Medicines for an aging population: The EMA perspective and policies.

The European Medicines Agency adopted their Geriatric Medicines Strategy more than a decade ago. The strategy aims at elucidating the evidence basis for marketing authorization of new medicines which will be used in the older population, and at ensuring the appropriate communication of findings to the patient and healthcare provider. During the past decade new tools and data sources have emerged to support the strategy goals, and their use should be considered. Possible concrete actions are presented to improve the design of clinical trials, the data collection both pre- and post-approval, the assessment of the findings, and the communication to assist informed prescription and safe medicine taking. Implementation and prioritization of these actions should be done from the perspective of addressing the needs of patients while maximizing efficient use of resources, with the aim of integrating geriatric aspects into routine medicines development and assessment.

Assessing Medicines for Use in the Geriatric Population.

The aging processes alter the body's response to a medicine's pharmacokinetics, pharmacodynamics, and susceptibility to adverse effects. In addition, older adults, especially the oldest age category (85+ years) or those with multiple chronic health conditions, polypharmacy, or frailty, are under-represented in clinical trials of new medicines. Evidence-based prescribing guidelines based on these trials might result in inappropriate prescription, increasing the risk of drug interactions and adverse drug reactions. Regulators face a conundrum between acquiring sufficient data and putting susceptible patients at risk in the early stages of a development program, when little is known about a medicine's effects. Healthcare professionals and patients deserve to have access to clear information on the knowledge and evidence gaps leading to the approval of a new medicinal product. This should also include proper consideration of the population of older patients. In the present article, we outline the approach taken by the European Medicines Agency (EMA) regulators in the assessment of a new medicine's dossier.

Regulatory experience of handling Risk Management Plans (RMPs) for medicinal products in the EU.

Introduction: Risk Management Plans (RMPs) aim to optimize a medicinal product's benefit/risk balance for the individual patient and the target population. Despite differences in regulatory RMP requirements between jurisdictions worldwide, their ultimate aim is to protect public health.Areas covered: The review presents findings of different RMP requirements by different regulatory authorities and additional risk minimization measures (issued between January 2010 and December 2018) indicate how RMPs and additional risk minimization measures translate into actions to protect public health within the European Union (EU) member states and worldwide. Areas covered also include the different International Council for Harmonization (ICH) regional requirements of RMPs by the different regulatory authorities as well as data regarding the number of RMP assessments carried out by the EMA, FDA and Japan, and number of safety communications issued in Malta (taken as an example of a typical small EU member state) and in the United States of America (USA).Expert opinion: The EU legislation adopted in 2010 required RMPs to be included in all new applications for medicinal products in the EU, both for EU centrally authorized and nationally authorized medicinal products. Lessons learnt by EU regulators during this process are discussed in this review.

Medication use among older people in Europe: Implications for regulatory assessment and co-prescription of new medicines.

AIMS: The aim of this study was to elucidate drug prescription patterns in older European people with the objective to support regulatory contextualisation of (1) the suitability of enrolment criteria for new clinical trials; and (2) the understanding of the potential interactions/incompatibilities of newly authorised medicines with those most frequently used by older people. METHODS: Medicines agencies in Portugal, Poland, Slovakia and England were approached to provide a list of the 10 most frequent prescriptions in 2016 for systemically used medicines per active substances (i.e. ATC level 5), in older people. For each active substance and for the most common therapeutic subgroups (i.e. ATC level 2), the percentages of older patients receiving at least one prescription were calculated per older age categories (65-74; 75-84; 85+) and gender. RESULTS: There was considerable alignment in the most commonly prescribed active substances and therapeutic subgroups represented; these were gastroprotectants (A02), lipid-modifying agents (C10) and analgesics (N02). Some gender differences were observed (A02 and N02 were prescribed more frequently to women), but trends on age categories were consistent; A02 and N02 prescriptions continued to rise with age, while C10 slightly decreased in the 85+ age group in all countries. CONCLUSIONS: The findings of this study are consistent with the major chronic diseases reported in the older European population. Evidence on co-medication of newly applied medicines with the currently identified most commonly used medicines in older people should be generated during the (non)clinical development of new medicines to support regulatory assessment and adequate user information.

Efficacy and Safety of Pulsed Radiofrequency as a Method of Dorsal Root Ganglia Stimulation in Patients with Neuropathic Pain: A Systematic Review.

OBJECTIVE: Pulsed radiofrequency (PRF) is a nonablative pain treatment that uses radiofrequency current in short high-voltage bursts, resulting in interruption of nociceptive afferent pathways. We conducted a systematic review with the aim to create a synthesis of evidence about the efficacy and safety of PRF applied to the dorsal root ganglion (DRG) for the treatment of neuropathic pain. METHODS: We searched MEDLINE, CINAHL, Embase, and PsycINFO through January 8, 2019, as well as ClinicalTrials.gov and the clinical trial register of the World Health Organization. All study designs were eligible. We assessed risk of bias using the Cochrane tool for randomized controlled trials and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I). We assessed level of evidence using the Oxford tool and quality of evidence with GRADE. RESULTS: We included 28 studies with participants suffering from lumbosacral, cervical, or thoracic radicular pain, post-herpetic neuralgia, neuropathicbone pain in cancer patients, or carpal tunnel syndrome. Only five studies were randomized controlled trials (RCTs), while others were of nonrandomized designs, predominantly before and after comparisons. A total of 991 participants were included, with a median number (range) of 31 (1-101) participants. Only 204 participants were included in the RCTs, with a median number (range) of 38 (23-62) participants. The overall quality of evidence was low, as the majority of the included studies were rated as evidence level 4 or 5. The quality of evidence was very low. CONCLUSIONS: Evidence about the efficacy and safety of PRF of the DRG for the treatment of neuropathic pain is based mainly on results from very small studies with low evidence quality. Current research results about the benefits of PRF of the DRG for the treatment of neuropathic pain should be considered preliminary and confirmed in high-quality RCTs with sufficient numbers of participants.

Efficacy and safety of pulsed radiofrequency as a method of dorsal root ganglia stimulation for treatment of non-neuropathic pain: a systematic review.

BACKGROUND: We systematically reviewed the evidence on the efficacy and safety of dorsal root ganglion (DRG) targeted pulsed radiofrequency (PRF) versus any comparator for treatment of non-neuropathic pain. METHODS: We searched MEDLINE, CINAHL, Embase, PsycINFO, clinicaltrials.gov and WHO clinical trial register until January 8, 2019. All study designs were eligible. Two authors independently conducted literature screening. Primary outcomes were pain intensity and serious adverse events (SAEs). Secondary outcomes were any other pain-related outcome and any other safety outcome that was reported. We assessed the risk of bias using the Cochrane tool and Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I). We conducted narrative evidence synthesis and assessed the conclusiveness of included studies regarding efficacy and safety. RESULTS: We included 17 studies with 599 participants, which analyzed various pain syndromes. Two studies were randomized controlled trials; both included participants with low back pain (LBP). Non-randomized studies included patients with the following indications: LBP, postsurgical pain, pain associated with herpes zoster, cervicogenic headache, complex regional pain syndrome type 1, intractable vertebral metastatic pain, chronic scrotal and inguinal pain, occipital radiating pain in rheumatoid arthritis and chronic migraine. In these studies, the PRF was usually initiated after other treatments have failed. Eleven studies had positive conclusive statements (11/17) about efficacy; the remaining had positive inconclusive statements. Only three studies provided conclusiveness of evidence statements regarding safety - two indicated that the evidence was positive conclusive, and one positive inconclusive. The risk of bias was predominantly unclear in randomized and serious in non-randomized studies. CONCLUSION: Poor quality and few participants characterize evidence about benefits and harms of DRG PRF in patients with non-neuropathic pain. Results from available studies should only be considered preliminary. Not all studies have reported data regarding the safety of the intervention, but those that did, indicate that the intervention is relatively safe. As the procedure is non-destructive and early results are promising, further comparative studies about PRF in non-neuropathic pain syndromes would be welcomed.

Impact of embryo quality and endometrial thickness on implantation in natural cycle IVF.

PURPOSE: The aim of this study is to assess the effect of the endometrial thickness and embryo quality on the implantation potential in natural cycle IVF (NC-IVF). METHODS: A retrospective single-center study was performed on 552 single embryo transfers after NC-IVF. The 'quality' of the embryos was evaluated trough the number and regularity of blastomeres, degree of fragmentation, and nuclear content of cells. Endometrial thickness was measured in millimeters with transvaginal ultrasound on the day of hCG application. RESULTS: Our findings showed a statistically significant difference in successful implantation until a plateau of 10 mm is reached (p = 0.001). Only one pregnancy was achieved where endometrial thickness was less than 7 mm, and this resulted in an early miscarriage. The predictors of favorable implantation were fragmentation (≤ 10%, p < 0.05) and the number of blastomeres (preferably 8-cell, p < 0.01) on day 3. Embryo quality (R = 0.052) and endometrial thickness (R = 0.18) were closely related to pregnancy rate. The overall implantation rate per embryo transfer was 18.8%. CONCLUSIONS: Embryo quality and endometrial thickness have a significant impact on implantation in NC-IVF. Highest implantation potential has an 8-cell embryo with ≤ 10% fragmentation in the third day following oocyte retrieval. Endometrial thickness of at least 7 mm seems to be the optimal edge of successful pregnancy.

Higher Post-Operative Serum Vitamin D Level is Associated with Better Survival Outcome in Colorectal Cancer Patients.

25-Hydroxyvitamin D (25-OHD) may have a prognostic value in colorectal cancer (CRC) patients. However, as 25-OHD concentration is strongly impacted by surgery, it is uncertain what is the most reliable time-point for 25-OHD assessment, pre- or post-operative. Therefore, we examined 515 CRC patients (AJCC I-III) who underwent surgery. Blood samples were collected either pre-operatively (n = 286; median = 1 day before surgery) or post-operatively (n = 229; median = 8 days). Serum 25-OHD concentration was determined by liquid chromatography-tandem mass spectrometry. Association between 25-OHD and survival was tested in the whole cohort, followed by stratified analyses in pre- and post-operatively sampled. Median 25-OHD in the cohort was 36.7 nmol/L and median follow-up time was 5.9 years. There were no differences between pre- and post-operative cohort in age, sex, 25-OHD, AJCC stage, or localization of tumor. After adjustment, higher 25-OHD (>50 nmol/L) was associated with better overall survival only in post-operative (HR = 0.53; 95% CI: 0.33-0.84; P = 0.006), but not in pre-operative cohort (HR = 1.13; 95% CI: 0.77-1.65; P = 0.53). In conclusion, higher post-operative 25-OHD levels were associated with better survival outcome in CRC patients, while no such association was found for pre-operative levels. Time-point of blood collection should be addressed carefully in future research as it might affect the prognostic value of 25-OHD in CRC.

The role of luteal support during IVF: a qualitative systematic review.

The aim of this review is to provide qualitative evidence-based synthesis regarding efficacy of luteal-phase support on fertility outcome in women undergoing in vitro fertilization (IVF) with respect to clinical or live birth rates and pregnancy loss rates. Although the need of luteal phase support in IVF/ICSI cycles is well-known, the optimal start, dosage, route and the duration of the luteal phase support is still subject of debate. Data suggest that the optimal period to start with the luteal phase support would be between 24-72 hours after oocyte-retrieval and should continue at least until a positive pregnancy test is achieved. However, the majority of IVF-centers worldwide provide progesterone support up to 8 weeks of pregnancy. Among the well-established routes of luteal support, oral dydrogesterone and subcutaneous progesterone represent new and interesting routes of progesterone administration. The current studies support these routes of progesterone administration use in terms of comparable pregnancy rates and pregnancy loss rates to vaginal and intramuscular progesterone. Furthermore, the acceptance and tolerability among patients seems to be even better. In the frozen-thawed embryo transfer, dydrogesterone and vaginal progesterone are not effective as monotherapy treatments; however, when combined there is no reason to avoid one or the other in this setting.

Neuromodulation with electrical field stimulation of dorsal root ganglion in various pain syndromes: a systematic review with focus on participant selection.

OBJECTIVE: We conducted a systematic review about patient selection, efficacy, and safety of neuromodulation with electrical field stimulation (EFS) of dorsal root ganglion (DRG) in various painful conditions. We also analyzed conclusion statements as well as conflict of interest and financing of the included studies. METHODS: All study designs were eligible for inclusion. We searched MEDLINE, CINAHL, Embase, PsycINFO, and clinical trial registries until September 7, 2018. We assessed risk of bias by using Cochrane tool for randomized controlled trials (RCTs). RESULTS: Among the 29 included studies, only one was RCT, majority being case series and case reports. The evidence is based on studies with small number of participants (median: 6, range 1-152) with various painful conditions. Neuromodulation with EFS of DRG was mostly performed in participants who have failed other treatment modalities. Most of the authors of the included studies reported positive, but inconclusive, evidence regarding efficacy of neuro-modulation with EFS of DRG. Meta-analysis was not possible since only one RCT was included. CONCLUSION: Available evidence suggest that neuromodulation with EFS of DRG may help highly selected participants with various pain syndromes, who have failed to achieve adequate pain relief with other pharmacological and nonpharmacological interventions. However, these findings should be confirmed in high-quality RCTs with sufficient numbers of participants.

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.

BACKGROUND: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. METHODS: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. RESULTS: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10- 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48). CONCLUSIONS: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.

Comparison of methodological quality rating of systematic reviews on neuropathic pain using AMSTAR and R-AMSTAR.

BACKGROUND: Systematic reviews (SRs) in the field of neuropathic pain (NeuP) are increasingly important for decision-making. However, methodological flaws in SRs can reduce the validity of conclusions. Hence, it is important to assess the methodological quality of NeuP SRs critically. Additionally, it remains unclear which assessment tool should be used. We studied the methodological quality of SRs published in the field of NeuP and compared two assessment tools. METHODS: We systematically searched 5 electronic databases to identify SRs of randomized controlled trials of interventions for NeuP available up to March 2015. Two independent reviewers assessed the methodological quality of the studies using the Assessment of Multiple Systematic Reviews (AMSTAR) and the revised AMSTAR (R-AMSTAR) tools. The scores were converted to percentiles and ranked into 4 grades to allow comparison between the two checklists. Gwet's AC1 coefficient was used for interrater reliability assessment. RESULTS: The 97 included SRs had a wide range of methodological quality scores (AMSTAR median (IQR): 6 (5-8) vs. R-AMSTAR median (IQR): 30 (26-35)). The overall agreement score between the 2 raters was 0.62 (95% CI 0.39-0.86) for AMSTAR and 0.62 (95% CI 0.53-0.70) for R-AMSTAR. The 31 Cochrane systematic reviews (CSRs) were consistently ranked higher than the 66 non-Cochrane systematic reviews (NCSRs). The analysis of individual domains showed the best compliance in a comprehensive literature search (item 3) on both checklists. The results for the domain that was the least compliant differed: conflict of interest (item 11) was the item most poorly reported on AMSTAR vs. publication bias assessment (item 10) on R-AMSTAR. A high positive correlation between the total AMSTAR and R-AMSTAR scores for all SRs, as well as for CSRs and NCSRs, was observed. CONCLUSIONS: The methodological quality of analyzed SRs in the field of NeuP was not optimal, and CSRs had a higher quality than NCSRs. Both AMSTAR and R-AMSTAR tools produced comparable quality ratings. Our results point out to weaknesses in the methodology of existing SRs on interventions for the management NeuP and call for future improvement by better adherence to analyzed quality checklists, either AMSTAR or R-AMSTAR.

Efficacy and Safety Outcome Domains and Outcome Measures in Systematic Reviews of Neuropathic Pain Conditions.

OBJECTIVES: Heterogeneity of outcome domains, used in interventional trials and systematic reviews (SRs) for neuropathic pain (NeuP), makes decisions on the comparative effectiveness of available treatments difficult. This study analyzed outcome domains and measures used in SRs of randomized controlled trials on efficacy and safety of interventions for NeuP and compared them with the core outcome set (COS) and core outcome measures (COMs) for chronic pain recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). METHODS: Five electronic databases were searched to find SRs of interventions for NeuP. Outcome domains and measures were independently extracted by 2 authors, and compared against the IMMPACT-recommended COS and COMs. Outcome domains specified in the methods and reported in the results were also compared. RESULTS: Ninety-seven SRs were analyzed. The 2 core domains most frequently specified in the methods and reported in the results of SRs were pain and symptoms and adverse events. Pain intensity was mostly assessed with Visual Analog Scale (n=59) and Numerical Rating Scale (n=29). The incidence (n=70) and severity (n=60) were most commonly reported for adverse events. There were 240 different outcome measures used for the assessment of treatment efficacy and safety. CONCLUSIONS: Authors of SRs in the field of NeuP insufficiently use relevant recommended COS and COMs for chronic pain. More effort should be put into the implementation of COS to ensure that the study results can be compared and combined. There is a need for defining core outcome domains and measures specific for NeuP.

Electrical Stimulation of Dorsal Root Ganglion in the Context of Pain: A Systematic Review of In Vitro and In Vivo Animal Model Studies.

OBJECTIVE: Dorsal root ganglion (DRG) has recently emerged as an attractive target for neuromodulation therapy since primary sensory neurons and their soma in DRGs are important sites for pathophysiologic changes that lead to neuropathic pain. Our aim was to create evidence synthesis about the effects of electrical stimulation of DRG in the context of pain from in vitro and in vivo animal models, analyze methodology and quality of studies in the field. METHODS: For conducting systematic review we searched three data bases: MEDLINE, Embase and Web of Science. The quality of included studies was assessed with the Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool for animal studies. The study was registered in the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies data base. RESULTS: We included six in vitro and eight in vivo animal studies. All included in vitro studies combined neurostimulation with substances or drugs and reported an improvement in pain-related parameters due to neurostimulation. Among in vivo studies, six used pulsed radiofrequency, while two used electrical field stimulation. All in vivo studies reported improvement in pain-related behavior following stimulation. Meta-analysis was not possible because of heterogeneity and missing data. The quality of included studies was suboptimal since all had an unclear risk of bias in multiple domains. CONCLUSIONS: Limited data from in vitro and in vivo animal studies indicate that electrical stimulation of DRG has a positive therapeutic effect in the context of pain-related outcomes. Further studies with a standardized methodological approach and outcomes will provide useful information about electrical stimulation of DRG in animal models.

Interventions for Neuropathic Pain: An Overview of Systematic Reviews.

Numerous interventions for neuropathic pain (NeuP) are available, but its treatment remains unsatisfactory. We systematically summarized evidence from systematic reviews (SRs) of randomized controlled trials on interventions for NeuP. Five electronic databases were searched up to March 2015. Study quality was analyzed using A Measurement Tool to Assess Systematic Reviews. The most common interventions in 97 included SRs were pharmacologic (59%) and surgical (15%). The majority of analyzed SRs were of medium quality. More than 50% of conclusions from abstracts on efficacy and approximately 80% on safety were inconclusive. Effective interventions were described for painful diabetic neuropathy (pregabalin, gabapentin, certain tricyclic antidepressants [TCAs], opioids, antidepressants, and anticonvulsants), postherpetic neuralgia (gabapentin, pregabalin, certain TCAs, antidepressants and anticonvulsants, opioids, sodium valproate, topical capsaicin, and lidocaine), lumbar radicular pain (epidural corticosteroids, repetitive transcranial magnetic stimulation [rTMS], and discectomy), cervical radicular pain (rTMS), carpal tunnel syndrome (carpal tunnel release), cubital tunnel syndrome (simple decompression and ulnar nerve transposition), trigeminal neuralgia (carbamazepine, lamotrigine, and pimozide for refractory cases, rTMS), HIV-related neuropathy (topical capsaicin), and central NeuP (certain TCAs, pregabalin, cannabinoids, and rTMS). Evidence about interventions for NeuP is frequently inconclusive or completely lacking. New randomized controlled trials about interventions for NeuP are necessary; they should address safety and use clear diagnostic criteria.

Extracting data from figures with software was faster, with higher interrater reliability than manual extraction.

OBJECTIVES: To compare speed and accuracy of graphical data extraction using manual estimation and open source software. STUDY DESIGN AND SETTING: Data points from eligible graphs/figures published in randomized controlled trials (RCTs) from 2009 to 2014 were extracted by two authors independently, both by manual estimation and with the Plot Digitizer, open source software. Corresponding authors of each RCT were contacted up to four times via e-mail to obtain exact numbers that were used to create graphs. Accuracy of each method was compared against the source data from which the original graphs were produced. RESULTS: Software data extraction was significantly faster, reducing time for extraction for 47%. Percent agreement between the two raters was 51% for manual and 53.5% for software data extraction. Percent agreement between the raters and original data was 66% vs. 75% for the first rater and 69% vs. 73% for the second rater, for manual and software extraction, respectively. CONCLUSIONS: Data extraction from figures should be conducted using software, whereas manual estimation should be avoided. Using software for data extraction of data presented only in figures is faster and enables higher interrater reliability.

Survey of Cochrane protocols found methods for data extraction from figures not mentioned or unclear.

OBJECTIVES: To analyze whether protocols of Cochrane systematic reviews address data extraction from figures in included trials. STUDY DESIGN AND SETTING: Protocols of Cochrane systematic reviews published between May 2013 and May 2014 were screened by two authors independently, and the following data were collected: date of protocol publication, country of authors' origin, number of authors, number of affiliated institutions, Cochrane review group, whether the protocol contains description about data extraction from figures, method of data extraction from figures, and literature reference for a method of data extraction from figures. RESULTS: Among 589 protocols, 33 (5.6%) mentioned data extraction from figures in Methods section. Only one protocol specified that computer software will be used for data extraction from figures, one specifically indicated that data from figures will not be used, few stated estimation or approximation, whereas others did not provide any description of methodology for data extraction from figures. CONCLUSION: Very few protocols of Cochrane systematic reviews mention data extraction from figures, and even when mentioned, methods for data extraction are unclear. Methodology for data extraction from figures should be incorporated into the Cochrane Handbook and new methodological standards for Cochrane systematic reviews.

Recombinant activated factor VII controls chemotherapy-related hemorrhage in patients with solid intra-abdominal tumors: a report of three pediatric cases.

Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) is used predominantly for the treatment of bleeding in patients with hemophilia and inhibitors, and in patients with traumatic injury. There are also literature reports of its use in chemotherapy-related bleeding in leukemia patients and intra- or postoperative bleeding in patients with solid tumors. We describe three pediatric patients where rFVIIa was successfully used to manage bleeding following the failure of conventional hemostatic treatments during chemotherapy for intra-abdominal tumors (hepatoblastoma, rhabdomyosarcoma and non-classified malignant sarcoma). Recombinant FVIIa proved effective and maintained hemostasis in two of three cases, with no evidence for toxic or adverse events in any of the treated patients.