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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]

The author comments on the study "Statistical Considerations on Subgroup Analysis in Clinical Trials" by M. Alosh and colleagues published in the current issue of the journal.

An essay is presented on the invention of airplanes. It discusses the effect of the first invented airplanes in Paris, France in 1909, the role of airplanes as exemplary object of modernity and the function of airplanes in several literary works which includes "The War in the Air" by H.G. Wells, "Mrs. Dalloway" by Virginia Woolf and Paul Nash's selection of oil and watercolor paintings.

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]

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.

This essay focuses on topography and the influence of poet William Wordsworth in the poetry of Edmund Blunden and Siegfried Sassoon. The author claims that both Blunden's and Sassoon's wartime poetry deals with the theme of the poet's relationship to nature, highlighting the conflict between the poet and the external world. The author discusses themes in Wordsworth's poetry, Blunden's book "Undertones of War," and Sassoon's "The Complete Memoirs of George Sherston."

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.

Objective: To investigate the association between several factors such as demographics, personal habits, reproductive factors, menstrual characteristics, contraception, and clinical profile and the probability of having endometriosis.Setting: Ten clinical institutions in the Montreal area.Patient(s): A total of 2,777 subjects who underwent surgery for diagnostic laparoscopy, tubal ligation, or hysterectomy between January 1998 and July 2002. Eight hundred ninety subjects were classified as cases on the basis of the presence of endometriotic lesions found at the time of surgery, whereas 1,881 controls had no surgical evidence of endometriosis.Main outcome measure(s): The association between potential risk factors and endometriosis was estimated by Pearson χ2 and by crude and adjusted odds ratios.Result(s): Results indicated a positive association between endometriosis and education level for subjects who underwent hysterectomy. An inverse relation between gravidity and endometriosis was also found within a subgroup of subjects who had diagnostic laparoscopy. Furthermore, the proportion of uterine leiomyoma was significantly higher in cases compared with in controls, among subjects who underwent surgery for diagnostic laparoscopy or hysterectomy but not for tubal ligation.Conclusion(s): These observations underline the importance of taking into account the clinical profile of subjects when investigating risk factors for endometriosis. [Copyright &y& Elsevier]

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]

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.

• This study is the first to use follitropin delta as a stimulatory medication in intrauterine insemination. • It provides validation of an original personalized intrauterine insemination dosing regimen based on anti-Müllerian hormone values and weight. • A total of 258 cycles led to 43 clinical pregnancies (16.7%), with six multiple pregnancies. • Only four live twin births were observed, representing 1.6% of the total cycles. What is the efficacy and safety of individualized follitropin delta dosing for ovarian stimulation in intrauterine insemination (IUI)? This single-centre, prospective, open-label, single-cohort study involving 106 patients established an original dosing regimen based on body weight and anti-Müllerian hormone (AMH) concentrations, with adjustments based on the ovarian response from the previous IUI cycle. Each participant was enrolled in a maximum of three IUI cycles. Mean age was 34.5 ± 4.5 years, mean weight 69.2 ± 11.2 kg, mean AMH 15.7 ± 8.6 pmol/l, mean FSH 6.3 ± 2.6 IU/l and mean antral follicle count 16.4 ± 8.2. The percentage of patients who produced more than three mature follicles was 1.9%, 0% and 1.5%, respectively, for the three IUI cycles. The percentage of patients with two or three mature follicles was 34.0%, 36.9% and 47.1% for the three IUI cycles. The clinical pregnancy rate per IUI cycle was 17.9%, 14.3% and 17.6% for the three cycles, with a cumulative clinical pregnancy rate of 40.6%. Out of 258 cycles, 43 (16.7%) resulted in clinical pregnancy, with six of those resulting in multiple pregnancies (14.0%). Two resulted in spontaneous reduction within the first trimester and four resulted in live twin births, representing only 1.6% of the total cycles. This study is the first to utilize follitropin delta for stimulation in IUI. It demonstrates that individualized dosing is both effective and safe, resulting in satisfactory cumulative pregnancy rates and an acceptable multiple pregnancy rate, thus achieving the primary objectives of the research. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience. [ABSTRACT FROM AUTHOR]

This study aimed to review the evidence on the efficacy of herbal preparations containing black cohosh for the treatment of menopausal symptoms. A systematic search of three databases (PubMed, Embase, and Cochrane library) was conducted to identify relevant literature. Two reviewers independently abstracted the data from the eligible studies. Of the 288 English language citations screened, nine randomized placebo-controlled trials were included. Among these trials, six demonstrated a significant improvement in the black cohosh group compared with the placebo group. Using data from seven trials, we calculated a combined estimate for the change in menopausal vasomotor symptoms. Preparations containing black cohosh improved these symptoms overall by 26% (95% confidence interval 11%-40%); there was, however, significant heterogeneity between these trials. Given that black cohosh is one of the most frequently used herbal medications for menopausal vasomotor symptoms in North America, more data are warranted on its effectiveness and safety. [ABSTRACT FROM AUTHOR]

Radical vaginal trachelectomy in patients with early-stage cervical cancer is an oncologically safe procedure in well-selected patients. Successful pregnancy in a patient with radical vaginal trachelectomy is possible, with two-thirds of pregnancies resulting in live birth. However, it presents a great challenge for assisted reproductive techniques and reproductive medicine in cases with subsequent severe cervical stenosis. This is a report of a 38-year-old patient who underwent radical vaginal trachelectomy at the age of 33 years for early stage (IA2) adenocarcinoma and subsequently presented with infertility due to cervical factors. The patient underwent ovarian stimulation using a novel SMART (Stimulation with Minimal Adverse effects, Retrieval and Transfer)-IVF protocol. As it was impossible to perform transcervical embryo transfer with an almost absent severely stenotic cervical opening, a transmyometrial embryo transfer under ultrasound guidance was performed. This resulted in a successful singleton full-term pregnancy delivered by Caesarean section at gestational age 37 weeks. As far as is known, this is the first reported case of successful pregnancy conceived by IVF with transmyometrial embryo transfer for a patient who had previously undergone radical vaginal trachelectomy. [ABSTRACT FROM AUTHOR]

Background: Obstetrical outcomes in assisted reproduction techniques (ART) were compared with naturally conceived pregnancies and among each other in multiple reports. However, many important changes in the practice of in vitro fertilization (IVF) over the years, including single embryo transfers (sET) and the introduction of modified natural IVF (mnIVF), and the advances in the frozen embryo transfer (FET) might have impacted the outcomes. Our study is the first to our knowledge to assess four different groups, including spontaneous pregnancies, mnIVF, stimulated IVF (sIVF), and FET altogether in a head-to-head comparison. This is a retrospective study on perinatal outcomes of singleton babies conceived naturally or using three different ART protocols between 2011 and 2014. The primary objective was the comparison of gestational age and birth weight between spontaneously conceived pregnancies (NAT, n= 15,770), mnIVF (n=235), sIVF (n=389), and FET (n=222). Results: Our results show a significant difference in favor of naturally conceived pregnancies over ART in term of gestational age. In fact, the gestational age of babies in the NAT group was statistically higher compared to each one of the ART groups alone. Regarding the birth weight, the mean was significantly higher in the FET group compared to the other categories. Conclusion: Differences in perinatal outcomes are still found among babies born after different modes of conception. However, there is still need for well-designed high-quality trials assessing perinatal outcomes between naturally conceived pregnancies and different ART protocols based on different maternal and treatment characteristics. [ABSTRACT FROM AUTHOR]

The recovery of a mature oocyte from a natural cycle followed by IVF (nIVF) is an attractive alternative to conventional IVF, involving ovarian stimulation, in the treatment of female infertility. Similarly, surgical recovery of spermatozoa from the epididymis by percutaneous sperm aspiration (PESA) has simplified the treatment of men with obstructive azoospermia. A couple sought treatment for diminished ovarian reserve and male factor infertility using IVF, A mature oocyte was retrieved and was inseminated by intracytoplasmic sperm injection (ICSI). following recovery of spermatozoa by PESA. A good quality embryo was transferred. A viable pregnancy was confirmed by ultrasound scan. A healthy baby boy was delivered naturally at 37 weeks gestation. This study reports the first ongoing clinical pregnancy and subsequent birth resulting from ICSI of spermatozoa retrieved by PESA into an oocyte recovered during a natural cycle. The use of a combination of less invasive assisted reproductive techniques (PESA and nIVF) can overcome barriers to fertility. [ABSTRACT FROM AUTHOR]

Abstract–The COVID-19 pandemic has a global impact on the conduct of clinical trials of medical products. This article discusses implications of the COVID-19 pandemic on clinical research methodology aspects and provides points to consider to assess and mitigate the risk of seriously compromising the integrity and interpretability of clinical trials. The information in this article will support discussions that need to occur cross-functionally on an ongoing basis to "integrate all available knowledge from the ethical, the medical, and the methodological perspective into decision making." This article aims at facilitating: (i) risk assessments of the impact of the pandemic on trial integrity and interpretability; (ii) identification of the relevant data and information related to the impact of the pandemic on the trial that needs to be collected; (iii) short-term decision making impacting ongoing trial operations; (iv) ongoing monitoring of the trial conduct until completion, including the possible involvement of data monitoring committees, and adequately documenting all measures taken to secure trial integrity throughout and after the pandemic, and (v) proper analysis and interpretation of the eventual interim or final trial data. [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]

Objective We compared the self-sampling performance of the newly designed HerSwab™ device with a physician-collected cervical sample and another self-sample using the cobas® PCR Female swab for the detection of cervical intraepithelial neoplasia (CIN) and cancer. Methods Women referred for colposcopy at McGill University affiliated hospital clinics collected two consecutive self-samples, one with HerSwab™ and one with cobas® swab, after receiving instructions. The order of sampling was randomized. The colposcopist then collected a cervical sample and conducted a colposcopic examination. Samples were tested for human papillomavirus (HPV) DNA. Sensitivity and specificity to detect CIN2+ and respective 95% confidence intervals (CI) were calculated to compare sampling approaches. The HPV testing agreement between samples was measured using the Kappa statistic. Results Of 1217 women enrolled, 1076 had complete results for HPV and cytology; 148 (13.8%) had CIN1, 147 (13.7%) had CIN2/3, and 5 (0.5%) had cancer. There was very good agreement between methods for HPV detection (HerSwab™ versus physician: kappa = 0.84; cobas® swabs versus physician: kappa = 0.81; HerSwab™ versus cobas® swabs: kappa = 0.87). The sensitivity of HPV detection for CIN2+ was 87.6% (95%CI: 79.8–93.2) with self-sampling using HerSwab™, 88.6% (95%CI: 80.9–94.0) with self-sampling using the cobas® swab, and 92.4% (95%CI: 85.5–96.7) with physician sampling. Corresponding estimates of specificity were 58.1% (95%CI: 54.1–62.1), 55.0% (95%CI: 50.9–59.0) and 58.7% (95%CI: 54.6–62.6). Cytology (ASC-US or more severe) done on the physician-collected specimen was 80.2% (95%CI: 70.8–87.6) sensitive and 61.4% (95%CI: 57.2–65.5) specific for CIN2+. Conclusions The HerSwab™ had good agreement with physician sampling in detecting HPV, and adequate performance in detecting high-grade lesions among women referred to colposcopy for abnormal cytology. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy-including representatives from patients' groups, academia, industry, and regulatory agencies-is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general. [ABSTRACT FROM AUTHOR]

A retrospective cohort study was performed to evaluate the outcome of modified natural IVF-intracytoplasmic sperm injection {mnlVF-ICSI) cycles to compare 81 mnlVF- ICSI first cycles using ejaculated spermatozoa with 44 mnlVF-ICSI first cycles using surgically retrieved spermatozoa. There were no differences between the two groups in terms of number of oocytes retrieved, oocyte maturity or female age. However, male age was significantly higher in the surgically retrieved compared with the ejaculated group (41.5 versus 36.5 years, P= 0.001). There were no significant differences in fertilization rate or cleavage rate between the ejaculated and the surgically retrieved groups; however the prevalence of embryo transfer was higher in the surgically retrieved group (65.9% versus 45.7%, P = 0.03). Only single-embryo transfer was performed. Biochemical (34.5% versus 37.8%) and clinical (31.0% versus 35.1%) pregnancy rates per embryo transfer were similar between the ejaculated and the surgically retrieved groups. The data suggest that mnlVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required. [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]

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]

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]

The objective of this retrospective analysis was to evaluate the number of spontaneous ovulations occurring before oocyte retrieval in natural cycle IVF (nIVF) with and without the use of indomethacin. A total of 121 patients who underwent modified nIVF cycle between December 2003 and July 2006 were included in the study; 171 cycles without indomethacin and 84 cycles with indomethacin, started when the leading follicle reached 14 mm in size, were compared. The number of cycles with ovulation before oocyte retrieval and the number of cycles with no oocytes at retrieval were assessed with and without indomethacin. In addition, the pregnancy rates in the two groups of patients were analysed. There were 28 cycles (16%) in which ovulation occurred before oocyte retrieval in the group where no indomethacin was used and five cycles (6%) in which ovulation occurred before retrieval in the group where indomethacin was used. There was a statistically significant association between premature ovulation and indomethacin, with an odds ratio of 3,8 (95% confidence interval, 1.2-12.3). The oocyte retrieval per started cycle was 64% without indomethacin and 76% with indomethacin (P < 0.04). The clinical pregnancy rate per embryo transfer was 14% without indomethacin and 21% with indometbacin (not significant). [ABSTRACT FROM AUTHOR]

A total of 134 controlled natural IVF (nIVF) cycles were reviewed retrospectively and compared with 370 stimulated IVF (sIVF) cycles. The clinical pregnancy rate per embryo transfer following nIVF was 27% and 47% in sIVF cycles for patients aged less than 35. However, natural cycle patients could attempt consecutive cycles with much less impact on their lives, both medically and financially. In patients under 35 years of age, the choice of controlled nIVF reduces the cost and risk to the patient, permitting her to have multiple, consecutive attempts, and cumulatively offers a clinical pregnancy rate which approaches that of sIVF. The multiple pregnancy rate in nIVF is significantly reduced compared with sIVF treatment cycles. In patients over 35 years of age the benefits of nIVF were much less evident (clinical pregnancy rate: 8% per embryo transfer) and the opportunity to transfer multiple embryos in these patients seems to be advantageous. [ABSTRACT FROM AUTHOR]

The recovery of a mature oocyte from a modified natural cycle followed by in-vitro fertilization (nIVF) is an attractive alternative to conventional IVF, involving ovarian stimulation, in the treatment of female infertility. Ovarian agenesis is a rare disorder resulting in primary amenorrhoea and infertility in affected females. A couple sought help for infertility due to ovarian agenesis of the female partner and decided to pursue treatment utilizing oocyte donation. Modified natural-cycle egg retrieval was carried out on the donor; one mature oocyte was retrieved and underwent IVF using a sperm sample from the male partner. A good-quality embryo was transferred. A viable pregnancy was confirmed by ultrasound scan and resulted in the delivery of a healthy baby boy at 36 weeks' gestation. This is the second published report of an ongoing clinical pregnancy and subsequent birth resulting from oocyte donation recovered during a modified natural cycle. The use of less invasive assisted reproduction techniques such as nIVF can be used in oocyte donation cycles successfully. [ABSTRACT FROM AUTHOR]

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]