Register to receive personalised research and resources by email, Gene therapy randomised clinical trials in Europe – a review paper of methodology and design, Faculty of Public Health, Medical University Sofia, Sofia , Bulgaria, Department of Health Technology Assessment, Faculty of Public Health, Medical University Sofia, Sofia , Bulgaria, Public Health Department, Aix-Marseille University , Marseille, France, Challenges with advanced therapy medicinal products and how to meet them, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, RoB 2: a revised tool for assessing risk of bias in randomised trials, Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial, Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial, CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials, Ad2/HIF-1α/VP16, Abbreviated Clinical Study Report: PADHIF00704, Effect of hypoxia-inducible factor-1α gene therapy on walking performance in patients with intermittent claudication, Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study, Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (calcium up-regulation by percutaneous administration of gene therapy in cardiac disease phase 2b), Allowing for uncertainty due to missing and LOCF imputed outcomes in meta-analysis, A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis, Standardising outcomes for clinical trials and systematic reviews, Clinical outcome endpoints in heart failure trials: a European society of cardiology heart failure association consensus document, Indicators of outcome quality in peripheral arterial disease revascularizations – a Delphi expert consensus, Progress in cystic fibrosis and the CF therapeutics development network. After the first interim assessment of unblinded patient safety data, assessment by the independent Data Monitoring Committee (DMC) was blinded [9]. 2004–002508-13 was estimated with ‘some concerns’. 2004–002508-13, the methods of outcome measurement were very specific and the same measurement methods and thresholds in both the intervention and placebo groups were used at comparable time points. Pre-Clinical. Browse over 50,000 other reports on our store. 1, 1847808. Spark Therapeutics, Pfizer, and UniQure all have gene therapy products in Phase III development. In all reviewed RCTs, in both intervention and placebo groups the size of the number of participants with missing outcome data and reasons for this were similar. Challenges in conducting CT with ATMP are also posed by their biological nature and specific manufacturing process. Currently, a program that is still ongoing started developing COS for CTs in renal cancer ( In study no. The need for better understanding of the pathophysiology of some of diseases and the mechanism of action of the therapies, along with limitations in recruitment of sufficient number of patients, makes generating adequate and robust data on the therapy safety and efficacy difficult. There were no observed inconsistencies between outcome measures and analyses intentions and publications in the reviewed RCTs. There were changes made in the protocol, but they were not specified, raising concerns about bias in selection of the reported results. 2011–004761-33, the primary analysis was done in the PP population but used ANCOVA-adjusted treatment effects that demonstrated no significant difference in the results from ITT and PP analyses. LOCF is commonly used as a method of imputing missing data in longitudinal studies. The relevant data were extracted once the database was locked and the researchers were unblinded [14]. Only in one of the reviewed RCTs (study no. This data is important for assessing the risk of bias in outcome measurement, especially when knowledge of the intervention can influence the judgment of the outcome assessor. The analysed CTs were performed according to RCT requirements, following standards for their planning and results reporting. In study no. This is due to the fact that a large number of GTs are developed for the treatment of rare diseases (113 [71%]) of the 159 clinical trials identified in this search. The frequent prophylactic infusions of recombinant FVIII (rFVIII) or recombinant FIX (rFIX) begin from the first one or two years of life, often continuing throughout adulthood. To learn about our use of cookies and how you can manage your cookie settings, please see our Cookie Policy. 2006–001246-13 did not provide specific information on the masking of participants. Not for Distribution. The study was an event-driven trial and all clinical events were reviewed by both a non-blinded Data Monitoring Committee and an independent blinded Clinical Endpoints Committee. 2006–001246-13 were common for cancer therapy (patient survival and progression-free survival). Browse over 50,000 other reports on our store. Because of the missing clear justification for using LOCF [4], the risk of bias due to missing outcome data was assessed as with ‘some concerns’. 2012–001700-37, 2011–004761-33 and 2006–001246-13, were assessed with low risk of bias in this domain. No deviations were observed between planned and published outcome measurements and analyses. This domain focuses mainly on differential errors related to intervention assignment. Registered in England & Wales No. In November 2019, BioMarin, a biotechnology company specialising in developing therapies for rare diseases driven by genetic causes, submitted a marketing authorization application (MAA) to the European Medicines Association (EMA) for its investigational product valoctocogene roxaparvovec, a gene therapy targeted to patients with severe haemophilia A. These results were published in the New England Journal of Medicine in January 2020. ... be in Phase 3 Studies by 2H 2020 Gene Therapy ( GTx) Phase 3. Statistical analysis based on the disease studied and the size of the study population adequately reflected the obtained outcomes with low risk of bias across the domains. This significantly limits the conclusions that can be drawn about the methodology and design of CTs with GTMPs due to the small number of identified RCTs. These sets serve to advise on a number of essential outcomes that should be measured and reported in all clinical trials for a specific condition [15]. The number of patients with missing test was similar across three treatment groups and placebo, and the reasons for not performing it were described in the published results. In addition, only limited data were provided in the reviewed RCTs regarding deviations from intended intervention that were inconsistent with the trial protocol. In Study no. The risk of bias due to the choice of reported results for all RCTs was considered low. Significant Investment in Gene Therapy Manufacturing of Viral Vectors to Support Rapid Drug Development and Access. In one of the RCTs the mechanism used to apply a random patient distribution sequence was not described. In clinical areas where potential GTs may offer treatment options, academia should consider the development of COS to evaluate efficacy and safety similar to the coreHEM project ( By closing this message, you are consenting to our use of cookies. There was no consensus reached on optimal phase II endpoints in acute or chronic heart failure trials [16] and study no. BioMarin’s recent submissions of an MAA in November 2019 to the EMA and of a biologics license application (BLA) in December 2019 to the FDA were based on results from a Phase I/II study (BioMarin Pharmaceutical, NCT02576795) alongside interim analysis results from the ongoing Phase III GENEr8-1 study (BioMarin Pharmaceutical, NCT03370913).