Cited by 36Animal testing and alternatives3D Printing in Biomedical ResearchStatistical Methods in Clinical Trials

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Alternative strategies in cardiac preclinical research and new clinical trial formats

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Kreutzer, Fabian Philipp, Meinecke, Anna, Schmidt, Kevin, Fiedler, Jan, Thum, Thomas·2022·Cardiovascular Research

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Abstract

An efficient and safe drug development process is crucial for the establishment of new drugs on the market aiming to increase quality of life and life-span of our patients. Despite technological advances in the past decade, successful launches of drug candidates per year remain low. We here give an overview about some of these advances and suggest improvements for implementation to boost preclinical and clinical drug development with a focus on the cardiovascular field. We highlight advantages and disadvantages of animal experimentation and thoroughly review alternatives in the field of three-dimensional cell culture as well as preclinical use of spheroids and organoids. Microfluidic devices and their potential as organ-on-a-chip systems, as well as the use of living animal and human cardiac tissues are additionally introduced. In the second part, we examine recent gold standard randomized clinical trials and present possible modifications to increase lead candidate throughput: adaptive designs, master protocols, and drug repurposing. In silico and N-of-1 trials have the potential to redefine clinical drug candidate evaluation. Finally, we briefly discuss clinical trial designs during pandemic times.

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Figure 1 Alternatives to 2D cell culture and animal models. (A) Traditional 2D cell culture usually has low predictivity of human physiology. (B) To investigate systemic effects, small and large animal models used, but due to limited representation of human physiology and disease in animals resemblance is limited. (C,D) 3D cell culture methods improve on several parameters and have to be chosen according to the research question. (E) The explantation of tissue from adult animals or humans preserves multicellular tissue structure and maturity. (F) All previous systems can be combined with microfluidic devices to generate organ-on-a-chip systems. If Chips of multiple organ are combined, limited systemic responses can be modelled. (G) The response seen in human often differs from animal data, but novel methods (C–F) can improve predictability.CC BY-NC · PubMed Central

Figure 2 Advancements in clinical trial structure. (A) While traditional clinical designs display long approval procedures in all three phases (cross-hatchings in the figure), several designs can shorten this process and rise efficacy of clinical trials. (B) Adaptive design allows to combine two phases in a single application and can include interim analyses to adapt the trial on-the-go. (C,D) Master protocols can investigate several interventions (umbrella design) or diseases (basket design) or subgroups (platform design) in parallel. As special cases, (E) N-of-1 trials investigate only one subject and (F) pandemic trials follow a shortened procedure due to the emergency pandemic situation.CC BY-NC · PubMed Central

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Authors: Kreutzer, F. P., Meinecke, A., Schmidt, K., Fiedler, J., & Thum, T.
Affiliations: Medizinische Hochschule Hannover (DE)
Corresponding author: Thum, Thomas
ORCID: Kreutzer, Fabian Philipp
Meinecke, Anna
Fiedler, Jan
Thum, Thomas
Venue: Cardiovascular Research
Publisher: Oxford University Press (OUP)
Published: 2021-03-08
Volume: 118
Issue: 3
Pages: 746-762
ISSN: 0008-6363 (ISSN-L)
1755-3245
DOI: 10.1093/cvr/cvab075
PMC: PMC7989574
OpenAlex: W3135746472
Cited by: 36
References: 255
Citations by year: 2026: 7 · 2025: 9 · 2024: 6 · 2023: 8 · 2022: 4 · 2021: 2
FWCI: 0.99
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (vor)
Locations: Cardiovascular Research (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
Funders: CARDINAL (Deutsche Forschungsgemeinschaft (316872437)
CardioREGenix (European Union (EU) Horizon (2020 #825670)
Cardiovascular ncRNA (Transregio (267, DFG #403584255)
Topics: Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Keywords: cardiovascular drug development, alternatives to animal testing, 3D cell culture, spheroids, organoids, microfluidics, organ-on-a-chip, adaptive trial design, master protocols, drug repurposing, in silico clinical trials, N-of-1 trials
MeSH terms: Animals, Clinical Trials as Topic, Drug Evaluation, Preclinical, Heart, Humans, Organoids, Quality of Life, Lab-On-A-Chip Devices

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Alternative strategies in cardiac preclinical research and new clinical trial formats

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