Tracking the Pharmaceutical Pipeline: Clinical Trials and Global Disease Burden

Aggregate data about pharmaceutical research and development (R&D) tend to examine Phase III trials. Hence, there are few published data about investigational drugs in earlier phases of clinical development that might fail. It is also unclear how well R&D corresponds to disease burden. We track the pharmaceutical pipeline using data from industry publications that provide otherwise unreported information about industry‐sponsored clinical trials. The sample includes 2,477 unique drug entities in 4,182 clinical trials. The majority of drugs targeted neoplasms (26.20%), neurological diseases/diseases of the sense organs (13.48%), infectious and parasitic diseases (10.5%), and endocrine, metabolic, nutrition, and immunity disorders (9.45%). Less than 6% of drugs targeted diseases of the circulatory system, which represent the most prevalent causes of global mortality. Detailing the pharmaceutical pipeline, our findings suggest that pharmaceutical development does not adequately address global disease burden. Future research on the under‐reported details of Phase I and II clinical trials is needed to understand how the industry operates and how its resource‐allocation matches global health concerns.     

Emergency Medicine Leadership in Industry-sponsored Clinical Trials

OBJECTIVE: To identify and characterize emergency medicine (EM) researchers who, since 1990, have served on a steering committee (SC) or as overall principal investigator (PI) of an industry-sponsored, multicenter clinical trial involving a pharmaceutical or device. METHODS: North American EM research directors (RDs) and other prominent EM investigators (for those hospitals without a RD) were identified from eight sources, including the Society for Academic Emergency Medicine RD Interest Group and the Multicenter Airway Research Collaboration (MARC) database. The identified investigators were sent a screening survey requesting information regarding industry-sponsored clinical research at their site. The individual EM investigators identified by this screening survey were then interviewed by telephone (validation survey) to further explore their leadership experience in industry-sponsored clinical trials. RESULTS: Of 153 identified RDs and prominent EM researchers, 138 responded to the screening survey (90% response rate). Eighty-five EM investigators reportedly had served on a SC or as overall PI for an industry-sponsored clinical trial. Of these 85 North American EM investigators, 77 were available for a structured telephone interview (91% response rate). Although 41 (53%) of the investigators confirmed their leadership role, 36 (47%) had not served in either role. Among the 41 confirmed investigators, 19 (25%) had served as a SC member, 10 (13%) had served as overall PI, and 12 (16%) had experience in both roles. Individual responses provided suggestions for pursuing such leadership positions. CONCLUSIONS: These data suggest the opportunity to expand EM leadership in industry-sponsored clinical trials and demonstrate the need for validation of reports obtained by a departmental research contact. The suggestions from EM researchers who have attained these leadership roles may provide strategies for investigators interested in pursuing these positions.     

Clinical Trials Update 2014: Year in Review

This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that were ongoing at the end of 2014, according to data obtained from both the “ClinicalTrials.Gov” website and from corporate press releases and presentations.     

Recruitment and Retention of Patients into Emergency Medicine Clinical Trials

The emergency medicine (EM) and prehospital environments are unlike any other clinical environments and require special consideration to allow the successful implementation of clinical trials. This article reviews the specific issues involved in EM clinical trials and provides strategies from EM and non‐EM trials to maximize recruitment and retention. While the evidence supporting some of these strategies is deficient, addressing recruitment and retention issues with specific strategies will help researchers deal with these issues in their funding applications and in turn develop the necessary infrastructure to participate in EM clinical trials. ACADEMIC EMERGENCY MEDICINE 2010; 17:1104–1112 © 2010 by the Society for Academic Emergency Medicine     

Evidence-Based Medicine and Clinical Trials in Pain Practice and Orthopedics

Abstract:   Medical practices should be based on scientific findings pursuant to the rules of evidence-based medicine. Quality standards for interventional pain therapy and orthopedic clinical studies have been lacking. As a result, the efficacy of many forms of therapy is insufficiently documented, making the level of evidence low.
This article identifies common deficiencies in the conduct of clinical trials, as well as limitations in conducting randomized controlled studies. Recommendations for improvement are provided. The discussion provides the clinically active physician with interpretation aids for the evaluation of meta-analyses, supports personal evidence-based decisions, and reviews the most important principles for planning and conducting of experimental clinical studies. Current examples in the literature verify the implementation of these principles and present current findings in accordance with evidence-based medicine (EBM) criteria.
In spite of an increasing emergence of EBM-based studies, we conclude that the number of well-designed, high quality, controlled studies conducted in accordance with the guidelines of Good Clinical Practice examining interventional pain therapy and orthopedic clinical studies remains unacceptably low.     

Assessing the Impact of the NIH CTSA Program on Institutionally Sponsored Clinical Trials

Objective

To assess the impact of the NIH CTSA program on patient enrollment in clinical trials sponsored/collaborated by CTSA consortium institutions.

Material and Methods

Using publicly available clinical trial data at ClinicalTrials.gov, we identify positive trend changes in the number of patients enrolled in clinical trials performed at CTSA consortium institutions over the years before and after their respective CTSA award dates. CTSA consortium institutions were matched with similar non‐CTSA institutions.

Results

As compared to matched non‐CTSA institutions CTSA consortium sites noted an increase in patient enrollment after the CTSA awards. In particular, we detected a change‐point, where a new enrollment trend emerged, 338 days after the CTSA award. No such trend was noted over the same period in the non‐CTSA institutions.

Conclusion

Our analysis provides evidence that the NIH CTSA funding program made a positive impact on patient enrollment.     

Patient Engagement in Neurological Clinical Trials Design: A Conference Summary

Objectives

The conference objectives included educating patients and advocates about clinical trials, educating the clinical research community about patient perspectives on participating in clinical trial design, and identifying strategies to increase participation in clinical trial design for neurological disorders.

Design

Observations were noted during a 1‐day conference attended by patients, patient advocates, clinical trial staff, and investigators. The conference offered didactic sessions, small, and large group discussions.

Participants

Conference participants were patients, patient advocates, clinical trial staff, students, and investigators interested in engaging patients in clinical trial design for neurological disorders.

Measures

Conference participants were asked to consider lessons learned that could increase patient engagement in clinical trial design.

Results

We found that there is growing interest in including patients in the design of clinical trials for neurological disorders. Several themes emerged on how to move forward: networking; the multifaceted roles of advocates in research; training and education; creating patient–researcher partnerships; and clinical trials regulation issues.

Conclusions

The conference provided a forum for dialogue regarding stakeholder engagement in the design of clinical trials for neurological disorders. This experience provides a template for replication and dissemination of this conference and informs next steps to accelerate the pathway from dialogue to action.     

Research Fundamentals: III. Elements of a Research Protocol for Clinical Trials

Abstract. A clinical trial is a powerful technique for evaluating the effectiveness of an experimental intervention. The initial stages of planning a clinical trial involve choosing and refining a research question, selecting a study design, and deciding on appropriate statistical tests and sample sizes. The success of the study depends upon how well these issues are thought out in advance, and how they can be put into practice. The protocol is the written document that allows the investigator to communicate details of how the research question will be answered. In the following article, the basic components of the research protocol are described. Issues related to quality control, data entry, and pilot testing are discussed. This is the third in a series of research fundamental concept papers, written by members of the SAEM Research Committee.     

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta‐amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current “anti‐Alzheimer's” agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov , and on database of the website Alzforum.org . As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so‐called “disease‐modifying agents”) — these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti‐Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials.     

Recent Trends and Controversies in Industry-sponsored Clinical Trials

In recent years, industry has become an important source of funding for biomedical research. Industry-sponsored clinical trials are a particular source of controversy. In light of recent developments, the authors reevaluate the 1995 SAEM guidelines for investigator involvement in industry-sponsored clinical trials. The authors divide industry-funded clinical trials into two categories: investigator-initiated and industry-initiated, and discuss the differences between them. They examine several areas of ethical debate, including exclusivity contracts between a principal investigator and a corporate sponsor, the size of per-patient reimbursements for recruiting patients into clinical trials, and authorship criteria. Finally, the authors oppose the assumption that industry-sponsored research is automatically biased, and suggest that multiple levels of review will help to uncover bias, whatever the source. Once mutual respect for ethical guidelines and practices are established, collaboration between emergency medicine researchers and industry should be encouraged.     

Trials and Tribulations of Ventricular Pacing

In this review, we describe the current evidence for permanent ventricular pacing and the unmet needs related to chronic cardiac pacing.     

Management and Interpretation of Data Obtained from Clinical Trials in Pain Management

Conducting a clinical trial involves various stages of planning and implementation. The three major components involved in clinical trials are the management of data, the quality control to ensure data integrity, and the interpretation of the data at the conclusion of the trial. Although each process is distinct and involves different levels of effort and knowledge to implement, all processes are intimately linked. Data management techniques include the process of data entry and the implementation of an organized, comprehensive approach to quality control. Some guidelines for quality control screening are recommended to address various common issues related to clinical data, such as missing data, invalid cases, subject “outliers,” and violation of distributional assumptions relevant to statistical analyses. In order to aid in interpreting the data, conditions that need to be met to make causal inferences are discussed. Taking into account baseline characteristics of the patient sample is also discussed as an extension to maintaining the internal validity of the study. Additionally, some common threats to statistical conclusion validity, including Type I error inflation and the problem of overpowered tests, are highlighted. Finally, the concept of the effect size as an important complement to statistical significance and how the various types of effect size measures can be interpreted within the context of a clinical trial are discussed.     

Quality Assessment in Clinical Trials: Considerations for Outcomes Research in Interventional Pain Medicine*

The assessment of quality in clinical trials involves multiple considerations. While compliance with both Good Clinical Practice and International Conference on Harmonisation guidelines is required, variations in many other factors contribute to the overall quality of the report. Principal among these factors is the development of a testable study question. Study questions that are feasible, interesting, novel, ethical, and relevant are desirable. The methodology used to answer the question should be described in sufficient detail and documented to provide for reproducibility and transparency. This is essential for both interpretation of the results and for assessing the applicability of the results to clinical practice. While randomized controlled trials (RCT) are currently the penultimate methodological standard for quality in research study design, they typically do not mimic clinical practice, which can present limitations to their value. This is particularly relevant with respect to interventional therapies, where RCT designs can be associated with scientific and ethical challenges. Well‐designed observational studies may overcome some of these drawbacks, but often require very large study populations. Technological advances in communication may permit the pooling of data and the emergence of new standards for interventional pain research.     

Vaccination Competence

ABSTRACT Objective: Vaccinating is one of the most significant methods of health promotion in the world. The purpose of this study was to describe vaccination competence from the perspective of professionals, clients, and students.
Design: A cross-sectional interview study.
Sample: Participants ( n =40) were public health nurses, physicians, nursing teachers and graduating public health nursing students, and vaccinated clients of various ages or vaccinated children's parents in Finland.
Measurements: Interview data were collected using semistructured interviews in focus groups and individual interviews, and were analyzed by content analysis.
Results: The participants pointed out that the competent vaccinator (CV) displays distinctive personal qualities, possesses the necessary attributes required in the vaccinator-client relationship, and is authorized to administer vaccinations. The competent vaccinator is a health care professional who is committed to vaccinating and who fosters social awareness of vaccinations. The competent implementation of the vaccination procedure consists of the vaccinator's actions before, during, and after the vaccination. The outcomes of a competent implementation are divided into immediate and long-term outcomes.
Conclusions: Vaccination competence is a broad entity. These results may be utilized for improving the practical implementation of vaccinations, administration, education, and research of vaccination procedures.     

Challenges in Implementing Hospice Clinical Trials: Preserving Scientific Integrity While Facing Change

Background/AimsNumerous changes can occur between the original design plans for clinical trials, the submission of funding proposals, and the implementation of the clinical trial. In the hospice setting, environmental changes can present significant obstacles, which require changes to the original plan designs, recruitment, and staffing. The purpose of the study was to share lessons and problem-solving strategies that can assist in future hospice trials.MethodsThis study uses one hospice clinical trial as an exemplar to demonstrate challenges for clinical trial research in this setting. Using preliminary data collected during the first months of a trial, the research team details the many ways their current protocol reflects changes from the originally proposed plans. Experiences are used as an exemplar to address the following questions: 1) How do research environments change between the initial submission of a funding proposal and the eventual award? 2) How can investigators maintain the integrity of the research and accommodate unexpected changes in the research environment?ResultsThe changing environment within the hospice setting required design, sampling, and recruitment changes within the first year. The decision-making process resulted in a stronger design with greater generalization. As a result of necessary protocol changes, the study results are positioned to be translational following the study conclusion.ConclusionResearchers would do well to review their protocol and statistics early in a clinical trial. They should be prepared for adjustments to accommodate market and environmental changes outside their control. Ongoing data monitoring, specifically related to recruitment, is advised.     

中文神经疾病临床对照试验数据库的建立

目的：建立中文神经疾病临床对照试验数据库。方法：分别采用计算机检索中国生物医学文献光盘数据库(CBMdisc)、中国循证医学图书馆(中文光盘版)临床对照研究数据库和人工检索与神经疾病相关的11种期刊和4本会议论文集，纳入已发表的神经疾病防治性研究的随机对照试验和有对照但未随机分组的临床对照研究，建立数据库并采用，Procite软件进行管理。结果：经计算机检索CBMdisc(1978年～2002年4月)和中国循证医学图书馆(中文光盘版)2002年1期，人工检索期刊11种，论文集4种。数据库共纳入与神经疾病有关的临床对照试验3641篇，其中随机对照试验828篇，占22．74％，临床对照研究(非随机但有对照)2813篇，占77．26％。结论：本数据库较为全面地收集了中国神经疾病领域已发表的防治性对照试验，为临床实践和卫生决策提供了该领域治疗方面中国当前的研究证据，也为Cochrane图书馆以及世界各国的临床对照试验数据库提供了资料，是对系统评价作者有帮助的资料来源     

Step‐forward Randomization in Multicenter Emergency Treatment Clinical Trials

The authors present a new centralized randomization method for multicenter emergency treatment clinical trials. With this step‐forward method, treatment randomization for the next subject is performed immediately after the enrollment of the current subject. This design ensures the readiness of the treatment assignment for each subject at the point of study enrollment, and it simultaneously provides effective control on treatment assignments balance and distributions of covariates. The authors also discuss procedures of the step‐forward randomization method along with its implementation for two National Institute of Neurological Disorders and Stroke–funded multicenter acute stroke trials, one double‐blinded and one open‐labeled. Advantages and limitations are presented based on experience gained in these two trials. ACADEMIC EMERGENCY MEDICINE 2010; 17:659–665 © 2010 by the Society for Academic Emergency Medicine