Select search scope: search across all journals or within the current journal
Restricted accessEditorialFirst published May, 2017pp. 272-273
Restricted accessResearch articleFirst published May, 2017pp. 274-275
Restricted accessResearch articleFirst published May, 2017pp. 276-284A cross-section of clinical research professionals convened at the June 2016 Drug Information Association annual meeting in Philadelphia to discuss and critically analyze the first-in-human (FIH) clinical trial conducted by a French CRO with BIA 10-2474 (BIA) under development for pain relief by Bial-Portela & Ca., S.A., that resulted in 6 healthy volunteers hospitalized with serious adverse events, which resulted in 1 death. This paper summarizes the background, presentations, and discussion points of Symposium no. 107 in an effort to share the learnings of our symposium with others who conduct studies. Novel investigational products studied in phase 1 clinical trials propose a heightened risk of adverse events that may not be foreseeable when relying on animal studies to project outcomes in humans. Novelty of molecular structure, drug class, mechanism of action, proper dose selection, pharmacokinetics, and therapeutic window are all contributing factors that heighten risks when transitioning from animal to human trials. The potential for catastrophic events confronts every sponsor/investigator in clinical trials. Minimizing risks to subjects is an essential ethical and scientific mandate for all those involved in the clinical trials. A complex matrix of planning, conducting, and communicating preclinical and clinical observations need to be considered carefully by the Sponsor, Investigator and others during the planning, execution, and interpretation of FIH studies, in order to promote participant safety and study data integrity. Suggestions may be applied to FIH studies, which may provide a new or improved way to address complex system and prevent or mitigate situations such as what occurred with the Bial FIH trial, where seemingly a number of issues coincided in a “perfect storm” and the system failed to sound a warning or detect an issue before a life was tragically lost.
Restricted accessResearch articleFirst published May, 2017pp. 285-287The clinical research industry is changing, and the number of protocols requiring specialty populations for early-phase clinical studies is increasing. In particular, the demand for studies on renal specialty populations has grown, given the prominent role of the renal system in excreting drugs from the body. Understanding the challenges associated with the use of specialty populations is critical to ensure that the study design will allow for the timely and successful completion of the project, while minimizing costs and safety risks.
Restricted accessResearch articleFirst published May, 2017pp. 288-297We describe a structured risk assessment and risk mitigation process that is currently used to evaluate proposed first-in human (FiH) studies. This process balances the inherent risks of an FiH study with maximal protection of subjects. Risk assessment should consider all available data, carefully identifying aspects that may lead to risk for healthy subjects. A structured risk assessment avoids omissions and promotes consistency. Such a risk assessment should be performed for Investigational Products as well as for challenge agents and study procedures. Careful risk assessment recognizes gaps of knowledge and emphasizes that FiH studies are tolerability, not toxicity, studies.
Restricted accessResearch articleFirst published May, 2017pp. 298-302This paper summarizes a discussion that took place at the 52nd Annual DIA Meeting in Philadelphia, PA, on June 30, 2016, titled “Hot-Button Protocol and Operational Issues between Sponsors and Sites in Clinical Pharmacology Studies.” The symposium was a moderated panel of phase 1 clinical research experts representing the sponsor, and investigational sites. Conference attendees of similar experience joined in the discussion after commentary by each panelist. The learning objectives of the symposium were (1) to recognize issues that can provoke sponsor/site conflict or diminish conduct efficiency when they arise in the course of preparing to conduct or execution of phase 1 clinical studies, (2) to discuss how to handle such issues with counterparts when they arise and describe ways to negotiate and formulate a successful resolution. Sponsors and sites both have challenges in executing clinical trials on time and within budget. Both need to set and maintain realistic expectations and communicate with honesty, transparency, and timeliness. Achieving this goal will advance the more important take-away message, that developing new drugs requires sound execution of clinical trials.
Restricted accessResearch articleFirst published May, 2017pp. 303-303
Restricted accessResearch articleFirst published May, 2017pp. 304-306Endpoints are the cornerstone of clinical trial design and are the critical elements for evaluating the success of a clinical study. Endpoints are communicated in clinical protocols, study reports, study registration and result posting sites, as well as publications. It is, therefore, important that endpoints are presented consistently, correctly, and completely. The FDAAA Final Rule expectations of describing endpoints in specific terms provides a way to keep this consistency across all documents.
Restricted accessResearch articleFirst published May, 2017pp. 307-313Ecuador is undergoing a process of clinical research development and strengthening. At the turn of the century, Ecuador experienced a favorable transition period of economic stability, which enabled advances in the health system and improvements in population welfare indicators. During this period, Ecuador created an institutional infrastructure to support the implementation and development of research projects. In turn, Ecuador created institutions, including the National Agency for Health Regulation, Control, and Surveillance (Agencia Nacional de Regulación, Control y Vigilancia Sanitaria [ARCSA]), and regulations establishing clinical trial (CT) design, conduct, recording, and reporting parameters, whose compliance ensures the protection of the rights of research subjects and requires compliance with Good Clinical Practice (GCP). Ecuador has favorable conditions for fostering the development of clinical research. The regulation of CTs is a process undergoing consistent changes toward harmonization with international standards and quality assurance.
Restricted accessResearch articleFirst published May, 2017pp. 314-321The level of job satisfaction among clinical research associates (CRAs) is of importance because it may affect CRAs’ retention, turnover, and then further affect the quality of clinical trials.
The objectives of this study were to (1) examine the level of job satisfaction among CRAs in China and (2) explore the association between CRAs’ demographic and work-related characteristics and their job satisfaction.
A Chinese CRA job satisfaction questionnaire was developed to measure CRAs’ attitudes in relation to their job. The questionnaire contained 6 subcomponents, including work content, work reward, supervisors, coworkers, investigators, and organization administration. Then an anonymous cross-sectional web-based survey was conducted among CRAs in China.
465 valid questionnaires were received (93% response rate). The overall job satisfaction of Chinese CRAs was moderate. As for the individual subcomponents, coworkers ranked the highest and work reward ranked the lowest. The female group was more satisfied with investigators than were the male group. Different scores with supervisors were seen among age groups. Different scores with overall satisfaction, work reward, and organizational administration were seen among geographic location groups and also among company type groups. There were no significant differences in job satisfaction based on marital status, education level, and working position of the respondents.
Chinese CRAs were moderately satisfied with their job. They were most satisfied with coworkers and most dissatisfied with work reward. Further, Chinese CRAs’ job satisfaction levels were more related with work-related characteristics, including geographic location and company type.
Restricted accessResearch articleFirst published May, 2017pp. 322-326The debate over off-label communications doesn’t begin or end with the
Restricted accessResearch articleFirst published May, 2017pp. 327-331Medical Information Centers (MedInfo Centers) at pharmaceutical companies receive a high volume of requests for product-related information. While this service is generally restricted to working hours, the use of a web-based self-service portal allows provision of information 24 hours a day 7 days a week (24/7).
In 2012 Sanofi (Frankfurt, Germany) launched their web-based self-service portal, which provides Medical Information for all Sanofi products in a nonpromotional manner. Here, we present data on the background and evolution of the service over time, as well as the rate of acceptance by pharmacists, physicians, and patients.
In the pilot phase of portal development (July 2012–January 2013), we provided information such as the summary of product characteristics (SmPC) and a list of frequently asked questions (FAQs). These were subsequently followed by patient information leaflets (PILs), as of February 2013. While SmPCs and FAQs were initially password protected, German drug law allowed us to make the PILs and SmPCs openly available in February 2013. Once content was obtainable without authentication, a good uptake of the online service for accessing both SmPCs and PILs was observed, while FAQs were initially less popular. Subsequent redesign of the user interface, provision of more access options and revision of content based on search engine optimization was able to substantially increase the use of FAQs. The web-based self-service portal led to the number of MedInfo Center requests falling by about 20% within the observation phase, with a corresponding increase in the use of web-based self-service.
The increasing demand for 24/7 information coupled with the wide accessibility of the Internet has led to a movement toward redirecting information requests received by pharmaceutical companies to the web. We have found that, wherever possible, publishing information in open-access areas and keeping the navigation simple are key factors in the success of this service.
Restricted accessResearch articleFirst published May, 2017pp. 332-341Although asthma attacks are known adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use, few studies have quantified these risks. The objectives of this study were to utilize an epidemiological approach to quantitatively evaluate the risk of acute asthma attacks associated with NSAID prescription in Japan and to compare the risks among NSAIDs according to their cyclooxygenase (COX)–2 selectivity.
We conducted a self-controlled case series study using Japanese health insurance claims data. Exposed cases were identified as those who had experienced both NSAID prescription and acute asthma attack, which was defined as the combination of an inhalation procedure and the prescription of any inhaled β2-agonist. The incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for NSAID prescription periods compared with baseline periods were calculated using conditional Poisson regression models; COX-2 selective and nonselective NSAIDs were similarly compared.
We identified 9769 subjects, more than 95% of whom were younger than 60 years. There was a significantly higher risk of acute asthma attacks during the NSAID prescription period when compared with the baseline period. The quantified IRRs were, in descending order, 93.94 (95% CI, 90.10-97.95) for the prescription start date, 3.96 (95% CI, 3.63-4.33) for 1 to 9 days after the prescription start date, 3.01 (95% CI, 2.78-3.25) for 7 days after the prescription end date, 2.19 (95% CI, 1.82-2.65) for >9 days after the prescription start date, and 1.44 (95% CI, 1.29 -1.61) for 7 days before the prescription start date. There were lower asthmatic risks for COX-2 selective NSAIDs compared with nonselective NSAIDs.
The use of NSAIDs in Japan was associated with an increased risk of acute asthma attacks. However, this risk was lower in COX-2 selective NSAIDs.
Restricted accessResearch articleFirst published May, 2017pp. 342-351Labeling decisions for core labeling and/or local labeling capture the outcome of all discussions on the product statements that are necessary to ensure safe and effective handling of pharmaceutical products, with a special focus on the decision concerning known, suspected, or hypothetical risks. Such decisions may determine if a topic is to be included in the label or provide a rationale for exclusion from the label. The need to provide special advice to users and the type of advice (eg, contraindications, precautions) are subject to labeling decisions as well. While the problem is well known to pharmaceutical companies, and technical solutions such as XML-based authoring/coding systems try to offer support from the information technology sector to handle the business problem, the current identification of medicinal products (IDMP) requirements raised by health authorities worldwide have put a new focus on the problem. This article will elaborate on the basic business problem and its requirements with respect to a solution.
Restricted accessResearch articleFirst published May, 2017pp. 352-354Rapid advances in technology and our understanding of disease will lead to a shift in how the health care system thinks about data, which will in turn challenge current regulatory constructs. In the future, there will be a shift away from milestone-based data to continuous, contextual data; we believe this data shift will impact the current model of medical product regulation, with potential implications across the regulatory landscape, reflecting the convergence of clinical development and clinical practice.
Restricted accessResearch articleFirst published May, 2017pp. 355-359The Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA) have provided a wide range of regulatory and scientific consultation menus to cover any development stage of drugs and regenerative medicine products, respectively. The current study compares Consultations by PMDA and Scientific Advice by EMA in terms of consultation types, consultation performances, and specific consultation procedures with timelines. Each agency sets intensive but highly professional procedures and timelines in order to provide sufficient advice in a timely manner. Both agencies complete the consultation process for approximately 3 months while an application is reviewed by experts and close communication with the applicant is provided. Although PMDA and EMA have some differences of approaches to provide well-considered scientific opinions as quickly as possible, both agencies have made efforts to support the development of better products for patients. Sharing technical insights through consultation experiences will contribute to earlier access of patents to new products in both Japan and the EU.
Restricted accessResearch articleFirst published May, 2017pp. 360-371Pediatric legislation in the US and the EU is driving pediatric product development on an international scale. To facilitate harmonization and global development of pediatric medicines, it is important to understand the legislative requirements that must be met along with incentives that exist in the US and the EU to include pediatric patients in therapeutic clinical trials. Although there are many similarities, differences exist. This review is an effort to enhance understanding of the pediatric legislation in both regions. It is intended as an overview to supplement the region-specific legislation and guidance documents that are available on the websites of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite differences, the goal of the legislation in both the EU and the US is to incentivize and require timely, ethical, and sound scientific development of pharmaceutical products for the pediatric population and to provide information for their safe and effective use.
Restricted accessResearch articleFirst published May, 2017pp. 372-379The objective of this research was to develop a caregiver-reported clinical outcome assessment (COA) measure designed to assess observable behaviors of children, ages 4 to 12 years, with autism spectrum disorder (ASD) for supporting labeling claims of treatment benefit.
Development of the measure included a review of the literature and existing instruments, conceptual disease model development, concept elicitation focus groups, item generation, and cognitive debriefing interviews.
Predominant characteristics and behaviors of ASD identified by the literature and instrument reviews included sociability, communication deficits, stereotypy, inattention and hyperactivity, irritability, anxiety, and familial impact. In each of the 10 instruments reviewed, evidence of content validity was limited or nonexistent. Predominant themes arose across 8 major categories during concept elicitation. A total of 27 concepts were identified through focus group feedback and formed the basis for item development and cognitive pre-testing. Revisions to the items yielded a final version of a daily diary containing 21 items assessing observable behaviors and characteristics of ASD in children 4 to 12 years old.
The Observable Behaviors of ASD Scale (OBAS) was developed as a self-administered, caregiver-reported measure containing 8 predominant themes. Items are scored on one of two 5-point ordinal categorical response scales, and the recall period for each item is “the past 24 hours.” This research provides evidence that the OBAS is content valid for assessing treatment benefit, which was found to be lacking in other instruments.
Restricted accessResearch articleFirst published May, 2017pp. 380-390Numerous statistically derived composite measures have recently been proposed as clinical outcome assessments (COAs) for clinical trials in the early stages of Alzheimer disease. Critical Path Institute’s Coalition Against Major Diseases (CAMD) advanced a proposed statistically derived composite measure to regulatory agencies with the goal of qualifying it as a COA for pre-dementia trials. In response to FDA’s requirement to demonstrate that proposed COAs are meaningful to patients, this project aimed to identify the most important cognition-related concerns patients and informants report early in the disease and determine how this information maps to what is assessed by several statistically derived composite measures.
Leveraging qualitative research completed by Critical Path Institute’s Patient-Reported Outcome Consortium, CAMD utilized a summary report that included frequency grids of reported concerns of amnestic mild cognitive impairment patients and their informants, as well as the narrative transcripts from focus groups. Transcripts were reviewed and analyzed to identify which cognitive domains the patient- and informant-reported concerns mapped onto. The results were then compared to see how well these cognitive domains were represented in various statistically derived composite measures.
The patient- and informant-reported concerns primarily mapped to the cognitive domains of episodic memory and, secondarily, orientation and language. Depending on the specified composite, there were varying levels of alignment between their subcomponents and these cognitive domains.
Through secondary analyses of existing qualitative data, this study examined several statistically derived composite measures and found that they generally capture cognitive domains that reflect aspects of day-to-day functioning that patients and informants consider meaningful.