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The methodology of randomized clinical trials is essential for the critical assessment and registration of therapeutic interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement was developed to alleviate the problems arising from the inadequate reporting of randomized controlled trials. The present article reflects on the items that we believe should be included in the CONSORT checklist in the context of conducting and reporting trials in allergen-specific immunotherapy. Only randomized, blinded (in particular blinding of patients, health care providers, and outcome assessors), placebo-controlled Phase III studies in this article. Our analysis focuses on the definition of patients’ inclusion and exclusion criteria, allergen standardization, primary, secondary and exploratory outcomes, reporting of adverse events and analysis. [ABSTRACT FROM AUTHOR]

The article comments on the study "Prevention of Cardiovascular Events With an Antihypertensive Regimen of Amlodipine Adding Perindopril as Required Versus Atenolol Adding Bendroflumethiazide as Required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm: A Multicentre Randomised Controlled Trial," by B. Dahlof, P. S. Sever, N. R. Poulter and colleagues. It explains that the trial suggests that atenolol is not an acceptable therapy for the treatment hypertension. Further, it suggests that a strategy using a calcium channel blockers is more effective than the β-blocker atenolol. It argues that the trial was not a trial of combination agent therapy and should not be interpreted as such. It also states the blood pressure in the trial was poorly controlled.

Severe acute malnutrition (SAM) remains a major global public health problem. SAM cases are treated using ready‐to‐use therapeutic food (RUTF) at a dosage of ∼200 kcal/kg/day per the standard treatment protocol (STD). Emerging evidence on simplifications to the standard protocol, which among other adaptations, includes reducing the daily RUTF dosage, indicates that it is effective and safe for treating children with SAM. In response to a foreseen stock shortage of RUTF, the government of Afghanistan endorsed the temporary use of a modified treatment protocol in which the daily RUTF dosage was prescribed at 1000 kcal/day (irrespective of body weight) until the child achieved moderate acute malnutrition status (weight‐for‐height z‐score ≥ −3 or mid‐upper arm circumference [MUAC] ≥ 115 mm), at which point 500 kcal/day was prescribed until cured (modified treatment protocol [MTP]). In this paper, we report the results of this nonweight‐based daily RUTF dosage experience. Data of 2042 children with SAM, treated using either the STD protocol (n = 269) or the MTP protocol (n = 1773) from August 2019 to March 2021 in five provinces, were analyzed. The per‐protocol analyses confirmed noninferiority of MTP protocol when compared to STD protocol for recovery rate [93.3% vs. 90.2%; ∆ (95% confidence interval, CI) = 3.1 (−0.9; 7.2) %] and length‐of‐stay [82.6 vs. 75.6 days; ∆ (95% CI) = 6.9 (3.3; 10.5) days], considering the margin of noninferiority of −10% and +14 days, respectively. Weight gain velocity was smaller in the MTP protocol group than in the STD protocol group [3.7 (1.7) vs. 5.2 (2.9) g/kg/day; ∆ (95% CI) = −1.5 (−1.8, −1.2); p < 0.001]. The STD group had a significantly higher mean than the MTP group for absolute MUAC gain [∆ (95% CI) = 1.7 (1.0; 2.3) mm; p < 0.001] and the MUAC velocity [∆ (95% CI) = 0.29 (0.20; 0.37) mm/week; p < 0.001]. Our results confirm the noninferiority of a nonweight‐based daily dosage and support the endorsement of this modification as an alternative to the standard protocol in resource‐constrained contexts. Key messages: More evidence supporting the use of the nonweight‐based daily ready‐to‐use therapeutic food (RUTF) dosage for treating uncomplicated severe acute malnutrition (SAM), in specific contexts, is needed.Our real‐world prospective nonrandomized study showed that the fixed nonweight‐based daily RUTF dosage protocol is as effective as the standard weight‐based protocol for treating uncomplicated SAM in children <5 in the Afghanistan context.Our findings support the reflection of a nonweight‐based daily RUTF dosage in resource‐constrained contexts in national and global policies and guidelines to improve coverage of all children in need of treatment. [ABSTRACT FROM AUTHOR]

Presents developments related to clinical trials of various diseases and their treatment. Role of delirium in the mortality rate of hospitalized older adults.

OBJECTIVE • To evaluate the impact of urisheaths vs absorbent products (APs) on quality of life (QoL) in men with moderate to severe urinary incontinence (UI). PATIENTS AND METHODS • A randomized, controlled, crossover trial in 61 outpatient adult men with stable, moderate to severe UI, with no concomitant faecal incontinence, was conducted from June 2007 to February 2009 in 14 urology centres. • Participants tested Conveen Optima urisheaths (Coloplast, Humlebaek, Denmark) with collecting bags and their usual AP in random order for 2 weeks each. • The impact of each on QoL was measured using the King’s Health Questionnaire (KHQ) and the short form-12 acute questionnaire, and each patient’s preference was recorded. • A 10-item patient questionnaire was also used to assess the product main advantages on an 11 point scale (0: worst; 10: best). A 72-h leakage diary was used to record the number and severity of leaks and daily product consumption. Safety was measured as the number of local adverse events. RESULTS • All dimensions of the KHQ were scored lower with urisheaths, indicating an improvement in QoL. The greatest mean score reductions were in Limitations of Daily Activities ( − 10.24, P= 0.01) and Incontinence Impact ( −7.05, P = 0.045). • The majority (69%) of patients preferred Conveen Optima urisheaths to their usual AP ( P = 0.002). • Urisheaths scored significantly higher for all categories in the patient questionnaire (efficacy, self-image, odour management, discretion, skinintegrity) except ease of use. • Safety was considered to be good. CONCLUSIONS • Conveen Optima urisheaths showed apositive impact on QoL (according to the KHQ results) in moderate to severe incontinent men, who were long-term usersof APs, and participants largely preferred urisheaths. • Conveen Optima urisheaths should be recommended to incontinent men in preference to APs. [ABSTRACT FROM AUTHOR]

Immunotherapy has been used extensively for 80 years as a specific treatment of allergy. In the last decade, the clinical practice of immunotherapy has changed markedly in certain parts of Europe. In southern Europe immunotherapy still represents the cornerstone of allergy treatment, while in Scandinavia and Great Britain a large number of allergic patients receive immunotherapy. In spite of the fact that a large number of recently published, wee-performed clinical trials have documented the evidently beneficial effect of immunotherapy, the decrease is probably caused by a combination of some degree of uncertainty as to the clinical efficacy, the risk of side effects, and the introduction of potent new drugs for prophylactic treatment of allergic diseases. With the overall aim of improving the safety of immunotherapy and making it more convenient to patients, routes other than the subcutaneous administration of allergens have been investigated.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention‐to‐treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment‐policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross‐industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation. [ABSTRACT FROM AUTHOR]

The novel coronavirus has created one of the biggest social and economic challenges in recent decades. Since a critical issue in overcoming a large‐scale pandemic involves finding effective treatments for the disease, there is typically urgent pressure on the health‐care sector to develop innovations to combat the pandemic. Recently, scholars have argued that repurposing – that is, reusing an existing innovation in a different context – allows for such rapid innovation responses and can reduce costs, as the groundwork has already been laid. In this paper, we compare these benefits with the considerable disadvantages associated with innovation repurposing, including lowered barriers to entry, which can lead to declining average quality and duplicate work. Using data on 2,456 COVID‐19‐related clinical trials initiated between December 2019 and July 2020, we find that merely one‐third of the trials actually investigated drugs or vaccines, whereas the rest focused on diagnostics and crisis management issues. In the trials concerning drug testing, we find that drug repurposing is a predominant innovation strategy, but many trials tested the same (combination of) drugs. This indicates an inefficient use of resources and reductions in the average variety and novelty of clinical trials. Furthermore, the small percentage of biopharmaceutical firms involved in the search for COVID‐19 treatments raises the question of whether firms may have insufficient incentives to redirect innovation efforts to respond to the pandemic. Our paper contributes to crisis management research, the nascent debate on COVID‐19, and the emerging literature on innovation repurposing. [ABSTRACT FROM AUTHOR]

Abstract: According to results of a recent literature search performed by the European Academy of Dermatology and Venereology (EADV) Task Forces (TF) on Quality of Life and Patient Oriented Outcomes (QoL and PO) and Acne, Rosacea and Hidradenitis Suppurativa (ARHS), most of the publications where health‐related (HR) QoL of acne patients was studied were clinical trials. Members of the EADV TF on QoL and PO decided to detect which acne treatment has the best influence on HRQoL of acne patients. A new literature search was organized to find publications on acne treatment where the HRQoL of patients was assessed as an outcome measure. From 186 papers with HRQoL assessment, 37 papers were included for further analysis. Our results revealed that oral isotretinoin had the best influence on HRQoL of acne patients. Several other treatment methods also showed good effects on the HRQoL of acne patients. Oral isotretinoin and norethindrone acetate/ethinyl estradiol, topical clindamycin phosphate/benzoyl peroxide and adapalene/benzoyl peroxide showed significantly better effect on HRQoL than placebo. There is limited number of the high‐quality studies on acne treatment where HRQoL was assessed. Dermatology‐specific and acne‐specific instruments showed much better sensitivity to successful therapeutic intervention than generic HRQoL instruments. The most frequently used HRQoL instrument was the Dermatology Life Quality Index questionnaire. [ABSTRACT FROM AUTHOR]

Objective: This paper describes a pilot study, in a small sample of older adults, designed to ascertain the feasibility, acceptability and potential effectiveness of group Cognitive Behavioural Therapy For Insomnia (CBT‐I). Methods: Eleven older adults participated in a 3‐week group CBT‐I intervention with pre‐ and post‐intervention outcome measures of sleep and fatigue. Acceptability was measured via post‐intervention focus groups. Feasibility was measured via recruitment, retention and completion data. Subjective sleep outcomes were measured pre‐ and post‐intervention using the Pittsburgh Sleep Quality Index. Fatigue was measured using the Fatigue Severity Index. Objective sleep outcome measures were obtained via pre‐ and post‐intervention wrist actigraphy. Results: Feasibility and acceptability were confirmed in the pilot study. Retention and completion levels were high, with participants largely positive in the focus group feedback. Preliminary sleep outcome data supported the potential effectiveness of the intervention in significantly improving several measures of sleep and fatigue including a three‐point reduction in the Global PSQI scores, an increase in total sleep time of almost an hour per night and these results were mirrored by a significant reduction of nine points in the overall measure of fatigue severity. Conclusions: A group CBT‐I intervention is a low‐cost, low‐risk intervention which improves subjective and objective measures of sleep in older adults. These positive sleep outcomes are translated into significantly decreased levels of fatigue. Future research should focus on a larger sample size with a randomised controlled trial design. [ABSTRACT FROM AUTHOR]

What is already known about this subject • The reviews already published on population pharmacokinetic/pharmacodynamic (PK/PD) analyses have focused on theory and have presented some clinical applications, evaluated validation practices in limited circumstances, defined the interest and sometimes the complexity of this approach in drug development or proposed a list of relevant articles. • None of them has exhaustively evaluated published analyses and more precisely the model-building steps. • In view of the statistical complexity of population PK/PD methodology, more attention is required to how models are built and how they are reported in the literature. What this study adds • With a strict methodology and by establishing a standardized tool, this survey provides an exhaustive, objective and up-to-date review of model-building practices. • It reveals deficiencies in information reporting in most articles and the genuine need for guidance in publishing. • An initial, minimal list of items is suggested, which can be used by authors and reviewers in pharmacology journals. • The value of published peer-reviewed papers could be greatly improved if authors were to address the suggested list of items systematically. Aims A descriptive survey of published population pharmacokinetic and/or pharmacodynamic (PK/PD) analyses from 2002 to 2004 was conducted and an evaluation made of how model building was performed and reported. Methods We selected 324 articles in Pubmed using defined keywords. A data abstraction form (DAF) was then built comprising two parts: general characteristics including article identification, context of the analysis, description of clinical studies from which the data arose, and model building, including description of the processes of modelling. The papers were examined by two readers, who extracted the relevant information and transmitted it directly to a MySQL database, from which descriptive statistical analysis was performed. Results Most published papers concerned patients with severe pathology and therapeutic classes suffering from narrow therapeutic index and/or high PK/PD variability. Most of the time, modelling was performed for descriptive purposes, with rich rather than sparse data and using NONMEM software. PK and PD models were rarely complex (one or two compartments for PK; Emax for PD models). Covariate testing was frequently performed and essentially based on the likelihood ratio test. Based on a minimal list of items that should systematically be found in a population PK–PD analysis, it was found that only 39% and 8.5% of the PK and PD analyses, respectively, published from 2002 to 2004 provided sufficient detail to support the model-building methodology. Conclusions This survey allowed an efficient description of recent published population analyses, but also revealed deficiencies in reporting information on model building. [ABSTRACT FROM AUTHOR]

In a survey of clinical trials concerning the efficacy of short- contact therapy with anthralin in psoriasis vulgaris, focusing principally on methodologic issues, twenty-four papers published between January 1982 and December 1989, in English, French, and Italian, were selected. Nine of 24 papers reported on more than one trial, giving a total of 37 clinical trials to be evaluated. A great heterogeneity was evident in many aspects of the design and conduct of these trials, making pooling of results impossible. Most trials suffered from flaws in general methodologic aspects such as randomization and blinding. Limitations in general applicability of results were discussed with reference to the popular use of self-control design and selection of composite indexes (e.g., PASI) as an outcome variable. Published trials are not a reliable guide to clinical decisions concerning short-contact therapy, and some methodologic observations we made could be of general interest in designing clinical trials of psoriasis. [ABSTRACT FROM AUTHOR]

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Purpose This is the third paper in a series that reviews strategies for optimizing the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. Whereas the two previous papers focused on design and implementation, here we address issues pertaining to data processing and statistical analysis. Scope Recommendations for enhancing data quality and utility are offered in sections on data coding and entry; and data format, structure and management. We discuss the need for preliminary data analyses that examine statistical power; patterns of attrition; between-group equivalence; and treatment integrity and discriminability. We discuss tests of treatment efficacy, as well as ancillary analyses aimed at explicating treatment processes. Conclusions Safeguards are necessary to protect data quality, and advance planning is needed to ensure that data formats are compatible with statistical objectives. In addition to treatment efficacy, statistical analyses should evaluate study internal and external validity, and investigate the change mechanisms that underlie treatment effects. [ABSTRACT FROM AUTHOR]

AIM: This paper reports the findings from a qualitative meta-synthesis concerning people with, or at risk of, tuberculosis, service providers and policymakers and their experiences and perceptions of tuberculosis and treatment. BACKGROUND: Directly observed therapy is part of a package of interventions to improve tuberculosis treatment and adherence. A Cochrane systematic review of trials showed an absence of evidence for or against directly observed therapy compared with people treating themselves. METHOD: Qualitative systematic review methods were used to search, screen, appraise and extract data thematic analysis was used to synthesize data from 1990 to 2002, and an update of literature to December 2005. Two questions were addressed: 'What does qualitative research tell us about the facilitators and barriers to accessing and complying with tuberculosis treatment?' and 'What does qualitative research tell us about the diverse results and effect sizes of the randomized controlled trials included in the Cochrane review?' Findings help explain the diverse trial results in a Cochrane systematic review of directly observed therapy and tuberculosis and consider implications for research, policy and practice. FINDINGS: Five themes emerged from the 1990 to 2002 synthesis: socio-economic circumstances, material resources and individual agency; explanatory models and knowledge systems in relation to tuberculosis and its treatment; the experience of stigma and public discourses around tuberculosis; sanctions, incentives and support, and the social organization and social relationships of care. Two additional themes emerged from the 2005 update. CONCLUSION: The qualitative meta-synthesis improved the relevance and scope of the Cochrane review of trials. The findings make a major contribution to the development of theory concerning global WHO-branded disease control and the practicality of local delivery to people. [ABSTRACT FROM AUTHOR]

Antimuscarinic drugs are generally thought to exert their therapeutic action on detrusor overactivity by reducing the ability of the detrusor muscle to contract. We review currently available published data to establish whether there is any evidence to support this contention. Using a PubMed data search, only 14 original articles (including two abstracts) were found that contained cystometric data for both filling and voiding phases and where the actions of antimuscarinic drugs have been reported in detail. These articles were separated into three groups dealing with neuropathic patients (three papers), patients with idiopathic overactive bladder (four papers) and a group whose aetiology was unclear (seven papers). Variables relating to bladder function during the filling phase (time of first desire to void, time to first unstable contraction, and bladder capacity) were identified. Similarly, variables relating to voiding were identified and compared (e.g. maximum detrusor pressure and detrusor pressure at maximum flow rate). The antimuscarinic drugs have a clearly significant effect on sensations of urge, time to first sensation to void, maximum bladder capacity, decrease in voiding frequency and reduction in incontinence episodes. However, only one article (studying neuropaths) reported a significant reduction of the variables associated with detrusor contraction. The remaining four studies (idiopaths/not stated), reported no change in bladder contractility with antimuscarinic drugs. Thus the available data do not support the conclusion that antimuscarinic drugs at doses used in current clinical practice exert their therapeutic action by inhibiting detrusor contractility, but they suggest effects on variables associated with sensation. [ABSTRACT FROM AUTHOR]

Equal randomization has been a popular choice in clinical trial practice. However, in trials with heterogeneous variances and/or variable treatment costs, as well as in settings where maximization of every trial participant's benefit is an important design consideration, optimal allocation proportions may be unequal across study treatment arms. In this paper, we investigate optimal allocation designs minimizing study cost under statistical efficiency constraints for parallel group clinical trials comparing several investigational treatments against the control. We show theoretically that equal allocation designs may be suboptimal, and unequal allocation designs can provide higher statistical power for the same budget or result in a smaller cost for the same level of power. We also show how optimal allocation can be implemented in practice by means of restricted randomization procedures and how to perform statistical inference following these procedures, using invoked population-based or randomization-based approaches. Our results provide further support to some previous findings in the literature that unequal randomization designs can be cost efficient and can be successfully implemented in practice. We conclude that the choice of the target allocation, the randomization procedure, and the statistical methodology for data analysis is an essential component in ensuring valid, powerful, and robust clinical trial results. [ABSTRACT FROM AUTHOR]

It is well known that the treatment effect of a molecularly targeted agent (MTA) may vary dramatically, depending on each patient's biomarker profile. Therefore, for a clinical trial evaluating MTA, it is more reasonable to evaluate its treatment effect within different marker subgroups rather than evaluating the average treatment effect for the overall population. The marker-stratified design (MSD) provides a useful tool to evaluate the subgroup treatment effects of MTAs. Under the Bayesian framework, the beta-binomial model is conventionally used under the MSD to estimate the response rate and test the hypothesis. However, this conventional model ignores the fact that the biomarker used in the MSD is, in general, predictive only for the MTA. The response rates for the standard treatment can be approximately consistent across different subgroups stratified by the biomarker. In this paper, we proposed a Bayesian hierarchical model incorporating this biomarker information into consideration. The proposed model uses a hierarchical prior to borrow strength across different subgroups of patients receiving the standard treatment and, therefore, improve the efficiency of the design. Prior informativeness is determined by solving a "customized" equation reflecting the physician's professional opinion. We developed a Bayesian adaptive design based on the proposed hierarchical model to guide the treatment allocation and test the subgroup treatment effect as well as the predictive marker effect. Simulation studies and a real trial application demonstrate that the proposed design yields desirable operating characteristics and outperforms the existing designs. [ABSTRACT FROM AUTHOR]

Meibomian gland dysfunction is one of the most common ocular disorders encountered by ophthalmologists and is the leading cause of evaporative dry eye. The disease causes significant morbidity in the population such that patients seek treatment. Multiple clinical studies on pharmacological and mechanical interventions for the treatment of meibomian gland dysfunction have been evaluated. However, there is limited comparative clinical evidence for the effectiveness of these interventions. This review paper aims to report the clinical evidence for pharmaceutical interventions for meibomian gland dysfunction in order to guide clinicians in the management of the disease. [ABSTRACT FROM AUTHOR]

Summary: When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all‐comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker‐stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker‐defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker‐stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker‐defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker‐based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker‐negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker‐positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided. [ABSTRACT FROM AUTHOR]

Stopping rules for clinical trials are primarily intended to control Type I error rates if interim analyses are planned, but less is known about the impact that potential stopping has on estimating treatment benefit. In this paper, we derive analytic expressions for (1) the over-estimation of benefit in studies that stop early, (2) the under-estimation of benefit in completed studies, and (3) the overall bias in studies with a stopping rule. We also examine the probability of stopping early and the situation in meta-analyses. Numerical evaluations show that the greatest concern is with over-estimation of benefit in stopped studies, especially if the probability of stopping early is small. The overall bias is usually less than 10% of the true benefit, and under-estimation in completed studies is also typically small. The probability of stopping depends on the true treatment effect and sample size. The magnitude of these effects depends on the particular rule adopted, but we show that the maximum overall bias is the same for all stopping rules. We also show that an essentially unbiased meta-analysis estimate of benefit can be recovered, even if some component studies have stopping rules. We illustrate these methods using data from three clinical trials. The results confirm our earlier empirical work on clinical trials. Investigators may consult our numerical results for guidance on potential mis-estimation and bias in the treatment effect if a stopping rule is adopted. Particular concern is warranted in studies that actually stop early, where interim results may be quite misleading. [ABSTRACT FROM AUTHOR]

Subgroup analyses are an essential part of fully understanding the complete results from confirmatory clinical trials. However, they come with substantial methodological challenges. In case no statistically significant overall treatment effect is found in a clinical trial, this does not necessarily indicate that no patients will benefit from treatment. Subgroup analyses could be conducted to investigate whether a treatment might still be beneficial for particular subgroups of patients. Assessment of the level of evidence associated with such subgroup findings is primordial as it may form the basis for performing a new clinical trial or even drawing the conclusion that a specific patient group could benefit from a new therapy. Previous research addressed the overall type I error and the power associated with a single subgroup finding for continuous outcomes and suitable replication strategies. The current study aims at investigating two scenarios as part of a nonconfirmatory strategy in a trial with dichotomous outcomes: (a) when a covariate of interest is represented by ordered subgroups, eg, in case of biomarkers, and thus, a trend can be studied that may reflect an underlying mechanism, and (b) when multiple covariates, and thus multiple subgroups, are investigated at the same time. Based on simulation studies, this paper assesses the credibility of subgroup findings in overall nonsignificant trials and provides practical recommendations for evaluating the strength of evidence of subgroup findings in these settings. [ABSTRACT FROM AUTHOR]

Multi-country randomised clinical trials (MRCTs) are common in the medical literature, and their interpretation has been the subject of extensive recent discussion. In many MRCTs, an evaluation of treatment effect homogeneity across countries or regions is conducted. Subgroup analysis principles require a significant test of interaction in order to claim heterogeneity of treatment effect across subgroups, such as countries in an MRCT. As clinical trials are typically underpowered for tests of interaction, overly optimistic expectations of treatment effect homogeneity can lead researchers, regulators and other stakeholders to over-interpret apparent differences between subgroups even when heterogeneity tests are insignificant. In this paper, we consider some exploratory analysis tools to address this issue. We present three measures derived using the theory of order statistics, which can be used to understand the magnitude and the nature of the variation in treatment effects that can arise merely as an artefact of chance. These measures are not intended to replace a formal test of interaction but instead provide non-inferential visual aids, which allow comparison of the observed and expected differences between regions or other subgroups and are a useful supplement to a formal test of interaction. We discuss how our methodology differs from recently published methods addressing the same issue. A case study of our approach is presented using data from the Study of Platelet Inhibition and Patient Outcomes (PLATO), which was a large cardiovascular MRCT that has been the subject of controversy in the literature. An R package is available that implements the proposed methods. [ABSTRACT FROM AUTHOR]

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation. [ABSTRACT FROM AUTHOR]

Purpose To critically appraise scientific evidence regarding the efficacy of nutritional supplementation with omega-3 and omega-6 fatty acids for the treatment of dry eye syndrome (DES). Methods A systematic review of randomized clinical trials was performed. Two independent reviewers selected and analysed the scientific papers that met inclusion and exclusion criteria. Objective and subjective efficacy outcomes were assessed. Results The trials involved a total of 2591 patients in fifteen independent studies. All studies were published between 2005 and 2015. The supplements used were mostly omega-3 and omega-6 in different proportions. Subjective improvement was measured using mainly Ocular Surface Disease Index ( OSDI) test and Dry Eye Severity Score ( DESS) test: significant differences in favour of the experimental group were found in seven of the studies. The objective amelioration was assessed by lacrimal function parameters: Tear break-up time ( TBUT) significantly increased in nine studies and Schirmer's test in four studies. Conclusion We observed a discrete improvement in the parameters of tear function. Scientific evidence is not strong enough to systematically recommend the use of omega-3 and omega-6 fatty acids as a standalone treatment of DES independently from its aetiology. However, they could be considered as an effective alternative to topical treatment in patients with DES secondary to certain pathologies. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are released by all cells and contribute to cell‐to‐cell communication. The capacity of EVs to target specific cells and to efficiently deliver a composite profile of functional molecules have led researchers around the world to hypothesize their potential as therapeutics. While studies of EV treatment in animal models are numerous, their actual clinical benefit in humans has more slowly started to be tested. In this scoping review, we searched PubMed and other databases up to 31 December 2023 and, starting from 13,567 records, we selected 40 pertinent published studies testing EVs as therapeutics in humans. The analysis of those 40 studies shows that they are all small pilot trials with a large heterogeneity in terms of administration route and target disease. Moreover, the absence of a placebo control in most of the studies, the predominant local application of EV formulations and the inconsistent administration dose metric still impede comparison across studies and firm conclusions about EV safety and efficacy. On the other hand, the recording of some promising outcomes strongly calls out for well‐designed larger studies to test EVs as an alternative approach to treat human diseases with no or few therapeutic options. [ABSTRACT FROM AUTHOR]

The aim of this paper is to provide a description of a significant process which takes place during a first psychiatric hospitalization and to shed some light on its context. This process involves a transformation of an individual considered mentally disturbed into a psychiatric patient which affects the person's identity. The ‘person’ becomes a ‘psychiatric patient’. Although it is self-evident that a patient never stops being a person, the context of the first hospitalization merits attention as it is the time when the patient is in most danger of being objectified and depersonalized. The paper describes a study of forty-six patients hospitalized for the first time on a psychiatric ward and their seventy-five parents. Their narratives from the beginning and the end of stay in hospital were compared and the language used during the introductory consultation and discharge consultation analysed. In this process an important role is played by patients' parents. The parents' narratives are seen to change in a direction of acceptance but at the same time a process of stigmatization is apparent. [ABSTRACT FROM AUTHOR]

Aims Over the last three decades, the randomized controlled trial or ‘psychotherapy technology’ approach has been the dominant model of inquiry in research on addiction treatment. This period has yielded impressive discoveries, but recent failures to confirm core research hypotheses such as occurred in Project MATCH and the Cocaine Collaborative Treatment Study have raised questions about future research directions. The paper identifies several testable assumptions of the psychotherapy technology model. Methods A review is conducted on four substance use disorder behavioral interventions—motivational interviewing, cognitive–behavioral treatment, behavioral couples treatment and 12-Step-oriented treatment—to determine whether these assumptions are supported by research findings. Results Overall, the review suggests weak support for the technology model of psychotherapy research. Lack of support is interpreted as indicating flaws in several model assumptions about how to conceptualize and measure patient responsivity and the interaction of non-specific and specific therapeutic factors. The paper offers alternative strategies for addressing these issues drawn from the general psychotherapy process literature and provides illustrative examples of how these could be used to spur innovation in addiction treatment research. Conclusions The addiction treatment research field is coming up against the limitations of the psychotherapy technology model as the dominant paradigm guiding treatment research. It is important for addiction treatment researchers to explore alternative conceptualizations and methodologies in order to understand more clearly how treatment works. [ABSTRACT FROM AUTHOR]

This article introduces the special issue on recent conceptual, practical, and research developments relevant to men and therapy. The paper reviews the considerable shifts that have emerged in our understanding and measurement of masculinity as it pertains to men's health and therapy. In addition, this introduction outlines the primary focus of each article in this special issue and describes the general guidelines offered to the contributors. Collectively, these special-issue articles describe promising paradigms, provide useful examples, and stress the need for further research on men, masculinity, and the therapeutic process. © 2005 Wiley Periodicals, Inc. J Clin Psychol 61: 627–631, 2005. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to summarize the state of the art in measuring quality of life in haemophila populations. The paper reviews the measures recently included in haemophila trials in the published literature. It also summarizes the development of four new disease-specific measures of health-related quality of life. Two of these were developed for children (the Haemo-QoL and the CHO-KLAT), and two for adults (the Hemofilia-QoL and the Hemolatin-QoL). These new measures show promise for use in clinical trials. Further research is in progress to complete the psychometric testing and cross-cultural validation. [ABSTRACT FROM AUTHOR]

The current popularity of complementary therapies presents an interesting challenge to nurses and midwives. If they are to deliver such therapies themselves, or support patients in choosing appropriate therapies they will need to consider the professional and legal issues, in particular those regarding safety. Evidence for the effectiveness for complementary therapies is also a requirement in order that their integration into nursing practice can be justified. Purchasers are currently hampered by the lack of credible evidence for effectiveness and until that evidence is provided, access to such therapies through the National Health Service (NHS) will remain limited. The form that evidence should take has led to a lively debate about possible methodological approaches. There appears to be a clash between the medical profession and those working in the field of complementary therapy research, with the medical establishment advocating randomized control trials (RCTs). This contrasts with the view held by some advocates of complementary therapies that the RCT approach is reductionist and not applicable to such approaches. The pivot of the debate on the methodological approaches for evaluating complementary therapies is the contrast of two apparently different and diverse world-views, and the assertion that methods developed in one world-view are not transferable to the other. There is also some confusion within the field of complementary therapy over the applicability of RCTs to therapies such as acupuncture, and the mistaken assumption that trials which include a control group, are also required to be double-blind. This paper is based on the need for good quality evidence of effectiveness in complementary therapy. It will set out the concerns associated with the use of RCTs within complementary therapy, together with the benefits and limitations of this approach. The paper will go on to review research options and propose some suggestions for future methodological approaches. [ABSTRACT FROM AUTHOR]

Objective To systematically review the published clinical trials, case series, and case reports on left unilateral ( LUL) electrode placement for clinical electroconvulsive therapy ( ECT). Method PubMed, Ovid Medline, and the Cochrane Library were searched for articles concerning LUL ECT. Number of patients, efficacy, and cognitive outcomes were extracted from the papers that met our inclusion criteria. Results A total of 52 articles were included in this review, consisting of 33 clinical trials, seven case series, and 12 case reports. Conclusion Overall, the efficacy of LUL electrode placement for the treatment of depression and psychosis is similar to that of right unilateral ( RUL) and bilateral ( BL) electrode placements. Patients receiving LUL ECT tend to experience more verbal memory impairment than patients receiving RUL ECT, but less verbal impairment than patients receiving BL ECT. In contrast, patients receiving LUL ECT tended to experience the least visual and nonverbal memory impairment, compared to patients receiving RUL or BL ECT. [ABSTRACT FROM AUTHOR]

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. [ABSTRACT FROM AUTHOR]

Interest among researchers in the diagnosis, aetiology, prevention, and treatment of root caries has increased substantially over the past two decades. However, there are some fundamental problems impeding the advancement of the field which remain to be addressed and resolved. A universally acceptable definition of root caries is not yet available. The relationship of root caries to coronal caries has not been established. The underlying disease process is still not clearly understood. The optimal utilisation of preventive/therapeutic agents for the treatment or prevention of root caries has not been determined. New treatment materials and preventive agents have not yet been tested in controlled clinical trials. These are a few of the issues and problems which we address in this paper. [ABSTRACT FROM AUTHOR]

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There has been an upsurge of multidisciplinary research since the adoption of a standardized definition of osteonecrosis of the jaw (ONJ) and the first bisphosphenate-related ONJ conference in 2007 held at the New York Academy of Sciences. This series of papers revisits topics presented at the conference in addition to covering recent advances in the history, mechanisms, clinical management, and prevention of bisphosphonate-related ONJ. [ABSTRACT FROM AUTHOR]

Generalized estimating equations (GEE) is a general statistical method to fit marginal models for longitudinal data in biomedical studies. The variance-covariance matrix of the regression parameter coefficients is usually estimated by a robust "sandwich" variance estimator, which does not perform satisfactorily when the sample size is small. To reduce the downward bias and improve the efficiency, several modified variance estimators have been proposed for bias-correction or efficiency improvement. In this paper, we provide a comprehensive review on recent developments of modified variance estimators and compare their small-sample performance theoretically and numerically through simulation and real data examples. In particular, Wald tests and t-tests based on different variance estimators are used for hypothesis testing, and the guideline on appropriate sample sizes for each estimator is provided for preserving type I error in general cases based on numerical results. Moreover, we develop a user-friendly R package "geesmv" incorporating all of these variance estimators for public usage in practice. [ABSTRACT FROM AUTHOR]

Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease ( GVHD) after allogeneic haematopoietic stem cell transplantation ( HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning ( RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-IV acute GVHD (9% vs. 25%, P = 0·015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov ( NCT00928018). [ABSTRACT FROM AUTHOR]

Chemoimmunotherapy followed by autologous stem cell transplantation ( ASCT) is a standard therapy for transplant-eligible patients with newly diagnosed mantle cell lymphoma ( MCL). The achievement of complete remission ( CR) and minimal residual disease ( MRD) negativity are associated with better outcomes. We tested an induction regimen of rituximab/bendamustine followed by rituximab/high-dose cytarabine ( RB/ RC). This phase 2 study ( NCT01661881) enrolled 23 transplant-eligible patients aged 42-69, of whom 70% were MCL international prognostic index low-risk. Patients received three cycles of RB followed by three cycles of RC. The primary endpoint of the trial was the rate of CR after six cycles of therapy, with a rate of 75% considered promising. 96% of patients achieved a CR/unconfirmed CR after treatment, meeting the primary objective. One patient progressed on study, one declined ASCT in CR, and the remaining 21 underwent successful stem cell collection and ASCT. After a median follow-up of 13 months, the progression-free survival rate was 96%. Among 15 MRD -evaluable patients who completed treatment, 93% achieved MRD negativity after RB/ RC. In conclusion, RB/ RC achieves very high CR and MRD negativity rates in transplant-eligible patients, with a favourable safety profile. RB/ RC warrants further comparative studies, and may become a useful alternative to RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-based induction regimens in this patient population. [ABSTRACT FROM AUTHOR]

In many randomized controlled trials, treatment groups are of equal size, but this is not necessarily the best choice. This paper provides a methodology to calculate optimal treatment allocations for longitudinal trials when we wish to compare multiple treatment groups with a placebo group, and the comparisons may have unequal importance. The focus is on trials with a survival endpoint measured in discrete time. We assume the underlying survival process is Weibull and show that values for the parameters in the Weibull distribution have an impact on the optimal treatment allocation scheme in an interesting way. Additionally, we incorporate different cost considerations at the subject and measurement levels and determine the optimal number of time periods. We also show that when many events occur at the beginning of the trial, fewer time periods are more efficient. As an application, we revisit a risperidone maintenance treatment trial in schizophrenia and use our proposed methodology to redesign it and compare merits of our optimal design. [ABSTRACT FROM AUTHOR]

Background The primary goals in conducting clinical trials of treatments for alcohol use disorders ( AUDs) are to identify efficacious treatments and determine which treatments are most efficacious for which patients. Accurate reporting of study design features and results is imperative to enable readers of research reports to evaluate to what extent a study has achieved these goals. Guidance on quality of clinical trial reporting has evolved substantially over the past 2 decades, primarily through the publication and widespread adoption of the Consolidated Standards of Reporting Trials statement. However, there is room to improve the adoption of those standards in reporting the design and findings of treatment trials for AUD. Methods This paper provides a narrative review of guidance on reporting quality in AUD treatment trials. Results Despite improvements in the reporting of results of treatment trials for AUD over the past 2 decades, many published reports provide insufficient information on design or methods. Conclusions The reporting of alcohol treatment trial design, analysis, and results requires improvement in 4 primary areas: (i) trial registration, (ii) procedures for recruitment and retention, (iii) procedures for randomization and intervention design considerations, and (iv) statistical methods used to assess treatment efficacy. Improvements in these areas and the adoption of reporting standards by authors, reviewers, and editors are critical to an accurate assessment of the reliability and validity of treatment effects. Continued developments in this area are needed to move AUD treatment research forward via systematic reviews and meta-analyses that maximize the utility of completed studies. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

Background Maternal depression is associated with poor child development and growth in low-income countries. This paper evaluates the effect of a community-based trial providing psychosocial stimulation and food supplements to severely malnourished children on maternal depressive symptoms in Bangladesh. Methods Severely underweight (weight-for-age Z-score < −3) hospitalized children aged 6-24 months ( n = 507), were randomly assigned to: psychosocial stimulation ( PS), food supplementation ( FS), PS+ FS, clinic control ( CC) and hospital control ( CH) at discharge. PS included play sessions with children and parental counselling to mothers during fortnightly follow-up visit at community clinics, conducted by trained play leaders for 6 months. FS involved cereal-based supplements (150-300 kcal/day) for 3 months. All groups received medical care, micronutrient supplements and growth monitoring. We used Bayley scales, Home Observation for Measurement of Environment ( HOME) inventory and a parenting questionnaire to assess child development, home stimulation and mothers' child-rearing practices, respectively. We assessed mothers' depressive symptoms using a modified version of Centre for Epidemiologic Studies Depression Scale at baseline and at 6 months post intervention. Results Maternal depressive symptoms were significantly lower in the CH group at baseline ( P = 0.014). After 6 months of intervention there was no significant effect of intervention after adjusting for baseline scores and all possible confounders. Maternal depressive symptoms were higher among poorer ( P = 0.06), older ( P = 0.057) and less educated ( P = 0.019) mothers, who were housewives ( P = 0.053), and whose husbands had more unstable jobs ( P = 0.058). At 6 months post intervention, children's cognitive ( P = 0.045) and motor ( P = 0.075) development, HOME ( P = 0.012) and mother's parenting score ( P = 0.057) were higher among mothers with lower depressive symptoms. Conclusion The study did not show a significant effect of the intervention on the level of maternal depressive symptoms. Interventions with higher intensity and/or of longer duration focusing directly on maternal psychosocial functioning are probably needed to reduce maternal depressive symptoms. [ABSTRACT FROM AUTHOR]

Objective: Inattention is a core feature of delirium, and valid assessment of attention is central to diagnosis. Methods of measuring attention in delirium can be divided into two broad categories: (i) objective neuropsychological testing; and (ii) subjective grading of behaviour during interview and clinical examination. Here, we review and critically evaluate studies of objective neuropsychological testing of attention in delirium. We examine the implications of these studies for delirium detection and monitoring in clinical practice and research, and how these studies inform understanding of the nature of attentional deficits in delirium. Methods: Searches of MEDLINE and ISI Web of Knowledge databases were performed to identify studies in which objective tests of attention had been administered to patients with delirium, who had been diagnosed using DSM or ICD criteria. Results: Sixteen publications were identified. The attention tests administered in these studies were grouped into the following categories: measures of attention span, vigilance tests, other pen-andpaper tests (e.g. Trail Making Test) and computerised tests of speeded reaction, vigilance and sustained attention. Patients with delirium showed deficits on all tasks, although most tasks were not considered pure measures of attention. Five papers provided data on differential diagnosis from dementia. Cancellation tests, spatial span tests and computerised tests of sustained attention discriminated delirium from dementia. Five studies presented reliability or validity statistics. Conclusions: The existing evidence base on objective assessment of attention in delirium is small. Objective testing of attention is underdeveloped but shows considerable promise in clinical practice and research. [ABSTRACT FROM AUTHOR]

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer ( mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel- T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. [ABSTRACT FROM AUTHOR]

Comorbidity is a well-established and documented phenomenon in mental disorders and medicine with heuristic value. The concept of comorbidity remains however poorly defined and lacks a comprehensive and coherent theoretical framework. There is a need to develop coherent methodological strategies in order to promote a fuller understanding of the implications of comorbidity and to exploit its potential value with regard to etiopathogenic and therapeutic issues. This position paper makes recommendations of improved methodological standards and procedures and discusses a range of options that can provide incremental information that is likely to improve therapeutic outcomes. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This study was undertaken to examine the appropriateness of test statistics used for split-mouth clinical trials. Twenty-two published trials were reviewed and the primary test statistics were labeled as appropriate, inappropriate, or absent. Only 5 of the 22 trials reported an appropriate test statistics, Of the remaining 17 trials, 12 used an inappropriate test statistics, and 5 did not report or did not use statistical tests. A serious problem is that more than half of the reviewed trials have reported the use of a one-way analysis of variance or a two-sample t test to investigate the data of the split-mouth trial. This mistake may have led to a large increase of the Type II errors due to the correlated nature of split-mouth data, Failure to detect genuine therapeutic differences because of inadequate attention to the data analysis can occur with inappropriate use of test statistics. It is concluded that there should be more concern for the use of appropriate test statistics. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Srinivas paper. To view this article visit https://doi.org/10.1111/apt.14169. [ABSTRACT FROM AUTHOR]

The safety of trial subjects is the tenet that guides the regulatory assessment of a Clinical Trial Authorization application and applies equally to trials involving small molecules and those with biological/biotechnological products, including Advanced Therapy Medicinal Products. The objective of a regulator is to ensure that the potential risk faced by a trial subject is outweighed by the potential benefit to them from taking part in the trial. The focus of the application review is to assess whether risks have been identified and appropriate steps taken to alleviate these as much as possible. Other factors are also taken into account during a review, such as regulatory requirements, and emerging non-clinical and clinical data from other trials on the same or similar products. This paper examines the regulatory review process of a Clinical Trial Authorization application from the perspectives of Quality, Non- Clinical and Clinical Regulatory Assessors at the Medicines and Healthcare products Regulatory Agency. It should be noted that each perspective has highlighted specific issues from their individual competence and that these can be different between the disciplines. [ABSTRACT FROM AUTHOR]

Pirfenidone has been shown in three recently published trials to slow down the progression of the devastating interstitial lung disease, idiopathic pulmonary fibrosis ( IPF). The precise mechanisms that initiate and perpetuate the histopathological process leading to lung fibrosis in IPF are still uncertain, but increased concentrations of reactive oxidative species and fibrogenetic factors have been observed in the pulmonary tissue of patients. Although the exact mechanisms of its action are unknown, pirfenidone is a small molecule with antifibrotic and some hydroxyl scavenger properties that has recently been approved in Europe and elsewhere for the treatment of IPF. Along with the new ATS/ ERS/ JRS/ ALAT 2011 statement for ' Evidence Based Guidelines for Diagnosis and Management', there is now a more profound basis for offering IPF patients an evidence-based evaluation and treatment. This review summarizes the background to the recommended use of pirfenidone for the treatment of IPF. Please cite this paper as: Hilberg O, Simonsen U, du Bois R and Bendstrup E. Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis. Clin Respir J 2012; 6: 131-143. [ABSTRACT FROM AUTHOR]