysis. The main outcome measures were unvaccinated women's attitudes and vaccine awareness, likelihood of future action regarding the vaccine, and reasons for inaction.</p> <p>Results</p> <p>Among the 185 non-vaccinees, 25.4% were married, 83.2% were white, and 89.2% had a college or higher level education. The vaccine was described as very important by 32.4% of subjects, and 30.1% had discussed the vaccine with a doctor and received a doctor's recommendation. Half or fewer of respondents were "very" or "extremely" likely to discuss the vaccine with their doctor (50.0%), do additional research on the vaccine (42.6%), ask a doctor to get the vaccine (37.5%), or make an appointment to get the vaccine (27.8%), while 48.0% were "somewhat", "very", or "extremely" likely to do nothing to get the vaccine. Among the latter, reasons for taking no action included being married or in a monogamous relationship (54.9%), belief that the vaccine is too new (35.4%), not having enough information about the vaccine (31.7%), concerns about side effects (24.4%), and uncertainty about insurance coverage (24.4%).</p> <p>Conclusions</p> <p>Educational interventions may be needed to enhance HPV vaccination rates among 19-26 year-old women, particularly regarding information about vaccine safety, vaccine efficacy, insurance coverage, and the value of vaccination to women in monogamous relationships.</p

Analysis of Canadian and Irish forage, oats and commercially available equine concentrate feed for pathogenic fungi and mycotoxins

Respiratory infections, recurrent airway obstruction (RAO) and exercise induced pulmonary haemorrhage (EIPH) are major causes of poor performance in horses. Fungi and mycotoxins are now recognised as a major cause of these conditions. The most notable fungi are Aspergillus and Fusarium. Fungal spores can originate from forage, bedding and feed and, in turn, these fungal spores can produce a series of mycotoxins as secondary metabolites