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Principles and Practice of Clinical Research, Fourth Edition has been thoroughly revised to provide a comprehensive look at both the fundamental principles and expanding practice of clinical research.

IntroductionThe number of patient preference studies in health has increased dramatically. There is growing use of patient preferences in a wide variety of contexts, including health technology assessment. Patient preference studies can help inform decision makers on the needs and priorities of patients and the tradeoffs they are willing to make about health technologies.MethodsThis International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force included international experts, health preference researchers and others from diverse backgrounds, including regulatory, health technology assessment, medicine, patient advocacy, and the pharmaceutical industry. The report underwent two rounds of written reviews by ISPOR Preferences Special Interest Group members until a final consensus was reached. The Task Force focused on developing a roadmap that would: (i) apply to the wide variety of preference methods, (ii) identify key domains to guide researchers and other stakeholders in making patient preference studies more useful to decision makers, and (iii) detail important questions to guide researchers conducting preference studies and those critically appraising them.ResultsThis Task Force report provides a novel roadmap that invites patient-preference researchers to work with decision makers, patients and other stakeholders to do even more to ensure that studies are useful and impactful. The ISPOR Roadmap consists of five key elements: (i) Context; (ii) Purpose; (iii) Population; (iv) Method; and (v) Impact. In this report, we define these five elements and provide good practices on how patient-preference researchers can actively contribute to increasing the usefulness and impact of patient preference studies in decision-making. We also present a set of key questions that can support researchers and other stakeholders in assessing efforts that promote preference studies’ intended and unintended impact.ConclusionsThis roadmap can help increase the usefulness and impact of patient preference studies in decision-making by challenging researchers to engage and partner with decision makers, patients and others, and together consider the intended and unintended impacts of patient preference studies on decision-making while actively fostering positive impact.

Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.Erratum to “NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors”dx.doi.org/10.1155/2014/606348

The FDA’s Center for Drug Evaluation and Research has recommended withdrawing the approval of Makena for the prevention of recurrent preterm birth after a trial failed both to verify clinical benefit to neonates and to substantiate a reduction in preterm birth.

There were several modifications in the paper. They are shown as follows.

Objective: To determine if genetic polymorphisms of CYP1A1, GSTM1, GSTP1, or GSTT1 are associated with an increased risk of developing esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), or either in a high-risk Asian population. Methods: We conducted a case-cohort analysis with 5 years of prospective follow-up. The analytical cohort contained 642 individuals who participated in either the Dysplasia Trial (DT) or the General Population (GPT) of the Nutrition Intervention Trials conducted in Linxian, China, and included 131 cases of ESCC and 90 cases of GCC. Genotyping analysis was performed on DNA extracted from red blood cells using a PureGene kit (Gentra Systems, Inc., Minneapolis, MN) and real-time PCR analysis amplification (Taq-Man). Relative risks and 95% confidence intervals were estimated using the case - cohort estimator for the Cox proportional hazards models. p-values from nested models with genotyping variables came from score tests. Results: The relative risks for developing ESCC, GCC, or either cancer were calculated in the entire analytic cohort for GSTM1, P1*B (A313G), and T1 and CYP1A1*2A (T3801C) and *2C (A2455G) genotypes, and no significant associations were identified. However, because of the difference in cancer risks between the DT (9.3 cases per 1000 person years) and the GPT (5.3 cases), the analytical cohort was stratified by trial; the DT participants who were heterozygous or homozygous for the variant-allele at CYP1A1*2A had a reduced risk for developing GCC (adjusted RR (95%CI) 0.47 (0.23-1.00) p = 0.037). Conclusions: This study found an association for the CYP1A1*2A variant allele and a reduced risk of GCC in people at high risk for development of this disease. This finding is consistent with previous studies suggesting that substrates for the cytochrome P-450 1A1 metabolic pathway, such as polycyclic aromatic hydrocarbons, may be etiologically significant in this high-risk region.

Longitudinal studies of health over time may be misleading if some people die. Self-rated health (excellent to poor) and the SF-36 profile scores have been transformed to incorporate death. We applied the same approaches to incorporate death into activities of daily living difficulties (ADLs), IADLs, mini-mental state examination, depressive symptoms, blocks walked per week, bed days, the timed walk, body mass index and blood pressure. The Cardiovascular Health Study of 5,888 older adults, was followed up to 9 years. Mean age was 73 at baseline, and 658 had an incident stroke during follow-up. We recoded each variable as the probability of being healthy 1 year in the future (PHF), conditional on the current value of the variable. This was done for 11 health variables, using three definitions of healthy, and two estimation models. Deaths were set to zero, and mean PHF was plotted in the 3 years before and after an incident stroke. Analyses without the deaths were too optimistic. The effect of stroke was greatest on hospitalization, self-rated health, and IADLs. Alternative transformation approaches had slightly different results. These methods provide an additional approach for handling death in longitudinal studies.

Observational studies are part of the toolbox of study designs. They may be hypothesis generating or the only feasible or ethical design such as when studying the effects of obesity or smoking on health. Observational studies range in size and detail; we may observe a single patient at the bedside or conduct a population-wide census. Studies may or may not have a planned control group. While at times debated, it is generally accepted that observational studies can distinguish associations between events but cannot conclude that one event causes another. A point that is forgotten at times, however, is even “unobtrusive” observation can still have a significant impact on those being observed and the world as a whole.

Time-to-event data, frequently referred to as survival data, consist of two pieces of information for each subject: the time under observation and the ultimate outcome at the end of that time. Analysis of these data is complicated because the follow-up time often is different for each participant, and the event of interest, such as myocardial infarction, often is not observed in all the subjects by the end of the study. For those participants in whom the event of interest is not observed, what is known is that their survival times are longer than their time spent in the study, but their exact survival times are unknown. This chapter describes features of time-to-event data and introduces the Kaplan–Meier or product-limit estimator for the survival function. It also presents several approaches for comparing two survival curves, a summary of stratified analysis methods, and Cox's proportional hazards regression analysis.

This chapter reviews several notable clinical trial designs, emphasizing the importance of matching the specific design selected to both the purpose of the trial and where the specific question being addressed sits on the spectrum of the research continuum. The most important first step is clearly articulating the research question to be answered, followed by a clear understanding of the existing scientific literature and the existing gaps in knowledge. General characteristics of early-, middle-, and late-stage clinical studies are reviewed, particularly in relationship to how these characteristics inform design decisions. Other critical issues in trial design, such as blinding (masking), choosing a comparison group, intervention development, and characteristics of placebos are discussed. The chapter ends with a discussion of key mistakes that can be made in designing a clinical trial and steps to alleviate them.