Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Koenig, Franz; Spiertz, Cécile; Millar, Daniel; Rodríguez-Navarro, Sarai; Machín, Núria; Van Dessel, Ann; Genescà, Joan; Pericàs, Juan M.; Posch, Martin; Sánchez-Montalva, Adrian; Estevez, Ana Belén; Sánchez, Àlex; Sanjuan, Anna; Sena, Elena; Granados, Emma; Arévalo de Andrés, Esther; Nuñez, Fátima; Arteaga, Gara; Fuentes Ruiz, Gabriela Perez; Fernández, Guillermo; Rivera-Esteban, Jesus; Comella, Joan; Ramos-Quiroga, Josep Antoni; Genescà, Joan; Espinosa, Juan; Pericàs, Juan Manuel; Murcia, Lada; Cash-Gibson, Lucinda; de Valles Silvosa, Maria; Barroso de Sousa, María Fernanda; Sánchez-Maroto Carrizo, Olga; Ibañez-Jiménez, Pol; Augustin, Salvador; Perez-Hoyos, Santiago; Rodríguez-Navarro, Sarai; Muñoz-Martínez, Sergio; Serres, Silvia; Kalko, Susana; Michon, Amelie; Ussi, Anton; Lydall, Ben; van de Ketterij, Edwin; Quiles, Ignacio; Carapina, Tamara; Kumaus, Constantin; Ramazanova, Dariga; Meyer, Elias Laurin; Koenig, Franz; Roig, Marta Bofill; Brunner, Martin; Posch, Martin; Krotka, Pavla; Zehetmayer, Sonja; Carton, Charlotte; Legius, Eric; Begum, Amina; Pariante, Carmine; Worrell, Courtney; Lombardo, Giulia; Sforzini, Luca; Brown, Mollie; Gullet, Nancy; Amasi-Hartoonian, Nare; Ferner, Rosalie; Kose, Melisa; Spitaleri, Andrea; Ghodousi, Arash; Di Serio, Clelia; Cirillo, Daniela; Cugnata, Federica; Saluzzo, Francesca; Benedetti, Francesco; Scarale, Maria Giovanna; Zini, Michela; Rancoita, Paola Maria; Alagna, Riccardo; Poletti, Sara; Dhaenens, Britt; Van Der Lei, Johan; de Steenwinkel, Jurriaan; Moinat, Maxim; Oostenbrink, Rianne; Hoogendijk, Witte; Hölscher, Michael; Heinrich, Norbert; Otte, Christian; Potratz, Cornelia; Zocholl, Dario; Kulakova, Eugenia; Tacke, Frank; Brasanac, Jelena; Leubner, Jonas; Krajewska, Maja; Freitag, Michaela Maria; Gold, Stefan; Zoller, Thomas; Chae, Woo Ri; Daniel, Christel; Kara, Leila; Vaterkowski, Morgan; Griffon, Nicolas; Wolkenstein, Pierre; Pais, Raluca; Ratziu, Vlad; Voets, David; Maes, Christophe; Kalra, Dipak; Thienpoint, Geert; Deckerck, Jens; Lea, Nathan; Singleton, Peter; Viele, Kert; Jacko, Peter; Berry, Scott; Parke, Tom; Michon, Amelie; Aydin, Burç; Kubiak, Christine; Demotes, Jacques; Ueda, Keiko; Matei, Mihaela; Contrino, Sergio; Röhl, Claas; Cordero, Estefania; Greenhalgh, Fiona; Jarke, Hannes; Angelova, Juliana; Boudes, Mathieu; Dressler, Stephan; Strammiello, Valentina; Anstee, Quentin; Gutierrez-Ibarluzea, Iñaki; Otte, Maximilian; Heimbach, Natalie; Hofner, Benjamin; Burgwinkel, Cora; Kaestel, Hue; Hees, Katharina; Nguyen, Quynh; Prieto-Alhambra, Daniel; Tan, Eng Hooi (Cheryl); Raviglione, Mario; de Colombani, Pierpaolo; Villa, Simone; Maron, Eduard; Evans, Gareth; Savitz, Adam J.; Van Dessel, Ann; Duca, Anna; Kaminski, Anne; Wouters, Bie; Porter, Brandon; Charron, Catherine; Spiertz, Cecile; Zizzamia, Christopher; Millar, Daniel; Hasselbaink, Danny; Orr, David; Kesters, Divya; Hubin, Ellen; Davies, Emma; Didden, Eva-Maria; Guz, Gabriela; Verstraete, Evelyn; Mao, Gary; Capuano, George; Martynowicz, Heddie; De Smedt, Heidi; Larsson, Ingela; Bruegelmans, Ines; Coste, Isabelle; Gonzalez Moreno, Jesus Maria; Niewczas, Julia; Xu, Jiajun; Rombouts, Karin; Woo, Katherine; Wuyts, Kathleen; Hersh, Kathryn; Oldenburg, Khrista; Zhang, Lingjiao; Schmidt, Mark; Szuch, Mark; Todorovic, Marija; Mangelaars, Maartje; Grewal, Melissa; Sandor, Molli; Di Prospero, Nick; Van Houten, Pamela; Minnick, Pansy; Bastos, Polyana; Patrizi, Robert; Morello, Salvatore; De Wilde, Severijn; Sun, Tao; Kline, Timothy; de Marez, Tine; Mielke, Tobias; Reijns, Tom; Popova, Vanina; Flossbach, Yanina; Tymofyeyev, Yevgen; De Groote, Zeger; Sverdlov, Alex; Bobirca, Alexandra; Krause, Annekatrin; Bobrica, Catalin; Heintz, Daniela; Magirr, Dominic; Glimm, Ekkehard; Baffert, Fabienne; Castiglione, Federica; Caruso, Franca; Patalano, Francesco; Bretz, Frank; Heimann, Guenter; Carbarns, Ian; Rodríguez, Ignacio; Ratescu, Ioana; Hampson, Lisa; Pedrosa, Marcos; Hark, Mareile; Mesenbrink, Peter; Penna, Sabina Hernandez; Bergues-Lang, Sarah; Baltes-Engler, Susanne; Arsiwala, Tasneem; Mondragon, Valeria Jordan; Guo, Hua; Da Costa, Jose Leite; Burman, Carl-Fredrik; Kirk, George; Aaes-Jørgensen, Anders; Dirach, Jorgen; Kjær, Mette Skalshøi; Martin, Alexandra; Hristov, Diyan; Rousseaux, Florent; Hittel, Norbert; Dornheim, Robert; Evans, Daniel; Sykes, Nick; Couvert, Camille; Leuven, Catherine; Notelet, Loïc; Gidh-Jain, Madhavi; Jouannin, Mathieu; Ammour, Nadir; Pierre, Suzanne; Haufe, Volker; Dong, Yingwen; Dubanchet, Catherine; de Préville, Nathalie; Baltauss, Tania; Jian, Zhu; Shnider, Sara; Bar-El, Tal; Bakker, Annette; Nievo, Marco; Iloeje, Uche; Conradie, Almari; Auffarrth, Ece; Lombard, Leandra; Benhayoun, Majda; Olugbosi, Morounfolu; Seidel, Stephanie S.; Gumí, Berta; Guzmán, Claudia García; Molero, Eva; Pairó, Gisela; Machin, Núria; Cardelús, Raimon; Ramasastry, Saira; Pelzer, Saskia; Kremer, Andreas; Lindfors, Erno; Lynch, Chris

doi:10.1016/j.eclinm.2023.102384

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…EU-PEARL had the ambition of transforming the current approach of conducting single-compound clinical trials into the use of cross-company integrated research platforms (IRPs) designed as a framework to conduct platform trials, taking into consideration both patients' interests and the opportunities from novel treatments for addressing medical needs. 1,2 In a platform trial, multiple treatments can be studied in a perpetual manner, with treatments allowed to enter or leave the platform during the ongoing trial. 3 Patient-centric data and knowledge sharing have the potential to accelerate the development of new treatments and to reduce the operational costs of clinical trials.…”

Section: Regulatory Issues Of Platform Trials: Learnings From Eu-pearlmentioning

confidence: 99%

“…Next steps for academics and industry to foster multistakeholder trials Recently, Koenig et al 2 summarized 10 learnings from EU-PEARL. The lack of sufficient regulatory guidance is considered as one obstacle.…”

Section: Conclusion and Next Stepsmentioning

confidence: 99%

“…Yet, especially for multistakeholder platform trials, this is not the main blocking issue. Independent sponsors, for example, contract research organizations or, as Koenig et al 2 suggest, academic hospitals, are needed to facilitate these trials. They state that additional efforts are needed to pave the route for such academic sponsors of (complex) clinical trials.…”

Section: Conclusion and Next Stepsmentioning

confidence: 99%

“…Sharing of data is identified as another issue. 2 The use of shared concurrent controls and especially shared NCCs leads to partial unblinding and information leakage once an arm is completed. This could lead to regulatory concerns.…”

Section: Conclusion and Next Stepsmentioning

confidence: 99%

“…72 Of note, comparisons of treatments might be of high interest to patients and payers. 2,18,73 Although this should be taken into consideration, this should not additionally hamper the uptake of platform trials. One should rather embrace the benefits which are there than asking for more.…”

Section: Reviewmentioning

confidence: 99%

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Regulatory Issues of Platform Trials: Learnings from EU‐PEARL

Nguyen,

Hees,

Hernandez Penna

et al. 2024

Clin Pharma and Therapeutics

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Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient‐Centric Clinical Trial Platforms (EU‐PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non‐concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient‐centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

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Section: Regulatory Issues Of Platform Trials: Learnings From Eu-pearlmentioning

confidence: 99%

Section: Conclusion and Next Stepsmentioning

confidence: 99%

Section: Conclusion and Next Stepsmentioning

confidence: 99%

Section: Conclusion and Next Stepsmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

See 3 more Smart Citations

Regulatory Issues of Platform Trials: Learnings from EU‐PEARL

Nguyen,

Hees,

Hernandez Penna

et al. 2024

Clin Pharma and Therapeutics

Self Cite

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Enhancing External Control Arm Analyses through Data Calibration and Hybrid Designs

Schneeweiss

2024

Clin Pharma and Therapeutics

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Almost all external control arm analyses to contextualize findings of a single arm trial struggle with two key issues: the lack of baseline randomization, and equally important, the difference in data collection between the experimental arm with its primary data collection, and the external control arm using secondary data. We illustrate the data calibration design to remedy issues arising from differential measurements in the two arms, and discuss the hybrid design that expands an underpowered randomized internal control arm with real‐world data to mitigate the lack of randomization of the external control arm. We show how the two approaches fit into an evidence‐development strategy that naturally builds on the incremental insights gained.

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Innovative approaches for vaccine trials as a key component of pandemic preparedness – a white paper

Bethe,

Pana,

Drosten

et al. 2024

Infection

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Background WHO postulates the application of adaptive design features in the global clinical trial ecosystem. However, the adaptive platform trial (APT) methodology has not been widely adopted in clinical research on vaccines. Methods The VACCELERATE Consortium organized a two-day workshop to discuss the applicability of APT methodology in vaccine trials under non-pandemic as well as pandemic conditions. Core aspects of the discussions are summarized in this article. Results An “ever-warm” APT appears ideally suited to improve efficiency and speed of vaccine research. Continuous learning based on accumulating APT trial data allows for pre-planned adaptations during its course. Given the relative design complexity, alignment of all stakeholders at all stages of an APT is central. Vaccine trial modelling is crucial, both before and in a pandemic emergency. Various inferential paradigms are possible (frequentist, likelihood, or Bayesian). The focus in the interpandemic interval may be on research gaps left by industry trials. For activation in emergency, template Disease X protocols of syndromal design for pathogens yet unknown need to be stockpiled and updated regularly. Governance of a vaccine APT should be fully integrated into supranational pandemic response mechanisms. Discussion A broad range of adaptive features can be applied in platform trials on vaccines. Faster knowledge generation comes with increased complexity of trial design. Design complexity should not preclude simple execution at trial sites. Continuously generated evidence represents a return on investment that will garner societal support for sustainable funding. Adaptive design features will naturally find their way into platform trials on vaccines.

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Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Cited by 11 publications

References 32 publications

Regulatory Issues of Platform Trials: Learnings from EU‐PEARL

Regulatory Issues of Platform Trials: Learnings from EU‐PEARL

Enhancing External Control Arm Analyses through Data Calibration and Hybrid Designs

Innovative approaches for vaccine trials as a key component of pandemic preparedness – a white paper

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