Analysis of Longitudinal Trials with Protocol Deviation: A Framework for Relevant,Accessible Assumptions,and Inference via Multiple Imputation

Protocol deviations, for example, due to early withdrawal and noncompliance, are unavoidable in clinical trials. Such deviations often result in missing data. Additional assumptions are then needed for the analysis, and these cannot be definitively verified from the data at hand. Thus, as recognized by recent regulatory guidelines and reports, clarity about these assumptions and their implications is vital for both the primary analysis and framing relevant sensitivity analysis. This article focuses on clinical trials with longitudinal quantitative outcome data. For the target population, we define two estimands, the de jure estimand, “does the treatment work under the best case scenario,” and the de facto estimand, “what would be the effect seen in practice.” We then carefully define the concept of a deviation from the protocol relevant to the estimand, or for short a deviation. Each patient's postrandomization data can then be divided into predeviation data and postdeviation data. We set out an accessible framework for contextually appropriate assumptions relevant to de facto and de jure estimands, that is, assumptions about the joint distribution of pre- and postdeviation data relevant to the clinical question at hand. We then show how, under these assumptions, multiple imputation provides a practical approach to estimation and inference. We illustrate with data from a longitudinal clinical trial in patients with chronic asthma.     

Aligning Treatment Policy Estimands and Estimators—A Simulation Study in Alzheimer’s Disease

Abstract

Draft ICH E9(R1) Addendum on “Estimands and Sensitivity Analysis in Clinical Trials” provides different strategies for addressing intercurrent events in defining an estimand and describing the treatment effect that is targeted. The set of considered intercurrent events will depend on the specific therapeutic setting and trial objectives. This article considers a case study of a long-term prevention trial investigating the treatment effect of a new drug in asymptomatic subjects who are at risk for developing Alzheimer’s dementia to illustrate the definition of different estimands, which correspond to different scientific questions of interest. The potential intercurrent events are identified. This article shows how the selection of various strategies for intercurrent events translates into different estimators. A simulation investigation is included, which explores the properties of several estimators aligned with estimands that apply a treatment policy strategy for the intercurrent event of treatment discontinuation. Different scenarios are considered for the on-treatment versus the off-treatment mean efficacy trajectory, under a potential range of retrieval rates of off-treatment data. This simulation exercise illustrates how the selection of the estimators for an estimand could have a strong impact on the estimates of the treatment effect and, consequently, on the decision making in a clinical trial.     

Causal Inference and Estimands in Clinical Trials

Abstract

The National Research Council’s report on the prevention and treatment of missing data highlighted the need to clearly specify causal estimands. This focus fundamentally changed how the missing data problem was perceived and addressed in clinical trials. The recent ICH E9(R1) addendum is another major step in promoting the use of the causal estimands framework that should further influence how clinical trial protocols and statistical analysis plans are written and implemented. The language of potential outcomes that is widely accepted in the causal inference literature is not widely recognized in the clinical trialists community and was not used in defining causal estimands in the NRC report or the ICH E9(R1). In this article, we attempt to bridge the gap between the causal inference community and clinical trialists to further advance the use of causal estimands in clinical trial settings. We illustrate how concepts from causal literature, such as potential outcomes and dynamic treatment regimens, can facilitate defining and implementing causal estimands and may provide a unifying language to describing the targets for both observational and randomized clinical trials.     

Estimands and Their Role in Clinical Trials

The National Research Council (NRC) highlighted the need to more clearly distinguish between the target of estimation (“estimand”) and the method of estimation (“estimator”) in clinical trials. While the NRC report on “The Prevention and Treatment of Missing Data in Clinical Trials” focuses on issues arising due to missing data, a framework to coherently align trial objectives and corresponding estimands is valuable in a broader sense. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has reinforced this by tasking a working group to develop an addendum to the ICH-E9 guideline “Statistical Principles for Clinical Trials.” In this article, we motivate the need for change, propose a structured framework to bridge trial objectives with proper inference tools, and discuss how it may impact the role of statisticians involved in clinical trial design and analysis.     

Treatment Effects,Comparisons, and Randomization

Abstract

The causal estimands of interest in a clinical trial are treatment effects, and a treatment effect is a comparison of the outcomes for the same patients, or for similar groups of patients, on different treatments. The draft addendum to ICH E9, Statistical Principles for Clinical Trials discusses five possible strategies for defining treatment effects to be estimated, on a more or less equal footing. Indeed, they may appear almost as items on a menu. However, the situations in which they can usefully be applied may be distinct. Furthermore, the classification into five categories may obscure some fairly close relationships between categories and some important differences within categories. Especially, the category of hypothetical estimands is so broad as to include useful estimands that are nothing like anything in the other categories, useful estimands that are notably similar to something else, and possibly useless estimands that are not clearly distinguished from useful ones. This article will discuss the strategies in the addendum. It will offer some advice on when different strategies for constructing estimands may be appropriate. It will classify strategies to make some differences and some similarities clearer; especially it will unpack the hypothetical category. The three classes to be considered are external comparisons, nonrandomized comparisons, and randomized comparisons.     

A Conservative Approach for Analysis of Noninferiority Trials With Missing Data and Subject Noncompliance

Abstract

Noninferiority clinical trials aim to show an experimental treatment is therapeutically no worse than standard of care, particularly if the new treatment is preferred for reasons such as cost, convenience, safety, and so on. Noninferiority trials are by nature less conservative than superiority studies: protocol violations may increase bias toward the alternative hypothesis of noninferiority. Our objective was to compare multiple imputation, a linear mixed model, and other methods for analyzing a longitudinal trial with missing data in intention-to-treat and per-protocol populations. We simulated trials with missing data and noncompliance due to treatment inefficacy under varying trial conditions (e.g., trajectory of treatment effects, correlation between repeated measures, and missing data mechanism), assessing each approach by estimating bias, Type I error, and power. We found that multiple imputation using auxiliary data on noncompliance in the imputation model performed best. A hybrid intention-to-treat/per-protocol multiple imputation approach with a missing not at random imputation model produced low Type I error, was unbiased and maintained reasonable power to detect noninferiority. We conclude that the anti-conservatism of noninferiority trial estimands conforming with the intention-to-treat principle may be offset by imputation models that include variables on intercurrent events. Supplementary materials for this article are available online.     

Secondary insomnia in the primary care setting: review of diagnosis,treatment, and management

ABSTRACT

Introduction: Insomnia is associated with a number of medical and psychiatric disorders, including chronic pain and clinical depression. Until recently, it was assumed that effective treatment of the underlying medical condition would also correct the sleep disturbance. However, some evidence indicates that treatment of secondary or comorbid insomnia should be considered separately from, and perhaps in addition to, optimizing treatment of the primary condition.

Methods: This article reviews the extant literature to examine the impact of secondary and comorbid insomnia on the patient, and on healthcare economics, in the primary care setting, and discusses current diagnostic and treatment approaches. A MEDLINE search was performed for literature published from 1980 to 2005, and retrieved randomized, controlled clinical trials and key review articles for the conditions most often accompanied by secondary insomnia: depression, chronic pain, and menopause/perimenopause. The search terms included those for commonly used pharmacologic treatments and behavioral therapy.

Results: Due to the paucity of clinical trial data in secondary insomnia patients, physicians have had to rely on evidence derived from primary insomnia trials. These data indicate that hypnotic medications are effective in treating sleep onset insomnia. However, few of these agents are effective against the most commonly occurring insomnia symptom – poor sleep maintenance – and many are associated with problematic residual sedation. Nevertheless, the cost of not treating these insomnia symptoms is often greater than the treatment inadequacies. Physicians should thus consider treating what they perceive as secondary insomnia with one of the available forms of therapy.

Conclusion: Patients experiencing sleep problems associated with a potential medical or psychiatric primary condition would likely benefit from increased physician awareness of secondary insomnia and the subsequent increased attention to diagnosing and treating this prevalent condition. Recommendations for managing secondary or comorbid insomnia in the primary care setting are discussed.     

Estimation of causal effects in clinical endpoint bioequivalence studies in the presence of intercurrent events: noncompliance and missing data

In clinical endpoint bioequivalence (BE) studies, the primary analysis for assessing equivalence between a generic and an innovator product is based on the observed per-protocol (PP) population (usually completers and compliers). However, missing data and noncompliance are post-randomization intercurrent events and may introduce selection bias. Therefore, PP analysis is generally not causal. The FDA Missing Data Working Group recommended using “causal estimands of primary interest.” In this paper, we propose a principal stratification causal framework and co-primary causal estimands to test equivalence, which was also recommended by the recently published ICH E9 (R1) addendum to address intercurrent events. We identify three conditions under which the current PP estimator is unbiased for one of the proposed co-primary causal estimands – the “Survivor Average Causal Effect” (SACE) estimand. Simulation shows that when these three conditions are not met, the PP estimator is biased and may inflate Type 1 error and/or change power. We also propose a tipping point sensitivity analysis to evaluate the robustness of the current PP estimator in testing equivalence when the sensitivity parameters deviate from the three identified conditions, but stay within a clinically meaningful range. Our work is the first causal equivalence assessment in equivalence studies with intercurrent events.     

Treatment of central sensitization in patients with chronic pain: time for change?

ABSTRACT

Introduction: Given our improved understanding of the role of central sensitization (CS) in many patients with chronic pain, it seems rational to account for CS during treatment.

Areas covered: First, the treatment rationale based on the complex mechanisms underlying CS in patients having chronic pain is presented. Second, emphasis is given to explaining the concept of CS when providing treatment, as well as why patients and clinicians should focus on long-term rather than short-term treatment effects. Third, possible pharmacological and non-pharmacological treatment options are discussed.

Expert opinion: Centrally acting drugs such as tricyclic compounds, serotonin-norepinephrine reuptake inhibitors, and α₂δ ligands each target mechanisms that are often dysfunctional in patients having chronic pain and CS, but decades of clinical practice and clinical trials have not resulted in satisfactory outcomes. This comes as no surprise; CS comprises complex psycho-neuro-immunological interactions, while each of the tested drugs targets one or two of those mechanisms from a purely biomedical viewpoint. Clinicians willing to take CS into account should design an individually tailored multimodal treatment plan comprising pain neuroscience education, cognition-targeted exercise therapy, sleep management, stress management, and/or dietary intervention.     

Interleukin (IL)-1β Receptor Type II (Gene Therapy), IL-1β Gene,Nitric Oxide Synthase (NOS), Cyclo-Oxygenase (COX)-2, Tumour Necrosis Factor (TNF)-α Convertase,IL-17, Superoxide Dismutase (SOD), Differential Display of Novel Genes Expressed in Human Osteoarthritis-Affected Cartilage,Human Arthritis-Affected Cartilage Proteases

Introduction: Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous ’pain targets’ have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT₂R) antagonist.

Areas covered: Herein, angiotensin II/AT₂R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT₂R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief.

Expert opinion: The functional importance of angiotensin II/AT₂R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT₂R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, small-molecule AT₂R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT₂R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.     

Phase II cancer clinical trials for biomarker-guided treatments

ABSTRACT

The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint.     

Ketamine for the treatment of chronic non-cancer pain

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-d-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes.

Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions.

What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief.

Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.     

Dronabinol and chronic pain: importance of mechanistic considerations

Introduction: Although medicinal cannabis has been used for many centuries, the therapeutic potential of delta-9-tetrahydrocannabinol (Δ9-THC; international non-proprietary name = dronabinol) in current pain management remains unclear. Several pharmaceutical products with defined natural or synthesized Δ9-THC content have been developed, resulting in increasing numbers of clinical trials investigating the analgesic efficacy of dronabinol in various pain conditions. Different underlying pain mechanisms, including sensitization of nociceptive sensory pathways and alterations in cognitive and autonomic processing, might explain the varying analgesic effects of dronabinol in chronic pain states.

Areas covered: The pharmacokinetics, pharmacodynamics and mechanisms of action of products with a defined dronabinol content are summarized. Additionally, randomized clinical trials investigating the analgesic efficacy of pharmaceutical cannabis based products are reviewed for the treatment of chronic nonmalignant pain.

Expert opinion: We suggest a mechanism-based approach beyond measurement of subjective pain relief to evaluate the therapeutic potential of dronabinol in chronic pain management. Development of objective mechanistic diagnostic biomarkers reflecting altered sensory and cognitive processing in the brain is essential to evaluate dronabinol induced analgesia, and to permit identification of responders and/or non-responders to dronabinol treatment.     

Missing Data: Turning Guidance Into Action

Recent research has fostered new guidance on preventing and treating missing data. This article is the consensus opinion of the Drug Information Association's Scientific Working Group on Missing Data. Common elements from recent guidance are distilled and means for putting the guidance into action are proposed. The primary goal is to maximize the proportion of patients that adhere to the protocol specified interventions. In so doing, trial design and trial conduct should be considered. Completion rate should be focused upon as much as enrollment rate, with particular focus on minimizing loss to follow-up. Whether or not follow-up data after discontinuation of the originally randomized medication and/or initiation of rescue medication contribute to the primary estimand depends on the context. In outcomes trials (intervention thought to influence disease process) follow-up data are often included in the primary estimand, whereas in symptomatic trials (intervention alters symptom severity but does not change underlying disease) follow-up data are often not included. Regardless of scenario, the confounding influence of rescue medications can render follow-up data of little use in understanding the causal effects of the randomized interventions. A sensible primary analysis can often be formulated in the missing at random (MAR) framework. Sensitivity analyses assessing robustness to departures from MAR are crucial. Plausible sensitivity analyses can be prespecified using controlled imputation approaches to either implement a plausibly conservative analysis or to stress test the primary result, and used in combination with other model-based MNAR approaches such as selection, shared parameter, and pattern-mixture models. The example dataset and analyses used in this article are freely available for public use at www.missingdata.org.uk.     

Modulation of sensitization processes in the management of pain and the importance of descending pathways: a role for tapentadol?

Abstract

Objective: This paper presents and discusses recent evidence on the pathophysiological mechanisms of pain. The role of tapentadol – an opioid characterized by an innovative mechanism of action (i.e. µ-opioid receptor [MOR] agonism and inhibition of noradrenaline [NA] reuptake [NRI]) – in the modulation of pain, and the most recent pharmacological evidence on this molecule (e.g. the µ-load concept) are also presented and commented upon.

Methods: Narrative review.

Results: Solid evidence has highlighted the importance of central sensitization in the transition from acute to chronic pain. In particular, the noradrenergic system holds a major role in limiting central sensitization and the progression to chronic pain. Therefore, pharmacological modulation of the noradrenergic system appears to be a well-grounded strategy for the control of chronic pain. Tapentadol is characterized by a to-date-unique mechanism of action, since it acts both as a MOR agonist and as an inhibitor of NA reuptake. The synergistic interaction of these two mechanisms allows a strong analgesic effect by acting on both ascending and descending pathways. Of note, the reduced µ-load of tapentadol limits the risk of opioid-related adverse events, such as gastrointestinal disturbances. Moreover, the NA component becomes predominant, at least, in some types of pain, with consequent specific clinical efficacy in the treatment of neuropathic and chronic pain.

Conclusions: According to these characteristics, tapentadol appears suitable in the treatment of severe uncontrolled chronic pain characterized by both a nociceptive and a neuropathic component, such as osteoarthritis or back pain.     

Novel therapeutic approaches in primary hyperoxaluria

ABSTRACT

Introduction: Currently, three types of primary hyperoxaluria (PH I–III) are known, all based on different gene-mutations affecting the glyoxylate metabolism in the liver. Disease hallmark is an increased endogenous oxalate production and thus massively elevated urinary excretion of oxalate and other type-specific metabolites. Hyperoxaluria induces the formation of calcium-oxalate kidney stones and/or nephrocalcinosis. In addition to that, a chronic inflammasome activation by hyperoxaluria per se, often leads to an early deterioration of kidney function, regularly resulting in end-stage renal disease (ESRD) at least in patients with type I PH. Except for vitamin B6 treatment in PH I, therapeutic regimen nowadays consists only of supportive measures, like significantly increased fluid intake and medication increasing the urinary solubility like alkaline citrate.

Areas covered: Disease burden can be severe, and both clinicians and scientist are eager in finding new therapeutic approaches. The currently ongoing clinical studies and promising research in this field are reported in this paper. To present a complete overview, we searched electronic databases, like Clinical trial gov, National Center for Biotechnology Information PubMed, congress reports, press releases and personal information acquired at congresses and conventions. Searches were conducted using the following medical headings: (primary) hyperoxaluria, PH, therapy, treatment and research.

Expert opinion: There is light on the horizon that new treatment options will be available in due time, as there are several promising therapeutic agents currently under investigation, some being at the first levels of drug development, but some already in ongoing clinical trials (phase I-III).     

The Win Ratio: On Interpretation and Handling of Ties

Abstract

To handle composite endpoints, the win ratio has been applied to data analysis and design of clinical trials. Its interpretation, however, is not always clear, and it could handle ties differently. We address these two aspects. First, we express the win ratio as a ratio of two proportions, namely, the proportion of patient-level comparisons in which the experimental treatment “wins” over the control divided by the proportion of “wins” for the control, taking into account the priority order of the components. This equivalent form, the ratio of proportions, can ease communication to clinical trial stakeholders—especially when the win proportions themselves are reported. We recommend such presentations. In some simple cases, we connect the win ratio to the odds ratio, the hazard ratio, the Mann–Whitney U, and the mean difference. In exploring the role of ties, we introduce the win odds, as an extension of the Mann–Whitney odds under the framework of prioritized pairwise comparisons. Finally, we discuss some practical aspects of the win ratio, including rules for defining winners (or losers) and ties, dependence on censoring, win ratio estimands, and benefit-risk assessments, as well as applications to two clinical studies.     

Pregabalin for the treatment of postsurgical pain

Importance of the field: Multimodal postoperative pain management targeted at diminishing harmful outcomes should include pregabalin in cases that need opioid reduction and when the risk of developing chronic neuropathic postsurgical pain is present. Gabapentanoids have grown in importance due to their opioid-sparing effects. They may also contribute to the prevention of chronic postsurgical pain.

Areas covered in this review: We reviewed the literature regarding the use of gabapentanoids and their role in treatment modalities in acute postsurgical pain. Dosing, therapeutic efficacy, side effects, and their role within a multimodal regimen are discussed. Particular emphasis is placed on their ability to provide an opioid-sparing effect, as well as on their potential for inhibiting chronic neuropathic pain. A Pubmed search of pregabalin, gabapentin, acute pain, multimodal analgesia, chronic postsurgical pain, and neuropathic pain between 2000 and 2010 was done. Relevant articles – including randomized controlled trials, retrospective trials, case series, case reports, and review articles – were filtered to include those that relate to postsurgical pain.

What the reader will gain: Readers will gain an increased appreciation of the role of pregabalin in postsurgical pain in patients at risk of developing chronic pain.

Take home message: Pregabalin is a safe and effective medication that may decrease perioperative opioid use in patients with more acute neuropathic pain than acute inflammatory pain. When surgery involves more neuropathic-type acute pain there is growing evidence that pregabalin may decrease the incidence of chronic pain.     

Anti-IL-6 Therapies for Neuromyelitis Optica Spectrum Disorders: A Systematic Review of Safety and Efficacy

Background Neuromyelitis Optica Spectrum Disorder (NMOSD) is a chronic autoimmune disease of the central nervous system that causes recurrent attacks of optic neuritis, myelitis, and brainstem symptoms, resulting in severe neurological disability. Preventive treatment with immunosuppressive agents reduces relapse rate and improves long-term prognosis. In recent years, the potential therapeutical effect of new agents has been investigated. Two of these, the anti-interleukin 6 (IL-6) agents tocilizumab and satralizumab, have been studied in active NMOSD.Objective To systematically review the current data regarding the efficacy and safety of anti-IL-6 agents in NMOSD.Results Fourteen case reports and 5 case series of intravenous tocilizumab have shown beneficial clinical and paraclinical effects compared to commonly used therapies, and another case series of subcutaneous tocilizumab has shown it is as effective as the IV formulation. A phase 2 comparative trial has shown tocilizumab IV to be more effective than azathioprine for relapse prevention. A phase 3 trial of subcutaneous satralizumab versus placebo, has shown a lower risk of relapse in the sartralizumab-treated group, both as add-on therapy to stable immunosuppressant and as monotherapy. Tocilizumab also reduced pain severity in two trials and fatigue scores in one trial, but satralizumab did not significantly improve pain and fatigue. Adverse events with both agents were relatively mild and comparable to placebo and azathioprine.Conclusion The anti-Il-6 agents tocilizumab and satralizumab show promising results in active NMOSD.Further randomized, larger-scale trials are needed to better define the role of these agents in the growing arsenal of NMOSD treatments.