Osteoarthritis subpopulations and implications for clinical trial design

Treatment guidelines for osteoarthritis have stressed the need for research on clinical predictors of response to different treatments. However, identifying such clinical predictors of response is less easy than it seems, and there is not a given classification of osteoarthritis subpopulations. This review article highlights the key methodical issues when analyzing and designing clinical studies to detect important subgroups with respect to treatment effect. In addition, we discuss the main osteoarthritis subpopulations and give examples of how specific treatment effects in these subpopulations have been assessed.     

Analysis of two-period crossover design in a multicenter clinical trial

A technique is discussed for analyzing a two-period crossover design for a multicenter trial using identical study protocols. The technique is a modification of the analysis originally proposed by Grizzle (1965, Biometrics 21, 467-480; 1974, Biometrics 30, 727) for analyzing a two-period crossover design when study is not a factor. A mixed model using the first baseline as a covariate is analyzed to increase the power of the test of significance of the treatment-by-period interaction. The baseline values are also used in a preliminary test.     

A regulatory view on adaptive/flexible clinical trial design

Recently there is growing interest in use of adaptive or flexible designs for development of pharmaceutical products. Statistical methodology has been greatly advanced in the literature. However, there are still some important issues with the methodology and application. In addition, there are many other challenges with these designs, including efficiency of these designs in the entire development program, trial conduct and logistics, the infrastructure of an adaptive trial, the regulatory evaluation of trial results and trial conduct, etc. Up till now, regulatory experience in these designs is very limited. We share some of the challenges.     

Insulin Glargine in the intensive care unit: A model-based clinical trial design

IntroductionCurrent successful AGC (Accurate Glycemic Control) protocols require extra clinical effort and are impractical in less acute wards where patients are still susceptible to stress-induced hyperglycemia. Long-acting insulin Glargine has the potential to be used in a low effort controller. However, potential variability in efficacy and length of action prevent direct in-hospital use in an AGC framework for less acute wards.MethodClinically validated virtual trials based on data from stable ICU patients from the SPRINT cohort who would be transferred to such an approach are used to develop a 24-h AGC protocol robust to different Glargine potencies (1.0×, 1.5× and 2.0× regular insulin) and initial dose sizes (dose = total insulin over prior 12, 18 and 24 h). Glycemic control in this period is provided only by varying nutritional inputs. Performance is assessed as %BG in the 4.0–8.0 mmol/L band and safety by %BG < 4.0 mmol/L.ResultsThe final protocol consisted of Glargine bolus size equal to insulin over the previous 18 h. Compared to SPRINT there was a 6.9–9.5% absolute decrease in mild hypoglycemia (%BG < 4.0 mmol/L) and up to a 6.2% increase in %BG between 4.0 and 8.0 mmol/L. When the efficacy is known (1.5× assumed) there were reductions of: 27% BG measurements, 59% insulin boluses, 67% nutrition changes, and 6.3% absolute in mild hypoglycemia.ConclusionBased on current understanding of Glargine behaviour, a robust protocol for a 24–48 clinical trial has been designed to safely investigate possible differences in efficacy and kinetics of Glargine in a critically ill population. This protocol is a first step towards developing a Glargine-based protocol for less acute wards. Ensuring robustness to variability in Glargine efficacy directly affects the performance and safety that can be obtained.     

Post-stratification in the randomized clinical trial

A topic of current biometric discussion is whether stratification should be used in randomized clinical trials and, if so, which kind. An approach based upon randomization theory is used to evaluate pre- versus post-stratification. The results obtained relate specifically to the effect of the size of the clinical trial on the bias and precision of estimated treatment contrasts.     

Application of predictive biosimulation within pharmaceutical clinical development: examples of significance for translational medicine and clinical trial design

The challenge of accurately predicting human clinical outcome based on preclinical data has led to a high failure rate of compounds in human clinical trials. A series of methods are described by which biosimulation can address these challenges and guide the design and evaluation of experimental and clinical protocols. Early compound development often proceeds on the basis of preclinical data from animal models. The systematic evaluation possible in a simulation can assist in the critical step of translating the preclinical outcomes to human physiology. Later in the process, clinical trials definitively establish a therapy's beneficial effects, as well as any adverse side effects. Biosimulation allows for the optimal design of clinical trials to ensure that key issues are addressed effectively and efficiently, and in doing so, improves the success rate of the trials.     

B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumaband implications for study design

B cells are believed to be central to the disease process in systemic lupuserythematosus (SLE), making them a target for new therapeutic intervention. In recentyears there have been many publications regarding the experience in SLE of B-celldepletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use.However, the two large randomised controlled trials in extra-renal lupus (EXPLORERstudy) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints.Based on the clinical experience with rituximab this failure was somewhat unexpectedand raised a number of questions and concerns, not only into the true level ofbenefit of B-cell depletion in a broad population but also how to test the true levelof effectiveness of an investigational agent as we seek to improve the design oftherapeutic trials in SLE. A better understanding of what went wrong in these trialsis essential to elucidate the underlying reasons for the disparate observations notedin open studies and controlled trials. In this review, we focus on various factorsthat may affect the ability to accurately and confidently establish the level oftreatment effect of the investigational agent, in this case rituximab, in the twostudies and explore hurdles faced in the randomised controlled trials investigatingthe efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based onthe lessons learned from the clinical trials, we make suggestions that could beimplemented in future clinical trial design to overcome the hurdles faced.     

Monitoring accumulating data in a clinical trial

A clinical trial is monitored for efficacy or safety; the variable of interest is death or a similarly serious event. The probability that one therapy has a greater mortality rate than the other is calculated ad libitum during the trial. Adjustments are made for differing patients' prognoses and for survival times.     

Two-stage clinical trial stopping rules

Two-stage stopping rules for clinical trials are considered. The nominal significance level needed for the second-stage test, for any choice of first-stage significance level, is derived for rules with overall significance levels of .01 and .05 and for studies with either half or two-thirds of the patients analyzed in the first stage. A graphical demonstration is given of the inherent tradeoff between power and expected sample size (or probability of early termination). A specific rule, intermediate to those advocated by Pocock (1977, Biometrika 64, 191-199) and O'Brien and Fleming (1979, Biometrics 5, 549-556), is recommended.     

Adaptive design of locomotion and foot form in prosobranch gastropods

A comparison of the locomotor types, speed, tenacity, and foot form of nearly 300 species in 52 families of marine prosobranchs has revealed that foot size and shape and even subtle variations of locomotion affect the speed and strength of adhesion to the substratum.Gastropods inhabiting soft substrata move primarily by pedal cilia or by discontinuous locomotion in which shell and foot move alternately. Both types of movement are accompanied by low tenacity. A specialized type of discontinuous locomotion, namely, leaping, surpasses all other methods of movement in speed. Species with ciliary locomotion have a very large foot while those with discontinuous movement have an exceedingly small foot relative to shell size.The majority of prosobranchs inhabit hard substrata, move by continuous pedal muscular gliding, and have moderately high tenacity during movement. Arhythmic pedal locomotion yields lower maximum speeds and tenacities than do rhythmic pedal waves. Foot size and shape relative to shell length in species with arhythmic locomotion vary from very short and broad to long and narrow. Studies of transects at several temperate and tropical marine littoral stations showed that these species are confined to low littoral or sublittoral habitats that are sheltered from heavy wave action. High speed and tenacity are simultaneously attained only by species with rhythmic pedal waves.Speed and tenacity do not represent competing selective pressures on the size and shape of the foot. Speed increases among species as the foot approaches or exceeds shell length and is highest if the foot is also broad; the greatest tenacities are attained by species with a long, broad foot whose dimensions do not exceed that of the shell. The optimal shape for both high tenacity and speed is a broad foot somewhat shorter than the shell; neither speed nor tenacity are much compromised by this form. In general, only species with rhythmic pedal waves whose foot size and shape approximate the optimal form for high tenacity and speed are found in habitats exposed to much wave action. Long rhythmic waves, moving a large proportion of foot area at once, are in theory energetically more economical than small, very rapid waves resulting in the same overall speed, but experiments showed that tenacity is significantly reduced in gastropods which increase speed by enlarging the waves. The optimal wave pattern of a species should be a balance between the demand for speed with the least expenditure of energy, favored by a pattern of many large waves at once, and the demand for tenacity, favored by a pattern of few and small waves.Retrograde ditaxic waves of elongation are the most common pattern encountered among prosobranchs, and are associated with a large range of foot sizes and shapes. Such waves are at least one third as long as the foot, while direct waves and other waves of compression are frequently much smaller. The range of foot forms of species with waves of compression is restricted, tending to be optimal for high tenacity or to be long and narrow. Waves of compression appear to be a specialization with the potential for maintaining high tenacity even at high speeds since the waves can be very small, and for giving superior speed since they can travel very rapidly.     

Novel serial positive enrichment technology enables clinical multiparameter cell sorting

A general obstacle for clinical cell preparations is limited purity, which causes variability in the quality and potency of cell products and might be responsible for negative side effects due to unwanted contaminants. Highly pure populations can be obtained best using positive selection techniques. However, in many cases target cell populations need to be segregated from other cells by combinations of multiple markers, which is still difficult to achieve--especially for clinical cell products. Therefore, we have generated low-affinity antibody-derived Fab-fragments, which stain like parental antibodies when multimerized via Strep-tag and Strep-Tactin, but can subsequently be removed entirely from the target cell population. Such reagents can be generated for virtually any antigen and can be used for sequential positive enrichment steps via paramagnetic beads. First protocols for multiparameter enrichment of two clinically relevant cell populations, CD4(high)/CD25(high)/CD45RA(high) 'regulatory T cells' and CD8(high)/CD62L(high)/CD45RA(neg) 'central memory T cells', have been established to determine quality and efficacy parameters of this novel technology, which should have broad applicability for clinical cell sorting as well as basic research.     

Adaptive trial designs: a review of barriers and opportunities

ABSTRACT: Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies. A broad definition of adaptive designs allows for countless variations, which creates confusion as to the statistical validity and practical feasibility of many designs. Determining properties of a particular adaptive design requires careful consideration of the scientific context and statistical assumptions. We first review several adaptive designs that garner the most current interest. We focus on the design principles and research issues that lead to particular designs being appealing or unappealing in particular applications. We separately discuss exploratory and confirmatory stage designs in order to account for the differences in regulatory concerns. We include adaptive seamless designs, which combine stages in a unified approach. We also highlight a number of applied areas, such as comparative effectiveness research, that would benefit from the use of adaptive designs. Finally, we describe a number of current barriers and provide initial suggestions for overcoming them in order to promote wider use of appropriate adaptive designs. Given the breadth of the coverage all mathematical and most implementation details are omitted for the sake of brevity. However, the interested reader will find that we provide current references to focused reviews and original theoretical sources which lead to details of the current state of the art in theory and practice.     

Rationale for,and design of,a clinical trial targeting polyamine metabolism for colon cancer chemoprevention

Summary. Polyamine metabolic genes are downstream targets of several genes commonly mutated in colon adenomas and cancers. Inhibitors of ornithine decarboxylase, such as difluoromethylornithine (DFMO), and agents that stimulate polyamine acetylation and export, such as non-steroidal anti-inflammatory drugs (NSAIDS), act at least additively to arrest growth in human cell models and suppress intestinal carcinogenesis in mice. These preclinical studies provided the rationale for colon cancer prevention trials in humans. A Phase IIb clinical study comparing the combination of DFMO and the NSAID sulindac versus placebo was conducted. Endpoints were colorectal tissue polyamine and prostaglandin E2 contents and overall toxicity to participants. Participants in the Phase IIb study served as a vanguard for a randomized, placebo-controlled prospective Phase III trial of the combination of DFMO and sulindac with the primary study endpoint the prevention of colon polyps. Seventy percent of participants will have completed the three years of treatment in December 2006.