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Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations.

ABSTRACT: An inherent challenge to clinical trials that aim to test the efficacy of experimental therapeutics for patients with amyotrophic lateral sclerosis (ALS) is the relative rarity of the disease. A promising solution to this problem is a multi-center approach that ideally includes sites distributed across a broad geographic area. In support of such an approach, the European E-RARE program and the United States National Institutes of Health (NIH) partnered to support the investigator-initiated ROCK-ALS trial (Eudra-CT-Nr.: 2017-003676-31, NCT03792490) as a multi-national collaboration between centers in Europe and North America that is led by European investigators. During the set-up of this international trial, however, a number of unanticipated legal, administrative, and financial complexities emerged that required significant adaptation of the proposed trial scheme. Here, we report our experience navigating these obstacles and describe the potential solutions that we explored. Our experience may inform future efforts to implement multi-national investigator-initiated trials that involve both European and United States centers.

SUBMITTER: Lingor P

PROVIDER: S-EPMC8289747 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations.

Lingor Paul P Koch Jan C JC Statland Jeffrey M JM Hussain Sumaira S Hennecke Christiane C Wuu Joanne J Langbein Thomas T Ahmed Raees R Günther René R Ilse Benjamin B Kassubek Jan J Kollewe Katja K Kuttler Josua J Leha Andreas A Lengenfeld Teresa T Meyer Thomas T Neuwirth Christoph C Tostmann Ralf R Benatar Michael M

Amyotrophic lateral sclerosis & frontotemporal degeneration 20210203 5-6

An inherent challenge to clinical trials that aim to test the efficacy of experimental therapeutics for patients with amyotrophic lateral sclerosis (ALS) is the relative rarity of the disease. A promising solution to this problem is a multi-center approach that ideally includes sites distributed across a broad geographic area. In support of such an approach, the European E-RARE program and the United States National Institutes of Health (NIH) partnered to support the investigator-initiated ROCK- ...[more]

PMID: 33533663

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Project description:ObjectiveIn children many antiepileptic drugs (AEDs) are prescribed off-label due to a lack of well-designed randomized controlled trials (RCTs). We conducted a multicenter RCT in the Netherlands to compare levetiracetam and valproic acid as monotherapy in children with newly diagnosed epilepsy. After 2 years, we had to stop this investigator-initiated trial prematurely because the inclusion rate was too low. We analyzed the reasons for this failure, assessed the various issues involved in performing RCTs in children, and now give recommendations for future studies.MethodsA questionnaire was completed by all investigators involved in the study. It included questions about the motivation to participate and the perceived reasons for recruitment failure. We also studied literature about financial, logistic, legal, and ethical aspects of RCTs in children.ResultsMain reasons for recruitment failure were overestimation of the number of eligible AED-naive children referred by general pediatricians; personal preferences of investigators for specific antiepileptic drugs; and the extensive administrative load due to extra regulations and guidelines for children. Fundraising for investigator-initiated trials is difficult and the majority of RCTs concerning AEDs are sponsored by pharmaceutical companies. Involving children requires balancing between protection and participation; the randomization procedure and obtaining informed consent are complex for both children and parents.SignificancePerforming RCTs with AEDs in children is important but complicated by logistic, regulatory, legal, and ethical restrictions. Based on our recent experience, our advice to colleagues who are planning a similar trial would be to perform a feasibility pilot study; to set up intensive collaboration with referring pediatricians; to arrange support of a clinical trials unit and a local research nurse during the complete trial period; and to incorporate the possibility of extending the recruitment period. Major investments, both financially from governmental organizations and in time, are imperative for independent RCTs in children.

Project description:BackgroundHealthcare decisions are ideally based on clinical trial results, published in study registries, as journal articles or summarized in secondary research articles. In this research project, we investigated the impact of academically and commercially sponsored clinical trials on medical practice by measuring the proportion of trials published and cited by systematic reviews and clinical guidelines.MethodsWe examined 691 multicenter, randomized controlled trials that started in 2005 or later and were completed by the end of 2016. To determine whether sponsorship/funding and place of conduct influence a trial's impact, we created four sub-cohorts of investigator initiated trials (IITs) and industry sponsored trials (ISTs): 120 IITs and 171 ISTs with German contribution compared to 200 IITs and 200 ISTs without German contribution. We balanced the groups for study phase and place of conduct. German IITs were funded by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), or by another non-commercial research organization. All other trials were drawn from the German Clinical Trials Register or ClinicalTrials.gov. We investigated, to what extent study characteristics were associated with publication and impact using multivariable logistic regressions.ResultsFor 80% of the 691 trials, results were published as result articles in a medical journal and/or study registry, 52% were cited by a systematic review, and 26% reached impact in a clinical guideline. Drug trials and larger trials were associated with a higher probability to be published and to have an impact than non-drug trials and smaller trials. Results of IITs were more often published as a journal article while results of ISTs were more often published in study registries. International ISTs less often gained impact by inclusion in systematic reviews or guidelines than IITs.ConclusionAn encouraging high proportion of the clinical trials were published, and a considerable proportion gained impact on clinical practice. However, there is still room for improvement. For publishing study results, study registries have become an alternative or complement to journal articles, especially for ISTs. IITs funded by governmental bodies in Germany reached an impact that is comparable to international IITs and ISTs.

Dataset Information

Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations.

Publications

Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations.

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