ALS drug development guidances and trial guidelines: Consensus and opportunities for alignment.
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SUBMITTER: Andrews JA
PROVIDER: S-EPMC6656654 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveAdvances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet "standard of care." Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS.MethodsCore clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement.ResultsA total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single-step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories.InterpretationThese evidence-based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.
| S-EPMC10646996 | biostudies-literature
Project description:ObjectiveTo revise the 1999 Airlie House consensus guidelines for the design and implementation of preclinical therapeutic studies and clinical trials in amyotrophic lateral sclerosis (ALS).MethodsA consensus committee comprising 140 key members of the international ALS community (ALS researchers, clinicians, patient representatives, research funding representatives, industry, and regulatory agencies) addressed 9 areas of need within ALS research: (1) preclinical studies; (2) biological and phenotypic heterogeneity; (3) outcome measures; (4) disease-modifying and symptomatic interventions; (5) recruitment and retention; (6) biomarkers; (7) clinical trial phases; (8) beyond traditional trial designs; and (9) statistical considerations. Assigned to 1 of 8 sections, committee members generated a draft set of guidelines based on a "background" of developing a (pre)clinical question and a "rationale" outlining the evidence and expert opinion. Following a 2-day, face-to-face workshop at the Airlie House Conference Center, a modified Delphi process was used to develop draft consensus research guidelines, which were subsequently reviewed and modified based on comments from the public. Statistical experts drafted a separate document of statistical considerations (section 9).ResultsIn this report, we summarize 112 guidelines and their associated backgrounds and rationales. The full list of guidelines, the statistical considerations, and a glossary of terms can be found in data available from Dryad (appendices e-3-e-5, doi.org/10.5061/dryad.32q9q5d). The authors prioritized 15 guidelines with the greatest potential to improve ALS clinical research.ConclusionThe revised Airlie House ALS Clinical Trials Consensus Guidelines should serve to improve clinical trial design and accelerate the development of effective treatments for patients with ALS.
| S-EPMC6448453 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder characterized by the loss of upper and lower motor neurons, resulting in debilitating muscle weakness and atrophy. Currently, there are no effective treatments available for ALS, posing significant challenges in managing the disease that affects approximately two individuals per 100,000 people annually. To address the urgent need for effective ALS treatments, we conducted a drug repurposing study using a combination of bioinformatics tools and molecular docking techniques. We analyzed sporadic ALS-related genes from the GEO database and identified key signaling pathways involved in sporadic ALS pathogenesis through pathway analysis using DAVID. Subsequently, we utilized the Clue Connectivity Map to identify potential drug candidates and performed molecular docking using AutoDock Vina to evaluate the binding affinity of short-listed drugs to key sporadic ALS-related genes. Our study identified Cefaclor, Diphenidol, Flubendazole, Fluticasone, Lestaurtinib, Nadolol, Phenamil, Temozolomide, and Tolterodine as potential drug candidates for repurposing in sporadic ALS treatment. Notably, Lestaurtinib demonstrated high binding affinity toward multiple proteins, suggesting its potential as a broad-spectrum therapeutic agent for sporadic ALS. Additionally, docking analysis revealed NOS3 as the gene that interacts with all the short-listed drugs, suggesting its possible involvement in the mechanisms underlying the therapeutic potential of these drugs in sporadic ALS. Overall, our study provides a systematic framework for identifying potential drug candidates for sporadic ALS therapy and highlights the potential of drug repurposing as a promising strategy for discovering new therapies for neurodegenerative diseases.
| S-EPMC10809234 | biostudies-literature
Project description:AimsThe European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) produce guidelines for the design of pivotal psychiatric drug trials used in new drug applications. It is unknown who are involved in the guideline development and what specific trial design recommendations they give.MethodsCross-sectional study of EMA Clinical Efficacy and Safety Guidelines and FDA Guidance Documents. Study outcomes: (1) guideline committee members and declared conflicts of interest; (2) guideline development and organisation of commenting phases; (3) categorisation of stakeholders who comment on draft and final guidelines according to conflicts of interest ('industry', 'not-industry but with industry-related conflicts', 'independent', 'unclear'); and (4) trial design recommendations (trial duration, psychiatric comorbidity, 'enriched design', efficacy outcomes, comparator choice). Protocol registration https://doi.org/10.1101/2020.01.22.20018499 (27 January 2020).ResultsWe included 13 EMA and five FDA guidelines covering 15 psychiatric indications. Eleven months after submission, the EMA had not processed our request regarding committee member disclosures. FDA offices draft the Guidance Documents, but the Agency is not in possession of employee conflicts of interest declarations because FDA employees generally may not hold financial interests (although some employees may hold interests up to $15,000). The EMA and FDA guideline development phases are similar; drafts and final versions are publicly announced and everybody can submit comments. Seventy stakeholders commented on ten guidelines: 38 (54%) 'industry', 18 (26%) 'not-industry but with industry-related conflicts', six (9%) 'independent' and eight (11%) 'unclear'. They submitted 1014 comments: 640 (68%) 'industry', 243 (26%) 'not-industry but with industry-related conflicts', 44 (5%) 'independent' and 20 (2%) 'unclear' (67 could not be assigned to a specific stakeholder). The recommended designs were generally for trials of short duration; with restricted trial populations; allowing previous exposure to the drug; and often recommending rating scale efficacy outcomes. EMA mainly recommended three arm designs (both placebo and active comparators), whereas FDA mainly recommended placebo-controlled designs. There were also other important differences and FDA's recommendations regarding the exclusion of psychiatric comorbidity seemed less restrictive.ConclusionsThe EMA and FDA clinical research guidelines for psychiatric pivotal trials recommend designs that tend to have limited generalisability. Independent and non-conflicted stakeholders are underrepresented in the guideline development. It seems warranted with more active involvement of scientists and independent organisations without conflicts of interest in the guideline development process.
| S-EPMC8157504 | biostudies-literature
Project description:Pharmacogenomic drug labels in the Summary of Product Characteristics (SmPC) provide an instrument for clinical implementation of pharmacogenomics. We compared pharmacogenomic guidance by Clinical Pharmacogenetics Implementation Consortium (CPIC), Dutch Pharmacogenetics Working Group (DPWG), the US Food and Drug Administration (FDA), and by the European agencies the European Medicines Agency (EMA), College ter Beoordeling van Geneesmiddelen Medicines Evaluation Board (CBG-MEB), and Federal Institute for Drugs and Medical Devices (FIDMD), collectively assigned as EMA/FIDMD+MEB shortened as EMA/FM. Of 54 drugs with an actionable gene-drug interaction in the CPIC and DPWG guidelines, only 50% had actionable pharmacogenomic information in the SmPCs and the agencies were in agreement in only 18% of the cases. We further compared 450 additional drugs, lacking CPIC or DPWG guidance, and found 126 actionable gene-drug labels by the FDA and/or the EMA/FM. Based on these 126 drugs in addition to the 54 above, the consensus of actionable pharmacogenomic labeling between the FDA and the EMA/FM was only 54%. In conclusion, guidelines provided by CPIC/DPWG are only partly implemented into the SmPCs and the implementation of pharmacogenomic drug labels into the clinics would strongly gain from a higher extent of consensus between agencies.
| S-EPMC7232863 | biostudies-literature
Project description:Cancer in children is rare with approximately 15,700 new cases diagnosed in the United States annually. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be "cured" of their disease, and 5-year event-free survival exceeds 80%. However, for patients surviving their malignancy, therapy-related long-term adverse effects are severe, with an estimated 50% having chronic life-threatening toxicities related to therapy in their fourth or fifth decade of life. While overall intensive therapy with cytotoxic agents continues to reduce cancer-related mortality, new understanding of the molecular etiology of many childhood cancers offers an opportunity to redirect efforts to develop effective, less genotoxic therapeutic options, including agents that target oncogenic drivers directly, and the potential for use of agents that target the tumor microenvironment and immune-directed therapies. However, for many high-risk cancers, significant challenges remain.
| S-EPMC6768308 | biostudies-literature
Project description:ObjectiveTo evaluate how frequently surfactant is used off-label in preterm infants.Study designWe conducted a retrospective cohort analysis of prospectively collected administrative data for 2005-2015 from 348 neonatal intensive care units in the US. We quantified off-label administration of poractant alfa, calfactant, or beractant in inborn infants born at <37 weeks of gestational age (GA). Off-label surfactant administration was defined according to the Food and Drug Administration (FDA) label.ResultsOf a total of 110 822 preterm infants who received surfactant, 68 226 (62%) received the surfactant off-label. The majority of infants who received surfactant off-label had a higher birth weight than those who received surfactant on-label (40 716 [37%]), had an older GA than those who received surfactant on-label (35 191 [32%]), or were treated with intubation and surfactant administration followed by immediate extubation (INSURE) (32 310 [29%]). Poractant alfa was administered via INSURE more frequently than beractant or calfactant (16 688 [38%], 7137 [20%], and 8485 [27%], respectively). An increasing number of infants received surfactant via INSURE from 2005 to 2015 (from 1697 [19%] to 3368 [36%]).ConclusionsThe majority of surfactant given to preterm infants is administered off-label. The uptrend in administration via INSURE coincides with increased supporting evidence. The gap between FDA labeling and current clinic practice exemplifies an opportunity for label expansion, which may require additional prospective or retrospective safety and/or effectiveness data for infants of older GA and higher birth weight.
| S-EPMC6486873 | biostudies-literature
Project description:This report describes consensus guidelines and recommendations for the treatment of canine osteoarthritis (OA) according to the "Canine OsteoArthritis Staging Tool excluding radiography" (COASTeR) stage of OA, by the COAST Development Group. The recommendations are based on evidence-based medicine and clinical experience and are proposed with international relevance in mind. The aim is to provide veterinarians with a practical reference to consolidated information and to support the development of patient-specific OA management protocols and informed treatment choices based on the stage of OA.
| S-EPMC10436090 | biostudies-literature
Project description:The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis.
| S-EPMC4809521 | biostudies-literature
Project description:During hunger, a series of high-amplitude contractions of the stomach and small intestine (phase III), which form part of a cycle of quiescence and contractions (known as the migrating motor complex, MMC), play a "housekeeping" role prior to the next meal, and may contribute toward the development of hunger. Several gastrointestinal (GI) hormones are associated with phase III MMC activity, but currently the most prominent is motilin, thought to at least partly mediate phase III contractions of the gastric MMC. Additional GI endocrine and neuronal systems play even more powerful roles in the development of hunger. In particular, the ghrelin-precursor gene is proving to have a complex physiology, giving rise to three different products: ghrelin itself, which is formed from a post-translational modification of des-acyl-ghrelin, and obestatin. The receptors acted on by des-acyl-ghrelin and by obestatin are currently unknown but both these peptides seem able to exert actions which oppose that of ghrelin, either indirectly or directly. An increased understanding of the actions of these peptides is helping to unravel a number of different eating disorders and providing opportunities for the discovery of new drugs to regulate dysfunctional gastric behaviors and appetite. To date, ghrelin and motilin receptor agonists and antagonists have been described. The most advanced are compounds which activate the ghrelin and motilin receptors which are being progressed for disorders associated with gastric hypomotility.
| S-EPMC3174087 | biostudies-literature