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Restricted accessEditorialFirst published November, 2015pp. 780-782
Restricted accessResearch articleFirst published November, 2015pp. 783-791Field-based patient-reported outcome (PRO) assessments, including measures of signs, symptoms, and events that are administered outside of the research clinic, can be critical in evaluating the efficacy and safety of new medical treatments. Collection of this type of data commonly involves providing subjects with stand-alone electronic devices, such as smartphones, that they can use to respond to assessments in their home or work environment. Although this approach has proven useful, it is also limited in several ways: For example, provisioning stand-alone devices can be costly for sponsors, and requiring subjects to carry a device that is exclusively dedicated to the study can be burdensome. The “Bring Your Own Device” (BYOD) approach, in which subjects use their own smartphone or Internet-enabled device to complete field-based PRO assessments, addresses many of these concerns. However, the BYOD model has its own limitations that should be considered. In this article, representatives of the ePRO Consortium review operational, privacy/security, and scientific/regulatory considerations regarding BYOD. We hope that this review will allow researchers to make informed decisions when choosing methods to collect field-based PRO data in future clinical trials. Additionally, we hope that the discussion in this article will establish a research agenda for further examination of BYOD approaches.
Restricted accessResearch articleFirst published November, 2015pp. 792-796The increase in the use of electronic patient-reported outcome (ePRO) instruments has presented study teams with considerations not previously encountered with paper. Specifically, in an effort to minimize missing data, there is now the opportunity of requiring subjects to provide a response to an item before allowing the subject to proceed to the next item. While the ability to require subjects to respond to ePRO items would seem to guarantee a complete data set, it raises questions about the conditions under which it is appropriate to require subjects to respond to the items in an instrument. This article provides guidance on the circumstances under which allowing a subject to opt out of responding to ePRO items may be appropriate. Three main scenarios are discussed: (1) requiring subjects to complete all items in all the instruments in the study, (2) allowing subjects to opt out of at least some selective items that do not support key primary or secondary endpoints, and (3) allowing subjects to opt out of responding to any or all items in the study. For either of the 2 scenarios allowing the subject to opt out of responding to an item, the use of programmed edit checks is highly recommended to confirm that the subject intended to “skip” or “opt out of” the item. This ensures that, at the end of the study, the database contains an explicit data point indicating when a subject has actively decided to skip an item. While this article is focused on patient-reported outcomes, the issues raised could also apply to other clinical outcome assessments, such as clinician- and observer-reported outcomes.
Restricted accessResearch articleFirst published November, 2015pp. 797-804For a number of compelling scientific, operational, and regulatory reasons, the use of electronic data capture is becoming the preferred means of collecting clinical outcome assessment (eg, patient-reported outcome [PRO]) data in clinical trials. Electronic PRO (ePRO) data collection leverages screen-based technologies (eg, handheld devices, tablet computers, and web-based systems) and telephone-based (eg, interactive voice response) systems. Data collection is routinely either site based (ie, clinical study site) or field based (eg, subject’s home, school, or workplace). While tablet computers are often used for site-based PRO data collection, handheld devices have become the mainstay for ePRO data capture in field-based settings. The data collection devices are usually provisioned to the sites or subjects by an ePRO system provider contracted by the clinical trial sponsor. With site-based data collection, study staff are responsible for ensuring subject compliance with the protocol-driven data collection procedures, whereas with field-based data collection, the subject is responsible for compliance with the data entry requirements and sites are accountable for remotely monitoring the data for compliance. In addition to site and subject compliance issues, technology-related factors must be anticipated in order to adhere to the electronic PRO data collection plan. The objective of this paper is to describe study site-, subject-, and technology-related factors that may lead to deviations from the planned electronic collection of PRO data (eg, defaulting to paper-based data collection) and to provide recommendations aimed at preventing potential problems or quickly resolving problems once they occur.
Restricted accessResearch articleFirst published November, 2015pp. 805-812Historically, the assessment of longitudinal construct validity in the field of psychosocial measurement involved defining hypotheses and calculating correlation coefficients using scores based on 2 measures at 2 or more time points. In the context of patient-reported outcomes, this evolved into sensitivity to change and responsiveness, including the computation of effect size estimates of change, standardized response means, and indices such as Guyatt’s statistic. Cross-sectional analyses or analyses based on 2 time points have been the standard practice. Evolving conceptualizations have incorporated more than 2 time points and have included depictions of individual trajectories of change in multiple measures, structural equation models, and mixed modeling techniques. The focus of this article is on methods to evaluate longitudinal construct validity. We describe a sample of these methods and provide considerations and recommendations for designing a thoughtful longitudinal construct validity evaluation of clinical outcome assessments.
Restricted accessResearch articleFirst published November, 2015pp. 813-821By bringing data collection closer to real time and minimizing recall bias, patient diaries or event-driven logs offer substantial benefits over retrospective questionnaires for many patient-reported disease concepts. Such assessments are increasingly used to support primary and secondary endpoints in randomized controlled trials. These diaries have the potential to provide more reliable and valid assessment of patients’ subjective experiences of symptoms and disease events. However, use of such diaries presents significant and unique challenges depending on the context of use. Of note, while symptom-related label claims are those most frequently granted by regulatory authorities, no guidance specific to support the development, psychometric evaluation, and interpretation of endpoints derived from patient diaries exists. This article provides an overview of key methodological, statistical, and clinical considerations for implementation of patient diaries with a regulatory perspective in mind. Approaches and solutions covered in this article include (1) techniques to establish content validity based on obtaining qualitative insights in naturalistic settings and real-life experience of diary completion, (2) demonstration of psychometric properties with respect to day-to-day variability, and (3) aggregation of data from multiple days/events to move from items to endpoints. The importance of the patients’ engagement is highlighted in order to help overcome these challenges throughout all stages of diary and endpoint development and evaluation. This article can inform researchers who are developing or implementing patient diaries as clinical trial endpoints to ensure that the nuances of this mode of data collection are considered in the development of endpoints and prior to regulatory interactions.
Restricted accessResearch articleFirst published November, 2015pp. 822-830Patients with cancer frequently experience multiple symptoms that may cause significant distress and may impair physical, emotional, and social functioning and health-related quality of life. Drug development in oncology is characterized by a high attrition rate of new compounds, faster development times encouraged by the regulatory process, studies that are often open and single-arm, and emphasis on survival-related endpoints, creating unique challenges for the inclusion of patient reported outcomes (PROs). These challenges to include PRO-related endpoints in oncology research are further exacerbated by downward pressure on budget and resources and also an overly rigorous application of the US Food and Drug Administration’s PRO guidance, which can in turn prevent study teams from optimally including PROs in oncology clinical trials. With increasing calls for demonstration of value of new cancer drugs from payers, patients, and their caregivers, study teams should consider the utility of PROs beyond regulatory needs. Optimal implementation of a PRO strategy in oncology research can be achieved by applying the PRO guidance to the greatest extent possible, making use of off-the-shelf PRO measures to capture concepts of interest, discussing plans with the regulatory bodies early in the process, and treating PRO-related endpoints with the same level of rigor as other endpoints.
Restricted accessResearch articleFirst published November, 2015pp. 831-839Several regulatory guidelines recommend that assessments of endpoints supporting drug approval should be verifiable by applicants and the regulatory agencies to minimize the potential for bias. This becomes especially critical when assessments are not based on measurable data but are derived from the interpretation of measurements, when they require the application of complex endpoint assessments, or when a study cannot be blinded. To make such interpretation more robust, a verification of (subjective) assessments by an independent panel of experts is frequently utilized. The objective of this paper was to analyze how often adjudicated methods across efficacy and safety assessments were used in drug approvals in the European Union and United States in 2013 and early 2014.
A total of 35 new molecular entities (NMEs) approved by the US Food and Drug Administration (FDA) and 88 European Medicines Agency (EMA) approvals in Europe were included in this analysis.
An adjudication method was used in phase III development programs in 69% of the NMEs approved in the United States and 41% of EMA approvals. Drugs developed for oncology and endocrinology typically used an independent review committee (IRC) in line with recommendations made in relevant regulatory guidance, whereas nervous systems, antivirals, and vaccines drugs typically did not. Central reading was most frequently used for efficacy endpoints or in a combination of efficacy endpoints and safety measures. Overall, approximately 20% to 30% of the primary endpoints analyzed in the US/EMA documentation were classified as subjective endpoints that were based on clinician-dependent (and subject-dependent) assessments. The remaining 70% to 80% were more robust endpoints that were reviewed by a central committee and/or were based on objective (measurable) endpoints, including laboratory tests.
While no one size fits all, the need to include an IRC depends on the subjectivity of the primary endpoint, the therapeutic area concerned, the clinical trial design, the need to assess reliability of marginal positive events, or if a critical assessment is required for adverse event accuracy.
Restricted accessResearch articleFirst published November, 2015pp. 840-851Social media presents new challenges to the biopharmaceutical industry for conducting pharmacovigilance activities. The authors reviewed worldwide regulatory guidance documents related to monitoring of adverse events posted on social media sites and identified gaps in current regulatory definitions for pharmacovigilance. Points to consider for addressing these gaps are made to offer standards for industry consideration and a potential framework for guidance from global health authorities.
Restricted accessResearch articleFirst published November, 2015pp. 852-860This study uses the data from many of the mandatory fields in ClinicalTrials.gov to examine changes, possibly leading to more complexity in the design and execution of commercially sponsored phase 3 clinical trials.
In this analysis we compare baseline year 2008 data, when a broad number of the protocol/study design and execution variables became mandatory, with the data from the last full year of results, 2013.
There has been relatively little change in the protocol and study design over the years covered in this study. The most pronounced change is associated with single-patient duration: there is a significant increase in the period of time a patient is treated in the study protocol. The study also highlights an important methodological issue: many of the claims in print about complexity have yet been substantiated through the use of peer-reviewed data or in settings where others can interrogate the results.
In general, there is limited evidence for significant increases in the study and protocol design and execution of phase 3 clinical trials sponsored by pharmaceutical companies.
Restricted accessResearch articleFirst published November, 2015pp. 861-868The field of oligonucleotide (OGN)–based therapeutics has been growing dramatically in the past decade, providing innovative platforms to develop agents for the treatment of a wide variety of clinical conditions. OGN agents have unique physicochemical properties and pharmacokinetic/pharmacodynamic characteristics. This review considers findings from the literature and information on new molecular entities submitted to the US Food and Drug Administration as OGN-based therapeutics. In addition, the article discusses several challenging issues from the perspective of clinical pharmacology, emphasizing the potential of immunogenicity, the effect of renal impairment on OGN exposure, drug-drug interactions, and the utility of pharmacokinetic/pharmacodynamic modeling. The field of OGN-based therapeutics is in evolution and will benefit from further studies as well as clinical experience to formulate guidelines and promote the development of this class of agents.
Restricted accessResearch articleFirst published November, 2015pp. 869-876The Tufts Center for the Study of Drug Development (Tufts CSDD) collaborated with the Clinical Data Interchange Standards Consortium (CDISC) on a joint working group study with 10 participating companies including biopharmaceutical, CROs, and eClinical technology vendors. The objective of the study was to examine current and projected use of eClinical technology and standards across respondent organizations and in clinical studies and to gather perceptions and attitudes about technology and standards adoption.
The Tufts CSDD study examined the use of eClinical technology and CDISC standards through a comprehensive survey combined with analyses of clinical study data among biopharmaceutical companies and contract research organizations.
The results suggest increasing use of specific eClinical technology solutions and standards. The barriers to adoption of eClinical trial tools are addressed as well as the benefits of standards adoption. Differences between respondent perceptions and actual study data are examined, and the survey results are compared with those from prior studies.
The results of the study indicate that increasing use of standards could translate into improvements in time, costs, and overall approval rates. The study also observed an uptake in the use of eClinical technologies that could potentially create efficiencies and streamline operational processes.
Restricted accessResearch articleFirst published November, 2015pp. 877-885Teams are the principal vehicle in developing new drug development strategy and executing the tasks required to accomplish those objectives. The key research questions related to the measurement of team innovation performance in the branded pharmaceutical industry and identification of the drivers for optimal team performance outcomes. This project evaluated the key drivers for team innovation performance (defined as “outcomes”). Team outcomes included new information creation, compression of development time, expansion of image, learning, capability development, growth satisfaction, and overall effectiveness.
A total of 13 questions, with multiple subparts, as part of 7 key dimensions were adapted from previously validated scales. Eligible participants were those who were employed in a pharmaceutical R&D organization and were a member of a drug discovery and/or development team. Survey respondents were prompted to respond to the degree they agreed or disagreed using 5- to 7-point Likert-type scales. All analyses (reliability tests, factor analysis, and multivariate regression) were performed in IBM SPSS v22.
While good correlations individually existed between team outcomes (dependent variable) and tested independent variables (autonomy, coaching, climate, proactive personality, empowering leadership, and transactive memory systems [TMSs]), the best predictors identified through multivariate regression analysis were leader and peer coaching and TMSs.
This research offers key insights for managers when forming and staffing teams. One is an emphasis on coaching. It is imperative for senior managers to assign individuals to teams who liaise with broader management that are capable of offering coaching and availability for team members to enhance their skills. This is particularly important in a growing hypercompetitive environment that is witnessing continuous strategic change. A second area of emphasis is on TMS, in an expertise-centered organization. As this is a central driver to team performance, it is imperative to improve adaptation skills of team members.
Restricted accessResearch articleFirst published November, 2015pp. 886-889Phosphate restriction is needed in most dialysis patients. The package inserts from some medications indicate that phosphate may be part of the excipient fraction of drugs. It is unclear whether its amount may be clinically significant since the phosphate content is unquantified.
We reviewed the package inserts for the branded formulations of the most widely used drugs at a dialysis chain. We measured the phosphate levels in a sample of the branded form of these drugs and some of their generic formulations. We also reviewed the available package inserts of 16 selected generic drug manufacturers for the presence of phosphate in drugs that were phosphate free in their branded formulation.
We identified 12 prescription products that contained phosphate, 9 of which contained clinically significant quantities (>10 mg per daily dose) notably in both branded and generic forms of amlodipine, lisinopril, paroxetine and bisoprolol. Phosphate was rarely present in a generic drug when its corresponding branded formulation was phosphate free.
Commonly prescribed drugs may contain clinically important levels of phosphate.
Restricted accessResearch articleFirst published November, 2015pp. 890-897To compare consumer preferences for a revised and current acetaminophen over-the-counter “Drug Facts” labels (ODFL) on warnings and self-reported correct intended action following signs of overdose.
Adults visiting a community center were randomly assigned to revised or current ODFLs using previously reported label comprehension methodology.
Participant (N = 110) ratings for both ODFLs were comparable for ease of finding and understanding information. In response to an emergent overdose scenario, the proportion reporting the correct intended action using the revised ODFL was significantly greater than the proportion using the current ODFL (91% [97.5% CI, 0.82-0.99] vs. 76% [97.5% CI, 0.64-0.89]). In side-by-side comparisons, the revised ODFL was superior for overall consumer preference, usefulness for first-time use, and better overdose-related directions. A revised bottle cap statement also outperformed the current statement used on brand acetaminophen.
Findings support revision of acetaminophen ODFLs to improve liver damage warnings and to optimize labeling likely to be useful in prevention of and response to overdose.
Restricted accessResearch articleFirst published November, 2015pp. 898-902The Pharmacovigilance Programme of India (PvPI) is responsible for collecting reports of adverse drug reactions (ADRs) to assess the association between particular drugs and ADRs. The aim of the present study was to apply statistical tools to determine associations between drugs and ADRs for signal detection in the PvPI.
Four methods were proposed for quantitative signal detection: one was based on Bayesian inference and others on classical inference procedures. The effectiveness of the proposed methods was assessed by applying them to 4 drug-ADR combinations.
The proposed methods were easy to apply and relevant to the Indian context. In selected methods, the information component value was more specific, whereas the proportional relative risk was more sensitive.
The proposed methods may help in the identification of new signals in Indian individual case safety reports.
Restricted accessResearch articleFirst published November, 2015pp. 903-910Data quality within the clinical research enterprise can be defined as the absence of errors that matter and whether the data are fit for purpose. This concept, proposed by the Clinical Trials Transformation Initiative, resulted from a culmination of collaboration with industry, academia, patient advocates, and regulators, and it emphasizes the presence of a hierarchy of error types, resulting in a more efficient and modern data-cleaning paradigm. While source document verification (SDV) is commonly used as a quality control method in clinical research, it is disproportionately expensive and often leads to questionable benefits. Although the current literature suggests that there is a need to reduce the burden of SDV, there is no consensus on how to replace this “tried and true” practice.
This article proposes a practical risk-based monitoring approach based on published statistical evidence addressing the impact of database changes subsequent to SDV.
The analysis clearly demonstrates minimal effects of errors and error corrections on study results and study conclusions, with diminishing effect as the study size increases, and it suggests that, on average, <8% SDV is adequate to ensure data quality, with perhaps higher SDV rates for smaller studies and virtually 0% SDV for large studies.
It is recommended that SDV, rather than just focusing on key primary efficacy and safety outcomes, focus on data clarification queries as highly discrepant (and the riskiest) data.
Restricted accessResearch articleFirst published November, 2015pp. 911-919The delay of initiation of clinical development is considered a causes of delay of approval of drugs (drug lag) in Japan.
For oncology drugs newly approved between 2000 and 2012 in Japan, a possible impact of delay of initiation of clinical development (development start lag [DSL]) on delay of approval (approval lag [AL]) was investigated, focusing on the delay from the US timelines. The equation defining the relationship between the DSL and AL of 33 oncology drugs was calculated by using simulation models, then the Pearson coefficient of correlation between parameters was calculated.
From the analysis of all drugs investigated, a positive relationship between the DSL and AL was suggested. However, the relationship seemed to have 2 phases, including a flat phase, followed by a linearly increased phase with a breakpoint at 2340 DSL days (approximately 6.4 DSL years).
Shortening the DSL is important for reducing large AL, but it is not necessary to eliminate the DSL completely for the purpose of minimizing the AL.
Restricted accessResearch articleFirst published November, 2015pp. 920-928The paper explores the problems of health care supply chain in Thailand. A national drug information database is designed and presented to facilitate drug information sharing.
Literatures are analysed in order to develop the information needed by stakeholders in health care supply chain. Expert interviews are conducted to verify the necessity of all of the attributes. A conceptual network of web-based services is designed.
The study purposes the use of a national drug information database containing drug information needed by all players and enabling nationwide information exchanges in a standard electronic format.
Due to fragmented data and information and lack of data standard problems, the study purposes the information sharing system by constructing a national drug information database. The database contains information needed by all players in health care supply chain. A conceptual network of web-based services is presented to facilitate drug information sharing among health care supply chain members as well nationwide implementation.
Open accessResearch articleFirst published November, 2015pp. 929-939The purpose of medicines is to improve patients' lives. Stakeholders involved in the development and lifecycle management of medicines agree that more effective patient involvement is needed to ensure that patient needs and priorities are identified and met. Despite the increasing number and scope of patient involvement initiatives, there is no accepted master framework for systematic patient involvement in industry-led medicines research and development, regulatory review, or market access decisions. Patient engagement is very productive in some indications, but inconsistent and fragmentary on a broader level. This often results in inefficient drug development, increasing evidence requirements, lack of patient-centered outcomes that address unmet medical needs and facilitate adherence, and consequently, lack of required therapeutic options and high costs to society and involved parties. Improved patient involvement can drive the development of innovative medicines that deliver more relevant and impactful patient outcomes and make medicine development faster, more efficient, and more productive. It can lead to better prioritization of early research; improved resource allocation; improved trial protocol designs that better reflect patient needs; and, by addressing potential barriers to patient participation, enhanced recruitment and retention. It may also improve trial conduct and lead to more focused, economically viable clinical trials. At launch and beyond, systematic patient involvement can also improve the ongoing benefit-risk assessment, ensure that public funds prioritize medicines of value to patients, and further the development of the medicine. Progress toward a universal framework for patient involvement requires a joint, precompetitive, and international approach by all stakeholders, working in true partnership to consolidate outputs from existing initiatives, identify gaps, and develop a comprehensive framework. It is essential that all stakeholders participate to drive adoption and implementation of the framework and to ensure that patients and their needs are embedded at the heart of medicines development and lifecycle management.
Restricted accessResearch articleFirst published November, 2015pp. 940-946It is widely acknowledged that patient recruitment is a significant challenge and represents one of the primary reasons for drug development delays. Data from the Center for Information and Study on Clinical Research Participation (CISCRP) “Perceptions & Insights” study indicate that the 18- to 34-year-old Generation Y subgroup was the least willing to participate in a clinical trial.
The willingness of Generation Y to participate in clinical studies was compared to that of older groups in the CISCRP study. These results were then compared to data from earlier studies.
Statistically significant differences existed between the willingness of Generation Y to participate in clinical studies when compared to older age groups. Generational perceptions and value differences were explored via corporate and sociological research findings to determine why disparities existed among age groups regarding the willingness for clinical trial participation.
Preliminary results indicate that members of Generation Y are less willing to participate in clinical studies and that these differences are truly generational and not simply age related.
Restricted accessResearch articleFirst published November, 2015pp. 947-956The increasing proportion of women conceiving later in life, associated with the higher probability of contracting a chronic disease, highlights an increasing need to understand the impact of drug use for chronic diseases pre- and postpartum. In this study, the authors report the results of systematic reviews of drug use during pregnancy by focusing on pregnant women with a chronic disease, specifically, epilepsy, rheumatoid arthritis (RA), or schizophrenia. The authors studied the clinical impact of drug use in these chronic diseases on the mother and fetus, as well as the ethical issues and socioeconomic impact of drug use during pregnancy for women with these conditions. The results indicate that treatment discontinuation in epilepsy and schizophrenia can lead to serious adverse effects, whereas pregnancy can have an ameliorating effect on RA symptoms. Delivery and neonatal complications were associated with the use of older generation drugs across the 3 diseases. Newer generation drugs were deemed safer but more expensive. Ethical considerations for physicians and patients involved mainly the potential risks of drug use for the fetus. In conclusion, treatment guidelines need to be developed in the future; additionally, better insight into the economics of pregnancy for women with chronic diseases will improve value for money in obstetric care.
Restricted accessResearch articleFirst published November, 2015pp. 957-965Adverse events (AEs) data compose the main body of safety data in clinical trials. Medically important imbalances of AEs in large double-blind randomized controlled trials (RCTs) are signals of potential adverse drug reactions. They will be further evaluated for causality and shape the initial label that gives users necessary information on the safe use of the drug. However, causality assessment in premarketing RCTs can be challenging. This article highlights key aspects that need attention and statistical analysis approaches that could be helpful for screening and evaluation of signals generated from imbalances of AEs in moderate or large RCTs.