Alternative strategies in cardiac preclinical research and new clinical trial formats
Open accessAbstract
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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The output of the drug discovery pipeline has significantly declined in recent decades primarily due to the lack of appropriate cardiac pre-clinical models.
“Despite the urgent need to develop new drugs to treat CVDs, the output of the drug discovery pipeline has significantly declined in recent decades (Fordyce et al., 2015) primarily due to the lack of appropriate cardiac pre-clinical models (Kreutzer et al., 2022).”
From A human engineered mini-heart platform for mimicking ventricular pump function (2025) · cites this paper as Kreutzer et al., 2022
The Introduction links clinical-trial failures to limited predictability and transferability of preclinical research, and §2.2 explains why rodent cardiac models may poorly predict human outcomes. But the paper says this link is suggested by a lack of efficacy; it does not establish inadequate cardiac models as the primary cause of low drug-development output. The Introduction also identifies costs, funding, and low expectations of success as obstacles. (LLM, conf=0.86)
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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
- 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
- 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
- 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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