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

The DOI matches its Crossref record; 252 of the 255 references it cites were found in a registry or an index.

Alternative strategies in cardiac preclinical research and new clinical trial formats

Open access
Kreutzer, Fabian Philipp, Meinecke, Anna, Schmidt, Kevin, Fiedler, Jan, Thum, Thomas·2022·Cardiovascular Research
DOI 10.1093/cvr/cvab075PMC PMC7989574
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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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Crossref · 10.1093/cvr/cvab075

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Graphical abstract CC BY-NC · PubMed Central
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.
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.
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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Metadata

Authors
Kreutzer, F. P., Meinecke, A., Schmidt, K., Fiedler, J., & Thum, T.
Affiliations
Medizinische Hochschule Hannover (DE)
Corresponding author
Thum, Thomas
ORCID
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
Licence
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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