A prospective proof-of-concept trial on the effect of personalized dosages of follitropin delta in intrauterine insemination.

RESEARCH QUESTION: What is the efficacy and safety of individualized follitropin delta dosing for ovarian stimulation in intrauterine insemination (IUI)? DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

End points in clinical trials in diffuse large B-cell lymphoma: time for more dialogue?

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.

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.

Dual staining for p16/Ki-67 to detect high-grade cervical lesions: Results from the Screening Triage Ascertaining Intraepithelial Neoplasia by Immunostain Testing study.

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.

Genome-wide DNA methylation profiling identifies two novel genes in cervical neoplasia.

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.

EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes.

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.

Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics.

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.

Validation of a new HPV self-sampling device for cervical cancer screening: The Cervical and Self-Sample In Screening (CASSIS) study.

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.

Seeking harmony: estimands and sensitivity analyses for confirmatory clinical trials.

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.

Prise en charge des fibromes utérins en présence d'une infertilité autrement inexpliquée.

OBJECTIF: Formuler des recommandations quant à la façon optimale d'assurer la prise en charge des fibromes dans le contexte de l'infertilité. Les options habituelles et novatrices de prise en charge des fibromes seront analysées en mettant l'accent sur leur applicabilité chez les femmes qui souhaitent obtenir une grossesse. OPTIONS: La prise en charge des fibromes chez les femmes qui souhaitent obtenir une grossesse met d'abord en jeu la documentation de la présence des fibromes en question et la détermination de la probabilité que ces derniers affectent le potentiel génésique. Dans un tel contexte, la prise en charge des fibromes s'effectue principalement de façon chirurgicale; toutefois, il faut s'assurer au préalable de mettre en balance les avantages factuels de l'approche chirurgicale en matière d'amélioration des issues cliniques et les risques propres à une telle approche. ISSUES: L'amélioration des taux et des issues de grossesse que permet la prise en charge des fibromes chez les femmes aux prises avec l'infertilité constitue l'issue principale sur laquelle nous nous sommes attardés. RéSULTATS: La littérature publiée a été récupérée par l'intermédiaire de recherches menées dans PubMed, CINAHL et Cochrane Systematic Reviews en novembre 2013 au moyen d'un vocabulaire contrôlé (p. ex. « leiomyoma ¼, « infertility ¼, « uterine artery embolization ¼, « fertilization in vitro ¼) et de mots clés (p. ex. « fibroid ¼, « myomectomy ¼) appropriés. Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais et français. Aucune restriction n'a été appliquée en matière de date. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu'en novembre 2013. La littérature grise (non publiée) a été identifiée par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques, et auprès de sociétés de spécialité médicale nationales et internationales. VALEURS: La qualité des résultats est évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs (Tableau). AVANTAGES, DéSAVANTAGES ET COûTS: Les présentes recommandations devraient permettre la prise en charge adéquate des femmes qui présentent des fibromes et qui sont aux prises avec l'infertilité, et ce, par la maximisation de leurs chances de grossesse grâce à la minimisation des risques mis en cause par la tenue de myomectomies inutiles. L'atténuation des complications et l'élimination des interventions inutiles devraient également mener à une baisse des coûts pour le système de santé. DéCLARATIONS SOMMAIRES: RECOMMANDATIONS.

On the need for increased rigour and care in the conduct and interpretation of network meta-analyses in drug development.

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.

The European medicines agency review of pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use.

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 (POM+LoDEX) 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 POM+LoDEX group versus 8.0 weeks (95% CI: 7.0-9.0) in the HiDEX 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]). The most 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 reactions were 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).

The management of uterine fibroids in women with otherwise unexplained infertility.

OBJECTIVE: To provide recommendations regarding the best management of fibroids in couples who present with infertility. Usual and novel treatment options for fibroids will be reviewed with emphasis on their applicability in women who wish to conceive. OPTIONS: Management of fibroids in women wishing to conceive first involves documentation of the presence of the fibroid and determination of likelihood of the fibroid impacting on the ability to conceive. Treatment of fibroids in this instance is primarily surgical, but must be weighed against the evidence of surgical management improving clinical outcomes, and risks specific to surgical management and approach. OUTCOMES: The outcomes of primary concern are the improvement in pregnancy rates and outcomes with management of fibroids in women with infertility. EVIDENCE: Published literature was retrieved through searches of PubMed, MEDLINE, the Cochrane Library in November 2013 using appropriate controlled vocabulary (e.g., leiomyoma, infertility, uterine artery embolization, fertilization in vitro) and key words (e.g., fibroid, myomectomy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English and French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2013. Grey (unpublished literature) was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: These recommendations are expected to allow adequate management of women with fibroids and infertility, maximizing their chances of pregnancy by minimizing risks introduced by unnecessary myomectomies. Reducing complications and eliminating unnecessary interventions are also expected to decrease costs to the health care system. Summary Statements 1. Subserosal fibroids do not appear to have an impact on fertility; the effect of intramural fibroids remains unclear. If intramural fibroids do have an impact on fertility, it appears to be small and to be even less significant when the endometrium is not involved. (II-3) 2. Because current medical therapy for fibroids is associated with suppression of ovulation, reduction of estrogen production, or disruption of the target action of estrogen or progesterone at the receptor level, and it has the potential to interfere in endometrial development and implantation, there is no role for medical therapy as a stand-alone treatment for fibroids in the infertile population. (III) 3. Preoperative assessment of submucosal fibroids is essential to the decision on the best approach for treatment. (III) 4. There is little evidence on the use of Foley catheters, estrogen, or intrauterine devices for the prevention of intrauterine adhesions following hysteroscopic myomectomy. (II-3) 5. In the infertile population, cumulative pregnancy rates by the laparoscopic and the minilaparotomy approaches are similar, but the laparoscopic approach is associated with a quicker recovery, less postoperative pain, and less febrile morbidity. (II-2) 6. There are lower pregnancy rates, higher miscarriage rates, and more adverse pregnancy outcomes following uterine artery embolization than after myomectomy. (II-3) Studies also suggest that uterine artery embolization is associated with loss of ovarian reserve, especially in older patients. (III) Recommendations 1. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (III-A) 2. Preoperative assessment of submucosal fibroids should include, in addition to an assessment of fibroid size and location within the uterine cavity, evaluation of the degree of invasion of the cavity and thickness of residual myometrium to the serosa. A combination of hysteroscopy and transvaginal ultrasound or hysterosonography are the modalities of choice. (III-B) 3. Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. (III-B) 4. A hysterosalpingogram is not an appropriate exam to evaluate and classify fibroids. (III-D) 5. In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. (II-2A) 6. Removal of subserosal fibroids is not recommended. (III-D) 7. There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualized. (III-C) 8. If fibroids are removed abdominally, efforts should be made to use an anterior uterine incision to minimize the formation of postoperative adhesions. (II-2A) 9. Widespread use of the laparoscopic approach to myomectomy may be limited by the technical difficulty of this procedure. Patient selection should be individualized based on the number, size, and location of uterine fibroids and the skill of the surgeon. (III-A) 10. Women, fertile or infertile, seeking future pregnancy should not generally be offered uterine artery embolization as a treatment option for uterine fibroids. (II-3E).

Objectif : Formuler des recommandations quant à la façon optimale d'assurer la prise en charge des fibromes dans le contexte de l'infertilité. Les options habituelles et novatrices de prise en charge des fibromes seront analysées en mettant l'accent sur leur applicabilité chez les femmes qui souhaitent obtenir une grossesse. Options : La prise en charge des fibromes chez les femmes qui souhaitent obtenir une grossesse met d'abord en jeu la documentation de la présence des fibromes en question et la détermination de la probabilité que ces derniers affectent le potentiel génésique. Dans un tel contexte, la prise en charge des fibromes s'effectue principalement de façon chirurgicale; toutefois, il faut s'assurer au préalable de mettre en balance les avantages factuels de l'approche chirurgicale en matière d'amélioration des issues cliniques et les risques propres à une telle approche. Issues : L'amélioration des taux et des issues de grossesse que permet la prise en charge des fibromes chez les femmes aux prises avec l'infertilité constitue l'issue principale sur laquelle nous nous sommes attardés. Résultats : La littérature publiée a été récupérée par l'intermédiaire de recherches menées dans PubMed, CINAHL et Cochrane Systematic Reviews en novembre 2013 au moyen d'un vocabulaire contrôlé (p. ex. « leiomyoma ¼, « infertility ¼, « uterine artery embolization ¼, « fertilization in vitro ¼) et de mots clés (p. ex. « fibroid ¼, « myomectomy ¼) appropriés. Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais et français. Aucune restriction n'a été appliquée en matière de date. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu'en novembre 2013. La littérature grise (non publiée) a été identifiée par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques, et auprès de sociétés de spécialité médicale nationales et internationales. Valeurs : La qualité des résultats est évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs (Tableau). Avantages, désavantages et coûts : Les présentes recommandations devraient permettre la prise en charge adéquate des femmes qui présentent des fibromes et qui sont aux prises avec l'infertilité, et ce, par la maximisation de leurs chances de grossesse grâce à la minimisation des risques mis en cause par la tenue de myomectomies inutiles. L'atténuation des complications et l'élimination des interventions inutiles devraient également mener à une baisse des coûts pour le système de santé. Déclarations sommaires 1. Les fibromes sous-séreux ne semblent pas exercer un effet sur la fertilité; la question de savoir si les fibromes intramuraux exercent un effet quelconque à cet égard demeure sans réponse définitive. Quoi qu'il en soit, si les fibromes intramuraux exercent bel et bien un effet sur la fertilité, ce dernier semble être faible et être encore moins significatif lorsque l'endomètre n'est pas mis en cause. (II-3) 2. Puisque la prise en charge médicale des fibromes est actuellement associée à la suppression de l'ovulation, à la diminution de la production d'œstrogènes ou à la perturbation de l'action ciblée des œstrogènes ou de la progestérone au niveau des récepteurs et qu'une telle prise en charge dispose du potentiel de nuire au développement endométrial et à l'implantation, elle ne peut être utilisée à titre traitement autonome pour contrer les fibromes au sein de la population infertile. (III) 3. La tenue d'une évaluation préopératoire des fibromes sous-muqueux constitue un facteur essentiel pour la prise d'une décision quant à la meilleure approche thérapeutique à adopter. (III) 4. Nous ne disposons que de peu de données probantes quant à l'utilisation de sondes de Foley, d'œstrogènes ou de dispositifs intra-utérins pour la prévention des adhérences intra-utérines à la suite d'une myomectomie hystéroscopique. (II-3) 5. Au sein de la population infertile, les approches laparoscopique et par minilaparotomie donnent lieu à des taux de grossesse cumulatifs semblables; toutefois, l'approche « laparoscopique ¼ est associée à une récupération plus rapide, à une atténuation de la douleur postopératoire et à moins de cas de morbidité fébrile. (II-2) 6. Par comparaison avec la myomectomie, l'embolisation de l'artère utérine donne lieu à des taux moindres de grossesse, à des taux accrus de fausse couche et à plus d'issues de grossesse indésirables. (II-3) Des études laissent également entendre que l'embolisation de l'artère utérine est associée à une atténuation de la réserve ovarienne, particulièrement chez les patientes plus âgées. (III) Recommandations 1. Chez les femmes qui sont aux prises avec l'infertilité, des efforts devraient être déployés pour que l'évaluation et la classification des fibromes (plus particulièrement en ce qui concerne ceux qui exercent des effets sur la cavité endométriale) soient adéquatement menées au moyen de l'échographie transvaginale, de l'hystéroscopie, de l'hystéroéchographie ou de l'imagerie par résonance magnétique. (III-A). 2. L'évaluation préopératoire des fibromes sous-muqueux devrait non seulement comprendre la détermination de la taille des fibromes et de leur emplacement dans la cavité utérine, mais également la détermination de l'épaisseur du myomètre résiduel se situant entre ces fibromes et la séreuse et celle du degré d'envahissement de la cavité. À cette fin, les modalités à privilégier sont les suivantes : l'utilisation combinée de l'hystéroscopie et de l'échographie transvaginale ou l'hystéroéchographie. (III-B) 3. La prise en charge des fibromes sous-muqueux s'effectue par hystéroscopie. La taille des fibromes devrait être inférieure à 5 cm, et ce, bien que des fibromes de plus grandes dimensions aient déjà été pris en charge par hystéroscopie; toutefois, la tenue d'une deuxième intervention est souvent nécessaire. (III-B) 4. L'hystérosalpingogramme ne constitue pas une modalité adéquate pour l'évaluation et la classification des fibromes. (III-D) 5. Chez les femmes qui présentent une infertilité autrement inexpliquée, les fibromes sous-muqueux devraient être retirés de façon à permettre une amélioration des taux de conception et de grossesse. (II-2) 6. Le retrait des fibromes sous-séreux n'est pas recommandé. (III-D) 7. Nous disposons de données probantes assez bonnes pour nous prononcer contre le recours à la myomectomie chez les femmes qui présentent des fibromes intramuraux (l'intégrité de l'endomètre ayant été confirmée par hystéroscopie) et une infertilité autrement inexpliquée, peu importe la taille des fibromes en question. (II-2D) Lorsque la patiente ne dispose d'aucune autre option, les avantages de la myomectomie devraient être mis en balance avec les risques mis en cause; de plus, la prise en charge des fibromes intramuraux devrait alors être personnalisée. (III-C) 8. Lorsque les fibromes sont retirés par voie abdominale, l'utilisation d'une incision utérine antérieure devrait être favorisée pour minimiser la formation postopératoire d'adhérences. (II-2A) 9. L'élargissement du recours à l'approche laparoscopique en matière de myomectomie pourrait être limité par le degré de difficulté technique qui est associé à cette intervention. La sélection des patientes devrait être personnalisée en fonction du nombre, de la taille et de l'emplacement des fibromes utérins, ainsi qu'en fonction des habiletés du chirurgien. (III-A) 10. D'ordre général, les femmes (fertiles ou infertiles) qui cherchent à obtenir une grossesse ne devraient pas se voir offrir une embolisation de l'artère utérine à titre d'option pour la prise en charge de leurs fibromes utérins. (II-3E).

An overview of statistical and regulatory issues in the planning, analysis, and interpretation of subgroup analyses in confirmatory clinical trials.

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.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease.

BACKGROUND: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. METHODS: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. RESULTS: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. CONCLUSIONS: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Decentralized Clinical Trials: Scientific Considerations Through the Lens of the Estimand Framework.

While industry and regulators' interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient's experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions, and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands.

The European medicines agency review of abiraterone for the treatment of metastatic castration-resistant prostate cancer in adult men after docetaxel chemotherapy and in chemotherapy-naive disease: summary of the scientific assessment of the committee for medicinal products for human use.

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.

The European Medicines Agency review of cabazitaxel (Jevtana®) for the treatment of hormone-refractory metastatic prostate cancer: summary of the scientific assessment of the committee for medicinal products for human use.

On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana® (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The active substance of Jevtana® is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment. In the main study submitted for this application, a 2.4-month longer median overall survival time and a 30% lower risk for death were observed for cabazitaxel, compared with mitoxantrone. The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea. This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).

Surgically retrieved spermatozoa versus ejaculated spermatozoa in modified natural IVF-ICSI cycles.

A retrospective cohort study was performed to evaluate the outcome of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) cycles to compare 81 mnIVF-ICSI first cycles using ejaculated spermatozoa with 44 mnIVF-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 mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required. The aim of the present study was to evaluate and compare the outcomes of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) with surgically retrieved spermatozoa (in male partners with obstructive azoospermia) and ejaculated spermatozoa (in couples with mild-to-moderate male factor). Eighty-one mnIVF-ICSI first cycles using ejaculated spermatozoa were compared with forty-four mnIVF-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. There were no significant differences in fertilization rate, or cleavage rate between the two groups; however, there were more patients having embryo transfers in the surgically retrieved group. Only single-embryo transfer was performed. Biochemical and clinical pregnancy rates per embryo transfer were similar between both groups. The data suggest that mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required.

Perspectives on Virtual (Remote) Clinical Trials as the "New Normal" to Accelerate Drug Development.

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.