Clinical Research Concepts Research Articles

Current Concepts in Clinical Research: Web-Based, Automated, Arthroscopic Surgery Prospective Database Registry

In 2011, postsurgical patient outcome data may be compiled in a research registry, allowing comparative-effectiveness research and cost-effectiveness analysis by use of Health Insurance Portability and Accountability Act-compliant, institutional review board-approved, Food and Drug Administration-approved, remote, Web-based data collection systems. Computerized automation minimizes cost and minimizes surgeon time demand. A research registry can be a powerful tool to observe and understand variations in treatment and outcomes, to examine factors that influence prognosis and quality of life, to describe care patterns, to assess effectiveness, to monitor safety, and to change provider practice through feedback of data. Registry of validated, prospective outcome data is required for arthroscopic and related researchers and the public to advocate with governments and health payers. The goal is to develop evidence-based data to determine the best methods for treating patients.

Barriers to conducting clinical research in reproductive medicine: India

Research in India is evolving at a rapid pace. Ergo, we need faster approval processes and review timelines. Improvement in the quality of institutional review boards would also contribute to good research practices. Clinical research should be included as a part of the undergraduate medical and pharmacy curriculum, and leading hospitals and practitioners should openly endorse research.

HIV Therapy Simulator: a graphical user interface for comparing the effectiveness of novel therapy regimens

Computer simulation models can be useful in exploring the efficacy of HIV therapy regimens in preventing the evolution of drug-resistant viruses. Current modeling programs, however, were designed by researchers with expertise in computational biology, limiting their accessibility to those who might lack such a background. We have developed a user-friendly graphical program, HIV Therapy Simulator (HIVSIM), that is accessible to non-technical users. The program allows clinicians and researchers to explore the effectiveness of various therapeutic strategies, such as structured treatment interruptions, booster therapies and induction-maintenance therapies. We anticipate that HIVSIM will be useful for evaluating novel drug-based treatment concepts in clinical research, and as an educational tool. HIV Therapy Simulator is freely available for Mac OS and Windows at http://sites.google.com/site/hivsimulator/. jmittler@uw.edu. Supplementary data are available at Bioinformatics online.

Comparative Effectiveness Research and Personalized Medicine

Comparative effectiveness research (CER) is generating intense attention as interest grows in finding new and better drug technology assessment processes. The federal government is supporting the expansion of CER through funding made available in the American Recovery and Reinvestment Act of 2009 (ARRA) and by establishing the Patient-Centered Outcomes Research Institute through the Patient Protection and Affordable Care Act of 2010. At the same time, personalized medicine is generating debate about its place in clinical medicine, and so, naturally, how CER can or cannot play a role in personalized medicine is part of these debates. At the heart of the debate around the role of CER in personalized medicine is the nature of personalized medicine and how it fits within contemporary clinical research concepts. We maintain in this article that CER can serve to catalyze personalized medicine, but we recognize that, for this to happen, researchers will need to embrace new data sources and new analytic approaches. We also recognize that drug technology assessment processes will have to undergo necessary adaptations to accommodate CER as configured for personalized medicine, and that clinicians will need to be educated appropriately and provided access to decision-support systems through health information technology to use the information coming from this research. To illustrate our argument, we describe two ongoing CER studies funded and managed in the private sector evaluating personalized medicine interventions that have important clinical and financial implications. One of the studies investigates the clinical and financial effects of pharmacogenomic testing for warfarin as prescribed in conditions of typical practice settings. The other study is also set in community practice settings and compares cardiovascular outcomes of patients receiving clopidogrel who are extensive metabolizer phenotypes for the cytochrome P450 2C19 hepatic isoenzyme with all patients receiving prasugrel.

Community Views on Neurologic Emergency Treatment Trials

We improve our understanding of the community consultation process for acute neurologic emergency trials conducted under the federal regulations for Exception From Informed Consent (EFIC) for emergency research. We performed a qualitative study using focus groups to collect data from patients with a previous stroke or brain injury and their families and from young men at risk for traumatic brain injury. Discussions were transcribed, coded, and analyzed for major themes and subthemes. Five focus groups, involving 40 participants, were convened. Major themes included the awareness and understanding of key clinical trial concepts, including prominent concerns about placebo and therapeutic misconception; inability to obtain informed consent and acceptable surrogate decision-making; EFIC in emergency research and whether existing regulations are acceptable; specific trial design problems, including comparison to standard of care versus 2 competing active therapies; and community consultation and representation. In this study sample, EFIC trials were deemed appropriate and acceptable for acute neurologic emergency research. Education, along with open discussion about basic clinical research concepts, disease- and trial-specific information, and potential surrogate decision-making, was essential to determine the acceptability of an EFIC trial. Approval by institutional review boards was highly regarded as a means of human protection and effective community consultation for such trials. A data repository of information gained from similar qualitative research may help investigators and regulators who wish to plan, conduct, review, and provide oversight for acute neurologic emergency trials under EFIC regulations.

The ongoing tyranny of statistical significance testing in biomedical research

Since its introduction into the biomedical literature, statistical significance testing (abbreviated as SST) caused much debate. The aim of this perspective article is to review frequent fallacies and misuses of SST in the biomedical field and to review a potential way out of the fallacies and misuses associated with SSTs. Two frequentist schools of statistical inference merged to form SST as it is practised nowadays: the Fisher and the Neyman-Pearson school. The P-value is both reported quantitatively and checked against the alpha-level to produce a qualitative dichotomous measure (significant/nonsignificant). However, a P-value mixes the estimated effect size with its estimated precision. Obviously, it is not possible to measure these two things with one single number. For the valid interpretation of SSTs, a variety of presumptions and requirements have to be met. We point here to four of them: study size, correct statistical model, correct causal model, and absence of bias and confounding. It has been stated that the P-value is perhaps the most misunderstood statistical concept in clinical research. As in the social sciences, the tyranny of SST is still highly prevalent in the biomedical literature even after decades of warnings against SST. The ubiquitous misuse and tyranny of SST threatens scientific discoveries and may even impede scientific progress. In the worst case, misuse of significance testing may even harm patients who eventually are incorrectly treated because of improper handling of P-values. For a proper interpretation of study results, both estimated effect size and estimated precision are necessary ingredients.

Informed consent: Are we doing enough?

The process of informed consent is an ethical mandate for all clinical trials. The principles of ethics in research involving human beings decrees the conduct of a process where the prospective research subjects should be informed of all aspects of the research study and after complete comprehension of all the features involved, should express willingness to be a part of the study, and the same should be duly documented. The consent should be fully informed and autonomous. However, with subject populations that are mostly medically naïve and for whom the whole concept of clinical research and the umpteen terms and concepts associated with it are alien; the true essence of an “informed” and “autonomous” decision is largely lost. The consent process thus gets reduced to mainly a “narration-followed-by-signature” process. Over the last few years, this gap in principles and practices of ethics and consent has been acknowledged and innovative concepts and attempts are being fostered, to make the informed consent process more “ethical”. The article discusses the loopholes associated with the informed consent process and the innovative concepts to make it more authentic.

Knowledge-data integration for temporal reasoning in a clinical trial system

Managing time-stamped data is essential to clinical research activities and often requires the use of considerable domain knowledge. Adequately representing and integrating temporal data and domain knowledge is difficult with the database technologies used in most clinical research systems. There is often a disconnect between the database representation of research data and corresponding domain knowledge of clinical research concepts. In this paper, we present a set of methodologies for undertaking ontology-based specification of temporal information, and discuss their application to the verification of protocol-specific temporal constraints among clinical trial activities. Our approach allows knowledge-level temporal constraints to be evaluated against operational trial data stored in relational databases. We show how the Semantic Web ontology and rule languages OWL and SWRL, respectively, can support tools for research data management that automatically integrate low-level representations of relational data with high-level domain concepts used in study design.

Comparing heterogeneous SNOMED CT coding of clinical research concepts by examining normalized expressions

Objective A continual problem confronting the implementation of standardized vocabularies such as SNOMED CT is that their expressive flexibility and power provide more than one way to represent a given concept. The goal of this study was to investigate how the CliniClue™ Expression Transformer tool could be used to help in discerning similarities and differences among three separate sets of clinical research concepts coded in SNOMED CT by three different paid expert coding companies. Methods Initial editing of the companies’ coded datasets was required to enable accurate input into CliniClue Version: 2006.2.0030 Expression Transformer tool. The normal forms of the company codings for the 319 clinical research question/answer sets were compared to determine whether they were equivalent or otherwise related (e.g., if one was subsumed by the other). Basic frequencies were computed for (957) pairwise comparisons of each of 319 concepts each coded by the three expert coders, and the implications of the results discussed. Results The primary finding from this study was that, for each of the paired comparisons, approximately half of the time the companies’ codings could be related, primarily via subsumption. The greatest percentage of equivalent concepts between any two companies was 33%. These same two companies also agreed most often on the core clinical concept measure from an earlier study by the authors. Conclusion Heterogeneity among coders using the same controlled terminology appears inescapable despite the extensive efforts of terminological standards developers and implementers. In our study, the computable determination of equivalence of discordantly coded concepts still failed to yield acceptably comparable data. A clearer articulation, and perhaps a simplification, of rules for the consistent use for terminologies such as SNOMED CT is needed.

Variation of SNOMED CT Coding of Clinical Research Concepts among Coding Experts

ObjectiveTo compare consistency of coding among professional SNOMED CT coders representing three commercial providers of coding services when coding clinical research concepts with SNOMED CT. DesignA sample of clinical research questions from case report forms (CRFs) generated by the NIH-funded Rare Disease Clinical Research Network (RDCRN) were sent to three coding companies with instructions to code the core concepts using SNOMED CT. The sample consisted of 319 question/answer pairs from 15 separate studies. The companies were asked to select SNOMED CT concepts (in any form, including post-coordinated) that capture the core concept(s) reflected in the question. Also, they were asked to state their level of certainty, as well as how precise they felt their coding was. MeasurementsBasic frequencies were calculated to determine raw level agreement among the companies and other descriptive information. Krippendorff’s alpha was used to determine a statistical measure of agreement among the coding companies for several measures (semantic, certainty, and precision). ResultsNo significant level of agreement among the experts was found. ConclusionThere is little semantic agreement in coding of clinical research data items across coders from 3 professional coding services, even using a very liberal definition of agreement.

Use of SNOMED CT to Represent Clinical Research Data: A Semantic Characterization of Data Items on Case Report Forms in Vasculitis Research

ObjectiveTo estimate the coverage provided by SNOMED CT for clinical research concepts represented by the items on case report forms (CRFs), as well as the semantic nature of those concepts relevant to post-coordination methods. DesignConvenience samples from CRFs developed by rheumatologists conducting several longitudinal, observational studies of vasculitis were selected. A total of 17 CRFs were used as the basis of analysis for this study, from which a total set of 616 (unique) items were identified. Each unique data item was classified as either a clinical finding or procedure. The items were coded by the presence and nature of SNOMED CT coverage and classified into semantic types by 2 coders. MeasurementsBasic frequency analysis was conducted to determine levels of coverage provided by SNOMED CT. Estimates of coverage by various semantic characterizations were estimated. ResultsMost of the core clinical concepts (88%) from these clinical research data items were covered by SNOMED CT; however, far fewer of the concepts were fully covered (that is, where all aspects of the CRF item could be represented completely without post-coordination; 23%). In addition, a large majority of the concepts (83%) required post-coordination, either to clarify context (e.g., time) or to better capture complex clinical concepts (e.g., disease-related findings). For just over one third of the sampled CRF data items, both types of post-coordination were necessary to fully represent the meaning of the item. ConclusionSNOMED CT appears well-suited for representing a variety of clinical concepts, yet is less suited for representing the full amount of information collected on CRFs.

Comment on “Clinical studies in spinal surgery” (B. Hanson and B. Kopjar)

Over the past few decades, we have seen a shift in both public and professional interest from clinical research studies to basic science, such as in the field of gene therapy. Research in this field is considered therapeutically and economically exciting, and rightly so, as it holds many promises for the future. However, when we as doctors stand in front of our patients, we have to rely on results that have emerged from clinical studies. A clinical study serves several functions: it offers the only systematic technique that can translate and remodel results from basic medical scientific research to useful clinical routine. It is also the only rational instrument that can guide us in incorporating new treatment options and discarding old ones. Finally, it can help to define the relationship between “opinion-based medicine” and “evidence-based medicine”. Clinical studies are thus the prerequisite for “evidence-based medicine”, which today is considered one of the most important concepts regarding our ability to set priorities among different treatment options. In the present article, orthopaedic surgeons (other colleagues are welcome to the table) are given a useful overview on basic clinical research concepts, including definitions and explanations that probably were not generally available to most of us when we attended medical studies and completed our training as specialists. The authors exemplify their theoretical presentation with references to previously published studies, cited in the text, which makes their points easy to follow. The importance of cooperation with both an epidemiologist and a biostatistician is rightly emphasised, and it must be stressed that these disciplines should be invited to join the research team in planning a clinical study, a statement that deserves to be repeated. In a short overview like this it is not possible to cover all aspects of clinical research, but I would have wanted some information on not only “treatment effectiveness”, but also “treatment efficacy” and “efficiency”, two expressions that are commonly (and sometimes confusingly) used in the literature. Also, when it comes to statistics, I think a discussion of confidence intervals, which are often more useful in describing uncertainty than p values, would have been appropriate. In summary, this is a useful overview of basic clinical research concepts, which may, along with the authors’ intentions, serve as a helpful checklist for those in the planning phase of clinical research, while for those already started, it could probably be too late. This paper could be one of many signs of a growing interest among spinal surgeons, and hopefully also among fund holders, of conducting clinical research studies.

Academic associate program: integrating clinical emergency medicine research with undergraduate education.

An educational program that teaches undergraduate students about clinical research related to emergency medicine is described. The students work as research assistants within the ED, thus providing a departmental framework for the enrollment of patients in clinical studies. Volunteers interested in the program undergo a physical examination, vaccination history, and standard serologic testing, and sit through a formal blood and body fluid exposure course offered by the university prior to their clinical research participation. A didactic curriculum on clinical research concepts and course examinations is provided. Over the 4 years since the department established its departmental research goals and this educational program, the departmental publication rate has increased from 2 to 20 manuscripts. While there was only 1 faculty member with a research publication in 1992, there were 9 faculty with manuscripts accepted for publication in the first 6 months of 1996. Similarly, more nurses and ancillary staff have become involved in prospective clinical research. Much of this success is attributed to the novel use of resources through the academic associate program.