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We observed lack of clarity and consistency in end point definitions of large randomized clinical trials in diffuse large B-cell lymphoma. These inconsistencies are such that trials might, in fact, address different clinical questions. They complicate interpretation of results, including comparisons across studies. Problems arise from different ways to account for events occurring after randomization including absence of improvement in disease status, treatment discontinuation or the initiation of new therapy. We call for more dialogue between stakeholders to define with clarity the questions of interest and corresponding end points. We illustrate that assessing different end point rules across a range of plausible patient journeys can be a powerful tool to facilitate such a discussion and contribute to better understanding of patient-relevant end points. Plain Language Summary What is this article about? This article talks about the lack of clarity and consistency in the definitions of outcomes used in clinical trials that investigate new treatments for diffuse large B-cell lymphoma. This is mainly due to how these different outcome definitions handle events such as absence of improvement in disease status, treatment discontinuation or initiation of new treatment. The authors discuss how these inconsistencies make it hard to interpret the results of individual clinical trials and to compare results across clinical trials. Why is it important? Defining the above events and consequently defining outcomes affects what we can learn from the trials and can lead to different results. Some approaches may not reflect good and bad outcomes for patients appropriately. This makes it challenging for patients, physicians, health authorities and payors to understand the true benefit of treatments under investigation and which one is better. What are the key take-aways? This article serves as a call-to-action for more dialogue among all stakeholders involved in drug development and the decision-making process related to drug evaluations. There is an urgent need for clinical trials to be designed with more clarity and consistency on what is being measured so that relevant questions for patients and prescribing physicians are addressed. Understanding patient journeys will be key to successfully understand what truly matters to patients and how to measure the benefit of new treatments. Such discussions will contribute toward more clarity and consistency in the evaluation of new treatments. Tweetable Abstract Time for more dialogue to harmonize end point definitions in lymphoma! Use patient journeys to bring more clarity, consistency and patient-relevance! Learn about key considerations for the choice of end points and why PFS is not always meaningful! Article highlights Background End points in clinical trials should reflect good and bad outcomes for patients appropriately. Clarity on end point definitions is critical when interpreting trial results. Review of phase III trials in diffuse large B-cell lymphoma (DLBCL) highlights the prevailing lack of clarity and consistency in the choice of end points and their definitions. Overall survival Combines the effect on survival of both the initial and any subsequent therapies received until death and captures potential effects of initial therapy on the choice, safety and efficacy of subsequent therapies. Challenging interpretation of clinical trial results in DLBCL with rapidly changing treatment options and multiple potentially curative subsequent treatments. Progression-free survival The response of stable disease is a bad outcome for DLBCL patients, and as progression-free survival (PFS) does not count it as event it might not be patient-relevant. Different approaches to consider the impact of new therapies initiated prior to PFS event or to exclude their impact address different questions. Good understanding of the reasons for treatment discontinuations and start of new therapy critical to interpret PFS results. Event-free survival Event-free survival (EFS) considers not only death and progression as events, but also a type of 'treatment failure'. Treatment discontinuation generally not used in confirmatory trials as 'treatment failure' event as it can be influenced by other factors not related to efficacy. Start of new therapy often considered as treatment failure event regardless of the reason, i.e., even if it follows discontinuation due to toxicities. In some trials, start of a new therapy for efficacy-related reasons is defined as an event, showing a focus on the anti-tumour activity of the drug. Additional considerations required for studies of treatment strategies with multiple interventions such as CAR-T or transplant strategies. Patient-reported outcomes Challenging to interpret the results in the absence of clear, well-defined research objectives. When defining research objectives, it is important to differentiate between short-term and long-term effects and to consider duration of treatment, frequency of patient-reported outcomes (PRO) assessments, the impact of new therapies and deaths and whether quality of life (QoL) at later timepoints reflects only the results in responding patients. Discussion Various elements of patient journey, disease setting and therapy type impact the appropriateness of end points. Dialogue between all stakeholders needed to define more explicitly the questions of interest and corresponding end points in DLBCL and to ensure that relevant data are collected, clinical trials are designed to address these questions and the results are easier to interpret. [ABSTRACT FROM AUTHOR]

Although the digital revolution has transformed many areas of human endeavor, pharmaceutical drug development has been relatively slow to embrace the emerging technologies to enhance efficiency and optimize value in clinical trials. The topic has garnered even greater attention in the face of the coronavirus disease 2019 (COVID‐19) outbreak, which has caused unprecedented disruption in the conduct of clinical trials and presented considerable challenges and opportunities for clinical trialists and data analysts. In this paper, we highlight the potential opportunity with virtual or digital clinical trials as viable options to enhance efficiency in drug development and, more importantly, in offering diverse patients easier and attractive means to participate in clinical trials. Special reference is made to the implication of artificial intelligence and machine‐learning tools in trial execution and data acquisition, processing, and analysis in a virtual trial setting. Issues of patient safety, measurement validity, and data integrity are reviewed, and considerations are put forth with reference to the mitigation of underlying regulatory and operational barriers. [ABSTRACT FROM AUTHOR]

We compared clinical performance of p16/Ki‐67 dual‐stained cytology and human papillomavirus (HPV) genotyping, via different algorithms—alone, or in combination with cytology—to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) in women referred to as colposcopy. We included 492 cervical specimens (134 normal, 130 CIN1, 99 CIN2, 121 CIN3, 8 cancers) randomly selected from 1158 specimens with valid conventional cytology, HPV (cobas 4800 HPV test) and biopsy results. Dual‐stained cytology was retrospectively performed (CINtec PLUS assay) on PreservCyt material; slides were read by a cytologist and confirmed by two pathologists, blinded to cytology, biopsy and genotyping results. Sensitivity and specificity (95% confidence intervals in parentheses) of dual‐stained cytology to detect CIN2+ and CIN3+ were compared to other screening tests available for the same women. Positivity rate for dual‐stained cytology increased with histological severity: 30.6% in normal, 41.5% in CIN1, 72.7% in CIN2, 86.8% in CIN3 and 87.5% in cancer. Dual‐stained cytology alone had lower sensitivity than HPV testing for CIN2+ [80.7% (75.0‐85.6) vs 89.9% (85.3‐93.5)] and CIN3+ [86.8% (79.7‐92.1) vs 92.3% (86.2‐96.2)]. However, corresponding specificity values were higher [64.0% (57.9‐69.8) vs 56.1% (49.8‐62.1) for CIN2+; 54.0% (48.7‐59.2) vs 44.4% (39.2‐49.6) for CIN3+]. Combining dual‐stained cytology with an ASC‐US abnormality threshold decreased specificity to 31.4% (25.9‐37.4) for CIN2+ and 24.2% (19.9‐29.0) for CIN3+. The corresponding values considering low squamous intraepithelial lesion threshold values were 42.8% (36.8‐49.0) and 35.0% (30.1‐40.1). Dual‐stained cytology and HPV testing exhibited similar performance, although the former improved the specificity by 7.9% and 9.6% for CIN2+ and CIN3+, respectively. What's new? Primary cervical cancer screening with DNA testing for human papillomavirus (HPV) is limited by its lower specificity relative to conventional cytology, thus requiring more efficient triage strategies to avoid excess colposcopy and overtreatment of cervical lesions. This study compared the clinical performance of dual‐stained cytology and HPV genotyping among women referred to colposcopy for abnormal cervical cancer screening results. The data provide further evidence that the combined biomarker p16/Ki‐67, indicative of transforming HPV infections, has a higher specificity for high‐grade cervical lesions than cytology and HPV genotyping. Dual‐stained cytology could support the triaging management of patients with positive high‐risk HPV. [ABSTRACT FROM AUTHOR]

DNA methylation analysis may improve risk stratification in cervical screening. We used a pan‐epigenomic approach to identify new methylation markers along the continuum of cervical intraepithelial neoplasia (CIN) to cervical cancer. Physician‐collected samples (54 normal, 50 CIN1, 40 CIN2 and 42 CIN3) were randomly selected from women at a single‐center colposcopy clinic. Extracted DNA was subjected to Illumina Infinium EPIC array analysis, and methylation was assessed blinded to histopathological and clinical data. CpG sites whose state of methylation correlated with lesion grade were assessed (Spearman correlation), and a weighted methylation score was calculated comparing normal to CIN3. Validation of the top selected genes was performed in an independent cohort (100 normal, 50 CIN1, 50 CIN2, 50 CIN3 and 8 cervical cancers) of new patients, referred for colposcopic examination at three hospitals, using targeted DNA methylation Illumina amplicon sequencing. The relationship between a combined weighted marker score and progression from normal through precancerous lesions and cervical cancer was compared using one‐way ANOVA. Our analyses revealed 7,715 CpGs whose methylation level correlated with progression (from normal to CIN1, CIN2 and CIN3), with a significant trend of increased methylation with lesion grade. We shortlisted a bigenic (hyaluronan synthase 1, HAS1 and ATPase phospholipid transporting 10A, ATP10A corresponding to cg03419058 and cg13944175 sites) marker set; r = 0.55, p < 0.0001. Validation of the four most discriminating genes (CA10, DPP10, FMN2 and HAS1) showed a significant correlation between methylation levels and disease progression (p‐value < 2.2 × 10−16, adjusted R2 = 0.952). Translational research of the identified genes to future clinical applications is warranted. What's new? While infection with high‐risk human papillomavirus (HPV) is a major cause of cervical intraepithelial neoplasia (CIN), not all CIN precursor lesions progress to cervical cancer. Here, using genome‐wide DNA methylation profiling and HPV genotyping of cervical samples from women with different CIN grades, the authors describe novel methylation markers of epigenetic changes that discriminate accurately between clinically significant and transient cervical disease. In particular, a DNA methylation classifier using two genes, ATP10A and HAS1, showed remarkable ability to discriminate among preinvasive cervical lesion grades. The identified markers are excellent candidates for future diagnostic or prognostic assays in cervical cancer screening. [ABSTRACT FROM AUTHOR]

On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310‐301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin‐cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60–75 years with untreated high‐risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin‐cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52–0.90; one‐sided p =.003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. Implications for Practice: Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia‐related changes and therapy‐related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML. This article addresses development and authorization of Vyxeos for the treatment of acute myeloid leukemia, summarizing the scientific review of the application leading to regulatory approval in the European Union. [ABSTRACT FROM AUTHOR]

Master protocols have received a growing interest during the last years. By assigning patients to specific substudies, they aim at targeting and accelerating clinical development. Given their complexity, basket, umbrella, and platform designs have raised challenging regulatory and statistical questions, especially the control of multiplicity in confirmatory trials. In basket trials, regulatory assessment of the benefit/risk in pooled populations and choice of the treatment indication is challenging. We provide here our perspectives on these topics. In master protocols, as long as the statistical hypotheses tested between the different substudies are independent, no supplementary adjustment for multiplicity over the different substudies should be required. Moreover, sharing a control arm within an umbrella or a platform trial investigating different drugs would not require a correction for the type I error rate, whereas the chance of multiple false positive regulatory decisions should be recognized. In basket trials, pooling across substudies requires a rationale supporting the intended indication and should be preplanned. Assessment of the benefit/risk in pooled target populations can be complicated by differences in design or in efficacy/safety signals between the substudies. While trials governed by a master protocol can offer logistic and financial advantages, more experience is needed to gain a deeper insight into this novel framework. [ABSTRACT FROM AUTHOR]

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers. [ABSTRACT FROM AUTHOR]

The European Union (EU) Paediatric Regulation requires that all new medicinal products applying for a marketing authorisation (MA) in the EU provide a paediatric investigation plan (PIP) covering a clinical and non-clinical trial programme relating to the use in the paediatric population, unless a waiver applies. Conducting trials in children is challenging on many levels, including ethical and practical issues, which may affect the availability of the clinical evidence. In scientifically justified cases, extrapolation of data from other populations can be an option to gather evidence supporting the benefit-risk assessment of the medicinal product for paediatric use. The European Medicines Agency (EMA) is working on providing a framework for extrapolation that is scientifically valid, reliable and adequate to support MA of medicines for children. It is expected that the extrapolation framework together with therapeutic area guidelines and individual case studies will support future PIPs. Extrapolation has already been employed in several paediatric development programmes including biological treatment for immune-mediated diseases. This article reviews extrapolation strategies from MA applications for products for the treatment of juvenile idiopathic arthritis, paediatric psoriasis and paediatric inflammatory bowel disease. It also provides a summary of extrapolation advice expressed in relevant EMA guidelines and initiatives supporting the use of alternative approaches in paediatric medicine development. [ABSTRACT FROM AUTHOR]

This article takes as its starting point the tension between objects and things in the early Second World War writing and painting of Paul Nash. By exploring a broad range of cultural artifacts—including film, fashion magazines, photographs, paintings—it demonstrates how Nash’s concerns with the materiality of airplanes, his favored mechanical object, reflect a broader wartime immersion in the imperatives of material culture. Nash transforms airplanes in two opposing ways: glorified objects become national subjects, patriotic agents; and desecrated objects are reduced to things. Moreover, it is argued that by attending to the reduction of airplanes to mechanical ruins—the transformation of military objects into things of waste—Nash, Cecil Beaton, and other image-makers ironically invoked John Bunyan’s muck-raker. While Bunyan derided the muck-raker for his obsession with material, not spiritual, things, in wartime the muck-raker’s materialist salvaging practices were embraced and encouraged, and, along with the celebration of Bunyan’s moral rectitude, both were recruited to the British war effort. [ABSTRACT FROM PUBLISHER]

The rise over recent years in the use of network meta-analyses (NMAs) in clinical research and health economic analysis is little short of meteoric driven, in part, by a desire from decision makers to extend inferences beyond direct comparisons in controlled clinical trials. But is the increased use and reliance of NMAs justified? Do such analyses provide a reliable basis for the relative effectiveness assessment of medicines and, in turn, for critical decisions relating to healthcare access and provisioning? And can such analyses also be used earlier, as part of the evidence base for licensure? Despite several important publications highlighting inherently unverifiable assumptions underpinning NMAs, these assumptions and associated potential for serious bias are often overlooked in the reporting and interpretation of NMAs. A more cautious, and better informed, approach to the use and interpretation of NMAs in clinical research is warranted given the assumptions that sit behind such analyses. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

On August 5, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pomalidomide in combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Pomalidomide is an immunomodulating agent. The recommended starting dose of pomalidomide is 4 mg once daily taken on days 1-21 of repeated 28-day cycles. The main evidence of efficacy for pomalidomide in MM was based on a phase III multicenter, randomized, open-label study (CC-4047-MM-003) in which pomalidomide plus low-dose dexamethasone therapy (POM1LoDEX) was compared with high-dose dexamethasone alone (HiDEX) in previously treated adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including both lenalidomide and bortezomib, and had demonstrated disease progression on the last therapy. For the intent-to-treat population, median progression-free survival based on International Myeloma Working Group criteria was 15.7 weeks (95% confidence interval [CI]: 13.0-20.1) in the POM1LoDEX group versus 8.0 weeks (95% CI: 7.0-9.0) in theHiDEX group (log-rank p value,.001). Overall survival (secondary endpoint) was also different in the two treatment groups (hazard ratio 0.53 [95% CI: 0.37-0.74]).Themost commonly reported adverse reactions to pomalidomide in clinical studies were anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%), fatigue (28.3%), pyrexia (21%), peripheral edema (13%), and infections including pneumonia (10.7%). Peripheral neuropathy adverse reactionswere reported in 12.3% of patients, and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3%of patients. Pomalidomide is expected to be teratogenic. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu). [ABSTRACT FROM AUTHOR]

Whether confirmatory or exploratory in nature, the investigation of subgroups poses statistical and interpretational challenges, yet these investigations can have important consequences for product licensing, labeling, reimbursement, and prescribing decisions. This article provides a high-level, nontechnical summary of key statistical issues in the analysis of subgroups, with a focus on the regulatory context in which drug development and licensing decisions are made. References to specific aspects of regulatory processes are based on the system in Europe, though it is hoped that the principles outlined can be generally applied to other regulatory regions. This article challenges the common assumption that a clinical trial population should be assumed to be homogeneous, with homogeneous response to treatment, and asks whether commonly employed strategies for handling and identifying potential heterogeneity are sufficient. Investigations into subgroups are unavoidable, yet subgroup analyses suffer from fundamental complications and limitations of which those planning and interpreting clinical trials must be aware. Some areas for further methodological work and an improved methodological framework for the conduct of exploratory subgroup analyses are discussed. Above all, the need for an integrated scientific approach is highlighted. [ABSTRACT FROM AUTHOR]

On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54-0.77; p.< 0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45- 0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To improve awareness of the natural age-related decline in female and male fertility with respect to natural fertility and assisted reproductive technologies (ART) and provide recommendations for their management, and to review investigations in the assessment of ovarian aging. Options: This guideline reviews options for the assessment of ovarian reserve and fertility treatments using ART with women of advanced reproductive age presenting with infertility. Outcomes: The outcomes measured are the predictive value of ovarian reserve testing and pregnancy rates with natural and assisted fertility. Evidence: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in June 2010, using appropriate key words (ovarian aging, ovarian reserve, advanced maternal age, advanced paternal age, ART). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated into the guideline to December 2010. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table). Benefits, harms, and costs: Primary and specialist health care providers and women will be better informed about ovarian aging and the age-related decline in natural fertility and about options for assisted reproductive technology. [Copyright &y& Elsevier]

Objective: To review the clinical aspects of ovarian hyperstimulation syndrome and provide recommendations on its diagnosis and clinical management.Outcomes: These guidelines will assist in the early recognition and management of ovarian hyperstimulation. Early recognition and prompt systematic supportive care will help avert poor outcomes.Evidence: Medline, Embase, and the Cochrane database were searched for relevant articles, using the key words "ovarian hyperstimulation syndrome" and "gonadotropins," and guidelines created by other professional societies were reviewed.Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table 1). [ABSTRACT FROM AUTHOR]

Abstract: Objective: To review the clinical aspects of ovarian hyperstimulation syndrome and provide recommendations on its diagnosis and clinical management. Outcomes: These guidelines will assist in the early recognition and management of ovarian hyperstimulation. Early recognition and prompt systematic supportive care will help avert poor outcomes. Evidence: Medline, Embase, and the Cochrane database were searched for relevant articles, using the key words “ovarian hyperstimulation syndrome” and “gonadotropins,” and guidelines created by other professional societies were reviewed. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table 1). [Copyright &y& Elsevier]

In October 2014, the Steering Committee of the International Conference on Harmonization endorsed the formation of an expert working group to develop an addendum to the International Conference on Harmonization E9 guideline (“Statistical Principles for Clinical Trials”). The addendum will focus on two topics involving randomized confirmatory clinical trials: estimands and sensitivity analyses. Both topics are motivated, in part, by the need to improve the precision with which scientific questions of interest are formulated and addressed by clinical trialists and regulators, specifically in the context of post-randomization events such as use of rescue medication or missing data resulting from dropouts. Given the importance of these topics for the statistical and medical community, we articulate the reasons for the planned addendum. The resulting “ICH E9/R1” guideline will include a framework for improved trial planning, conduct, analysis, and interpretation; a draft is expected to be ready for public comment in the second half of 2016. [ABSTRACT FROM AUTHOR]

This article examines the use of flowers as imagery in four war poems. The poems are by John McRae, Ivor Gurney, Keith Douglas and John Jarmain. The flower imagery has often been construed as emblematic of national commemoration. However, the author contends that they can be interpreted much more ambiguously to include the trauma that commemoration often obscures.

The author reports on the discussion of the white paper on adaptive dose-ranging designs by the Phrma working Group in Great Britain. He states that the discussion is focusing on methodological issues and drug development. He stresses out that the white paper conducts simulations to compare a traditional approach with alternative design-focused and analysis-focused approaches. He also discusses the different level of phases on the pre-clinical trials.

The article aims to draw three key books from the golden age literature, namely, "Alice's Adventures in Wonderland," by Lewis Caroll, "The Wind in the Willows," by Kenneth Grahame and "Winnie-the-Pooh," by A. A. Milne and demonstrates how nostalgia works to cover over aspects of childhood insipid to adult sensibilities. According to the author, nostalgia is defined as a function of the imagination, infused in spatial longing and the illusive object of that longing is childhood.

Discusses the correlation between narrative and pain based on the writings of William Halse Rivers and Siegfried Sassoon. Narratives exchanged between patient and physician during the 18th century; Views of psychoanalyst Sigmund Freud on the narratives of the patient; Analysis of the cultural tensions created and sought by Rivers and Sassoon.

The use of interim analyses and data safety monitoring boards (DSMBs) can assist greatly in the timely determination of whether or not a medicine has an acceptable benefit-risk profile. Regulatory authorities regard the appropriate use of interim analyses favourably, but will consider the extent to which the conduct of interim analyses and the involvement of DSMBs may have compromised the evidence of efficacy and safety from a clinical trial. Issues of particular concern, which may potentially introduce bias, include the dissemination of interim data and the rules by which a trial might be terminated early. If data from trials which employ a DSMB are to be considered reliable and scientifically valid, it is the responsibility of the trial sponsor to demonstrate that the DSMB is set up and run appropriately and to verify that any bias introduced has had no important effect on the conclusions. [ABSTRACT FROM AUTHOR]

To evaluate the effects of synthetic growth hormone-releasing factor (GRF) in women with idiopathic infertility who were treated with human menopausal gonadotrophin (HMG), 13 women with this condition were randomly assigned to undergo treatment with HMG—GRF (500 μg twice daily) or HMG—placebo. Conception occurred in four of six women (14 cycles) who received HMG—GRF and in one of seven women (22 cycles) who received HMG—placebo. No difference was found in the amount of HMG and the duration of HMG required to induce ovulation between the two groups of patients. The overall serum growth hormone and insulin-like growth factor I concentrations were higher in the GRF than in the placebo group. No difference was found in serum oestradiol or inhibin concentrations between the two groups. Our results suggest that in women with idiopathic infertility, administration of GRF does not decrease the duration or the amount of HMG required to induce ovulation. However, it appears that in this small group concomitant treatment with GRF increases the pregnancy rates in women who are treated with HMG (4/14 cycles compared with 1/22 cycles). [ABSTRACT FROM PUBLISHER]

Presents information from a study on the ectopic pregnancy masked by follicular initiation of gonadotropin-releasing hormone (GnRH) agonist for pituitary desensitization in relation the the in vitro fertilization (IVF). Information on the transvaginal ultrasound performed in the study; Disadvantages of commencing the administration of GnRH agonists; Discussion on the study.

Background: In recent years, experience on the application of adaptive designs in confirmatory clinical trials has accumulated. Although planning such trials comes at the cost of additional operational complexity, adaptive designs offer the benefit of flexibility to update trial design and objectives as data accrue. In 2007, the European Medicines Agency (EMA) provided guidance on confirmatory clinical trials with adaptive (or flexible) designs. In order to better understand how adaptive trials are implemented in practice and how they may impact medicine approval within the EMA centralised procedure, we followed on 59 medicines for which an adaptive clinical trial had been submitted to the EMA Scientific Advice (SA) and analysed previously in a dedicated EMA survey of scientific advice letters. We scrutinized in particular the submission of the corresponding medicines for a marketing authorisation application (MAA). We also discuss the current regulatory perspective as regards the implementation of adaptive designs in confirmatory clinical trials.Methods: Using the internal EMA MAA database, the AdisInsight database and related trial registries, we analysed how many of these 59 trials actually started, the completion status, results, the time to trial start, the adaptive elements finally implemented after SA, their possible influence on the success of the trial and corresponding product approval.Results: Overall 31 trials out of 59 (53%) were retrieved. Thirty of them (97%) have been started and 23 (74%) concluded. Nine of these trials (39% out of 23) demonstrated a significant treatment effect on their primary endpoint and 4 (17% out of 23) supported a marketing authorisation (MA). An additional two trials were stopped using pre-defined criteria for futility, efficiently identifying trials on which further resources should not be spent. Median time to trial start after SA letter was given by EMA was 5 months. In the investigated trial registries, at least 18 trial (58% of 31 retrieved trials) designs were implemented with adaptive elements, which were predominantly dose selection, sample size reassessment (SSR) and stopping for futility (SFF). Among the 11 completed trials including adaptive elements, 6 demonstrated a significant treatment effect on their primary endpoint (55%).Conclusions: Adaptive designs are now well established in the drug development landscape. If properly pre-planned, adaptations can play a key role in the success of some of these trials, for example to help successfully select the most promising dose regimens for phase II/III trials. Interim analyses can also enable stopping of trials for futility when they do not hold their promises. Type I error rate control, trial integrity and results consistency between the different stages of the analyses are fundamental aspects to be discussed thoroughly. Engaging early dialogue with regulators and implementing the scientific advice received is strongly recommended, since much experience in discussing adaptive designs and assessing their results has been accumulated. [ABSTRACT FROM AUTHOR]

The article offers the author's insights on the effect of the European Medicines Agency's (EMA) scientific advice (SA) on the compliance and changes in the clinical trials design and the success of marketing authorization application (MAA). Information regarding the approval of new drug from the basis of the benefit-risk assessment of the Medicinal Products for Human Use (CHMP), and the rate of compliance with SA.

Background: Since the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures.Methods: We performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the proposed design and its context in the drug development program, as well as the responses of the Committee for Human Medicinal Products (CHMP)/Scientific Advice Working Party (SAWP), were extracted and categorized. For 41 more recent procedures (1 January 2009 to 8 May 2012), additional details of the trial design and the CHMP/SAWP responses were assessed. In addition, case studies are presented as examples.Results: Over a range of 5½ years, 59 scientific advices were identified that address adaptive study designs in phase II and phase III clinical trials. Almost all were proposed as confirmatory phase III or phase II/III studies. The most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment. While 12 (20%) of the 59 proposals for an adaptive clinical trial were not accepted, the great majority of proposals were accepted (15, 25%) or conditionally accepted (32, 54%). In the more recent 41 procedures, the most frequent concerns raised by CHMP/SAWP were insufficient justifications of the adaptation strategy, type I error rate control and bias.Conclusions: For the majority of proposed adaptive clinical trials, an overall positive opinion was given albeit with critical comments. Type I error rate control, bias and the justification of the design are common issues raised by the CHMP/SAWP. [ABSTRACT FROM AUTHOR]