ObjectivesTo evaluate the comparative effectiveness and safety of intravitreal bevacizumab, ranibizumab and aflibercept for patients with choroidal neovascular age-related macular degeneration (cn-AMD), diabetic macular oedema (DMO), macular oedema due to retinal vein occlusion (RVO-MO) and myopic choroidal neovascularisation (m-CNV).DesignSystematic review and random-effects meta-analysis.MethodsMultiple databases were searched from inception to 17 August 2017. Eligible head-to-head randomised controlled trials (RCTs) comparing the (anti-VEGF) drugs in adult patients aged ≥18 years with the retinal conditions of interest. Two reviewers independently screened studies, extracted data and assessed risk of bias.Results19 RCTs involving 7459 patients with cn-AMD (n=12), DMO (n=3), RVO-MO (n=2) and m-CNV (n=2) were included. Vision gain was not significantly different in patients with cn-AMD, DMO, RVO-MO and m-CNV treated with bevacizumab versus ranibizumab. Similarly, vision gain was not significantly different between cn-AMD patients treated with aflibercept versus ranibizumab. Patients with DMO treated with aflibercept experienced significantly higher vision gain at 12 months than patients receiving ranibizumab or bevacizumab; however, this difference was not significant at 24 months. Rates of systemic serious harms were similar across anti-VEGF agents. Posthoc analyses revealed that an as-needed treatment regimen (6–9 injections per year) was associated with a mortality increase of 1.8% (risk ratio: 2.0 [1.2 to 3.5], 2 RCTs, 1795 patients) compared with monthly treatment in cn-AMD patients.ConclusionsIntravitreal bevacizumab was a reasonable alternative to ranibizumab and aflibercept in patients with cn-AMD, DMO, RVO-MO and m-CNV. The only exception was for patients with DME and low visual acuity (<69 early treatment diabetic retinopathy study [ETDRS] letters), where treatment with aflibercept was associated with significantly higher vision gain (≥15 ETDRS letters) than bevacizumab or ranibizumab at 12 months; but the significant effects were not maintained at 24 months. The choice of anti-VEGF drugs may depend on the specific retinal condition, baseline visual acuity and treatment regimen.PROSPERO registration numberCRD42015022041.
Health conditions and obstetrical complications alone in older women do not account for increased rates of CS. The preferences of the individual care provider and the mother on CS rates may play a key role and require further investigation.
BackgroundIt has been suggested that ultra-rare diseases should be recognized as distinct from more prevalent rare diseases, but how drugs developed to treat ultra-rare diseases (DURDs) might be distinguished from drugs for ‘other’ rare diseases (DORDs) is not clear. We compared the characteristics of DURDs to DORDs from a health technology assessment (HTA) perspective in submissions made to the CADTH Common Drug Review. We defined a DURD as a drug used to treat a disease with a prevalence ≤ 1 patient per 100,000 people, a DORD as a drug used to treat a disease with a prevalence > 1 and ≤ 50 patients per 100,000 people. We assessed differences in the level and quantity of evidence supporting each HTA submission, the molecular basis of treatment agents, annual treatment cost per patient, type of reimbursement recommendation made by CADTH, and reasons for negative recommendations.ResultsWe analyzed 14 DURD and 46 DORD submissions made between 2004 and 2016. Compared to DORDs, DURDs were more likely to be biologic drugs (OR = 6.06, 95%CI 1.25 to 38.58), to have been studied in uncontrolled clinical trials (OR = 23.11, 95%CI 2.23 to 1207.19), and to have a higher annual treatment cost per patient (median difference = CAN$243,787.75, 95%CI CAN$83,396 to CAN$329,050). Also, submissions for DURDs were associated with a less robust evidence base versus DORDs, as DURD submissions were less likely to include data from at least one double-blinded randomized controlled trial (OR = 0.13, 95%CI 0.02 to 0.70) and have smaller patient cohorts in clinical trials (median difference = −108, 95%CI –234 to −50). Furthermore, DURDs are less likely to receive a positive reimbursement recommendation (OR = 0.22, 95%CI 0.05 to 0.91), and low level of evidence was the major contributor for a negative recommendation.ConclusionsThe results suggest that DURDs could be viewed as distinct category from an HTA perspective. Applying the same HTA decision-making framework to DURDs and DORDs might have contributed the higher rate of negative reimbursement recommendations made for DURDs. Recognition of DURDs as a distinct subgroup of DRDs by explicitly defining DURDs based on objective criteria may facilitate the implementation of HTA assessment process that accounts for the issues associated with DURD.
BackgroundA shift in biochemical research towards drugs for rare diseases has created new challenges for the pharmaceutical industry, government regulators, health technology assessment agencies, and public and private payers. In this article, we aim to comprehensively review, characterize, identify possible trends, and explore reasons for negative reimbursement recommendations in submissions made to the Common Drug Review (CDR) for drugs for rare diseases (DRD) at the Canadian Agency for Drugs and Technologies in Health (CADTH), a publicly funded pan-Canadian health technology assessment agency. A public database (cadth.ca) was screened to identify DRD submissions to CDR. A diseases prevalence of ≤50 per 100,000 people was considered a rare disease. We calculated descriptive statistics for prevalence, study design, study size, treatment cost, reimbursement recommendation types, and reasons for negative reimbursement recommendations.ResultsFrom 2004 to 2015, 63 of 434 submissions to the CDR were for DRD (range: 1 submission in 2005 to 10 submissions in 2013). Most (74.6%) submissions included at least one double-blind randomized controlled trial (RCT). The average study size was 190 patients (range: 20 to 742). The average annual treatment cost was C$215,631 (range: $9,706 to $940,084). Reimbursement recommendations were positive for 54% of the submissions. Negative reimbursement recommendations were made due to a lack of clinical effectiveness (38.5%), insufficient evidence (30.8%), multiple reasons (23.1%), or lack of cost effectiveness/high cost (7.7%).ConclusionThe number of DRD submissions to CDR increased since 2013; from 4 to 5 per year between 2004 and 2012, to 10, 9, and 8 in 2013, 2014, and 2015 respectively. More than half of DRD submissions received positive reimbursement recommendation. Poor quality evidence and/or lack of supportive clinical evidence was at least partly responsible for a negative reimbursement recommendation in all cases. Although the average cost of DRD treatments was high, high cost was a reason for a negative reimbursement recommendation in only two (7.7%) of negative reimbursement recommendations.
Whether folic acid supplementation in pregnancy can prevent the occurrence of gestational hypertension/preeclampsia remains uncertain.
ObjectivesClinical discoveries are heralded by observing unique and unusual clinical cases. The effort of identifying such cases rests on the shoulders of busy clinicians. We assess the feasibility and applicability of an augmented intelligence framework to accelerate the rate of clinical discovery in preeclampsia and hypertensive disorders of pregnancy-an area that has seen little change in its clinical management. MethodsWe conducted a retrospective exploratory outlier analysis of participants enrolled in the folic acid clinical trial (FACT, N=2,301) and the Ottawa and Kingston birth cohort (OaK, N=8,085). We applied two outlier analysis methods: extreme misclassification contextual outlier and isolation forest point outlier. The extreme misclassification contextual outlier is based on a random forest predictive model for the outcome of preeclampsia in FACT and hypertensive disorder of pregnancy in OaK. We defined outliers in the extreme misclassification approach as mislabelled observations with a confidence level of more than 90%. Within the isolation forest approach, we defined outliers as observations with an average path length z score less or equal to -3, or more or equal to 3. Content experts reviewed the identified outliers and determined if they represented a potential novelty that could conceivably lead to a clinical discovery. ResultsIn the FACT study, we identified 19 outliers using the isolation forest algorithm and 13 outliers using the random forest extreme misclassification approach. We determined that three (15.8%) and 10 (76.9%) were potential novelties, respectively. Out of 8,085 participants in the OaK study, we identified 172 outliers using the isolation forest algorithm and 98 outliers using the random forest extreme misclassification approach; four (2.3%) and 32 (32.7%), respectively, were potential novelties. Overall, the outlier analysis part of the augmented intelligence framework identified a total of 302 outliers. These were subsequently reviewed by content experts, representing the human part of the augmented intelligence framework. The clinical review determined that 49 of the 302 outliers represented potential novelties. ConclusionsAugmented intelligence using extreme misclassification outlier analysis is a feasible and applicable approach for accelerating the rate of clinical discoveries. The use of an extreme misclassification contextual outlier analysis approach has resulted in a higher proportion of potential novelties than using the more traditional point outlier isolation forest approach. This finding was consistent in both the clinical trial and real-world cohort study data. Using augmented intelligence through outlier analysis has the potential to speed up the process of identifying potential clinical discoveries. This approach can be replicated across clinical disciplines and could exist within electronic medical records systems to automatically identify outliers within clinical notes to clinical experts.
Background The comparative safety and efficacy between anti-vascular endothelial growth factor agents (anti-VEGFs) and between combined therapies for patients with neovascular age-related macular degeneration (nAMD) is unclear. We conducted a systematic review to examine the comparative safety and efficacy anti-VEGFs for adults with nAMD. Methods Studies were identified through MEDLINE, EMBASE, and Cochrane CENTRAL (inception to June 3, 2019), grey literature, and scanning reference lists. Two reviewers independently screened citations and full-text articles to identify randomized controlled trials (RCTs), extracted data, and appraised risk of bias. Pairwise random-effects meta-analysis and Bayesian network meta-analysis (NMA) were conducted. The primary outcomes were the proportion of patients experiencing moderate vision gain (≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart) and the proportion of patients experiencing moderate vision loss (≤ 15 letters). Results After screening 3647 citations and 485 potentially relevant full-text articles, 92 RCTs with 24,717 patients were included. NMA (34 RCTs, 8809 patients, 12 treatments) showed small differences among anti-VEGFs in improving the proportion of patients with moderate vision gain, with the largest for conbercept versus broluczumab (OR 0.15, 95% CrI: 0.05–0.56), conbercept versus ranibizumab (OR 0.17, 95% CrI: 0.05–0.59), conbercept versus aflibercept (OR 0.19, 95% CrI: 0.06–0.65), and conbercept versus bevacizumab (OR 0.2, 95% CrI: 0.06–0.69). In NMA (36 RCTs, 9081 patients, 13 treatments) for the proportion of patients with moderate vision loss, small differences were observed among anti-VEGFs, with the largest being for conbercept versus aflibercept (OR 0.24, 95% CrI: 0–4.29), conbercept versus brolucizumab (OR 0.24, 95% CrI: 0–4.71), conbercept versus bevacizumab (OR 0.26, 95% CrI: 0–4.65), and conbercept versus ranibizumab (OR 0.27, 95% CrI: 0–4.67). Conclusion The only observed differences were that ranibizumab, bevacizumab, aflibercept, and brolucizumab were statistically superior to conbercept in terms of the proportion of patients with nAMD who experienced moderate vision gain. However, this finding is based on indirect evidence through one small trial comparing conbercept with placebo. This does not account for drug-specific differences when assessing anatomic and functional treatment efficacy in variable dosing regimens. Systematic review registration PROSPERO registration number CRD42015022041.
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