Amid the Surge in Animal Testing Alternatives, Two Critical Challenges Dominate the Organoid Industry

Over the past decade, the development of organoids has been regarded as one of the most exciting advances in stem cell research. Since the Hans Clevers laboratory first cultured intestinal organoids in 2009, organoid technology has advanced rapidly. In recent years, China has continuously strengthened its expertise and resources in organoid research, and the application prospects of organoid technology have been highlighted in the National Key R&D Program during the 14th Five-Year Plan period. Although a fully formed domestic organoid industry cluster has not yet emerged, a number of innovative companies have already arisen.

Organoids hold immense potential in basic research, clinical diagnosis and treatment research, and regenerative medicine. However, the industry as a whole remains in its early developmental stage, with one of the primary challenges being the lack of mature industry standards. If standardized protocols for organoids can be established and subsequently incorporated into clinical practice guidelines or even covered by medical insurance, organoid technology would gain greater recognition among downstream clients, thereby paving the way for broader commercialization pathways.

To what extent can organoids replace animal models in the future, and how far has this field progressed? How can industry standards for organoids be established to meet industrialization requirements and persuade downstream customers, including pharmaceutical companies?Recently, VCBeat New Medicine and Yeasen Biotechnology jointly invited organoid-focused startups and end-users of organoid technologies to compare the development of the organoid sector in China and abroad, and to discuss the two most pressing issues in the industry.

Guests participating in the discussion included: Chen Rui, Head of the Phase I Ward at the Clinical Pharmacology Research Center of Peking Union Medical College Hospital; Fu Peng, Assistant President of Saifu Pharmaceutical Group; Hua Guoqiang, Founder and Chairman of Danwang Medical; Zhou Yu, Co-founder and CEO of Daxiang Technology; and Rao Guiqiang, Product Director of Yeasen Biotechnology.

In August, the FDA approved the world’s first new drug to enter clinical trials based on preclinical data derived from organ-on-a-chip studies. This decision not only reflects the drug developer’s confidence in the data provided by organ-on-a-chip research but also demonstrates the FDA’s recognition of the credibility of such research.

In late September, the U.S. Senate unanimously passed the FDA Modernization Act, which aims to eliminate the federal mandate for animal testing of new drugs and could significantly reduce the use of laboratory animals in the coming years.

From Laboratory Techniques to Applications: To What Extent Can Organoids Replace Animal Models in the Future? Where Does the Organoid Sector Stand Today?

Chen Rui | Peking Union Medical College Hospital:China has seen a significant increase in the development of original drugs over the past 5 to 10 years, and we currently have a substantial number of first-in-class drug candidates in our pipeline. I believe that regarding this trend,The construction of animal models faces greater challenges.

For the development of original drugs, it is necessary to use animal models to obtain evidence of efficacy, as there are no comparable drugs to serve as references. Additionally, establishing a translational bridge from animals to humans is crucial, particularly in extrapolating human data from animal data. In pharmacokinetics, certain metabolic pathways can be predicted with high accuracy—often exceeding 90%—when translating from animals to humans; however, in other cases, the metabolic enzymes involved differ completely between animals and humans.

In the increasingly crowded field of fast-follow drug development, time is money. If organoid models can be standardized and normalized to streamline the IND application process, while ensuring that the resulting data are credible, compliant, and reliable, they would become a highly competitive advantage.

Zhou Yu | Daxiang:Whether it be organoids, organ-on-a-chip, or organoid-on-a-chip systems, I believe that the replacement of animal models with these new technological platforms is an inevitable trend, although this transition will necessarily occur through a gradual, step-by-step process.

First, there is a wide variety of animal models available, and numerous modeling methods are well-established, making them the primary tools and approaches for non-clinical research at present. Second, regulatory agencies require time to recognize and accept new technologies. I believe that as data from organ-on-a-chip systems continue to accumulate, along with growing evidence from drug validation studies,This cognitive shift is accelerating. Currently, organ-on-a-chip technology may serve as a complementary alternative to animal models, but I believe it will evolve into a direct replacement in the future.

The application of organoid technology will initially focus on scenarios where suitable animal models are lacking, difficult to establish, or exhibit disease phenotypes that differ significantly from those in humans.

Hua Guoqiang | Danwang Medical:The recent publication of clinical validation data from some top-tier hospitals both domestically and internationally has significantly accelerated the industrialization of the organoid field.If we were to assess the developmental stage of organoids as a whole, I would liken it to next-generation sequencing (NGS) in 2014 or 2015.Hans Clevers, the pioneer of organoids, defines organoids as NGD, i.e., Next Generation Diagnosis,Compared with NGS, NGD is in a more rapid growth phase.

Organoid product customers are primarily laboratories or individuals at universities, hospitals, and research institutions, as well as pharmaceutical companies.The key to a product lies in its scalability and industrialization; stability levels and production costs are core competitive advantages for organoid companies. However, the lack of mature industry standards for organoids also affects downstream customers’ acceptance of these products.

How Should We Evaluate Organoid Products? What Are the Current Industry Efforts Toward Standardization?

Hua Guoqiang | Danwang Medical:Any robust disease model should be evaluated using specific metrics and parameters, and organoids are no exception.Evaluating the quality of an organoid model also requires consideration of its application scenarios, of which there are primarily two for organoids.

One scenario involves predicting clinical drug responses using patient-derived organoids. The most critical evaluation metrics are the similarity to in vivo samples and the concordance with clinical efficacy.

Secondly, the application of organoid models in basic drug screening requires ensuring their validity and stability, necessitating the establishment of standards and parameters for the entire organoid model preparation workflow. This includes standards for clinical sample transportation, clinical sample quality, sample preparation, and culture conditions, as well as drug sensitivity parameters for clinical trials. Determining how to assess organoid sensitivity and defining cutoff values are critical for the standardization of organoid models.

Zhou Yu | Daxiang:A critical aspect of organ-on-a-chip standardization lies in the standardization of model functionality. In the application of organ-on-a-chip technology, international pharmaceutical companies have established the IQ Consortium, which has published several articles in recent years defining functional metrics for organ-on-a-chip models, such as those representing the intestine, liver, lung, and kidney.

For example, a critical function of the liver is metabolism, which involves the secretion of products such as albumin and urea. Therefore, in an in vitro cellular model, it is crucial to assess whether the expression levels of these products remain stable during cell culture or testing processes.

What functional metrics are required for organoid models, and to what extent must these metrics be met for the models to be integrated into pharmaceutical companies’ R&D pipelines? In fact, such standards already exist; although they have not yet received regulatory or official accreditation, they can serve as reference benchmarks during model development.

At the application level, organ-on-a-chip or organoid-on-a-chip technologies serve as evaluation models and tools. Industrial clients place great emphasis on the stability and reproducibility of their results. Therefore, the systems we develop must exhibit high stability and meet the fundamental requirements for drug screening, such as maintaining a sufficiently low coefficient of variation (CV) and a sufficiently high Z-factor.

What characteristics of organoid products do pharmaceutical companies value most?

Hua Guoqiang | Danwang Medical:In our current collaborations with several leading domestic pharmaceutical companies, we have identified diverse needs for organoids at various stages of the drug development process.For instance, some pharmaceutical companies collaborate with us on drug target models based on specific gene mutations; others validate compound efficacy using specific organoids; and a further group is taking more advanced steps by conducting organoid-based clinical trials.Danwang Medical maintains a substantial organoid library. In response to a pharmaceutical company’s request, approximately 100 organoids were selected from the library to simulate and evaluate the drug’s response rate in patient populations using human-derived organoid models.

I believe pharmaceutical companies exhibit high sensitivity to the application of organoids and impose stringent requirements on disease modeling:They will evaluate the quality system for organoids, including which hospitals the samples are sourced from, whether the sourcing is legitimate, any ethical issues, completeness of clinical data for drug screening, availability of drug tolerance data, and whether organoid models in the Biobank have been validated (including gene sequencing, pathology, etc.). Furthermore, they place greater emphasis on the stability of disease models after establishment.Pharmaceutical companies will thoroughly mine the data and also request the provision of additional new data,For instance, what is the actual stability of disease models within ten generations? Therefore, I believe that pharmaceutical companies have relatively high overall requirements for disease models.

As an emerging technology, organoids are far from perfect and require continuous iteration. They cannot yet fully replicate metabolic processes, such as blood metabolism in the human body, or the complex interactions between organs. Nevertheless, organoids hold immense potential and promise a bright future.

How should we view the broader application prospects of organoid technology? What competitive advantages will Chinese organoid companies have in terms of commercial growth?

Fu Peng | Saifu Pharmaceutical Group:In addition to in vitro organoids, the potential value of in vivo organoids as therapeutic agents represents a significant research direction. For instance, current published data suggest that islet organoids hold promise for improving blood glucose regulation.

In the field of retinal macular degeneration, drug delivery technology represents a significant barrier in the treatment of ophthalmic diseases, where organoids can also find applications. Furthermore, liver organoids are applicable in conditions such as hepatitis-induced liver failure, including non-alcoholic steatohepatitis (NASH). Therefore, I believe that organoids will hold substantial scientific and application value both in vitro and in vivo in the future.

Zhou Yu | Daxiang:I am personally very optimistic about the prospects of organoid technology. If the technology becomes more mature and costs continue to decline, could it be possible to make further progress?to evolve into a high-throughput drug discovery platform and play a more significant role in bridging clinical translation between animals and humans.

Chen Rui | Peking Union Medical College Hospital:I believe that organoid technology needs to persuade more people through practical cases, including researchers at scientific research institutions, doctors, and drug regulatory authorities.Such cases can also be oriented toward scientific research in the early stages, by developing organoid disease models for certain common or rare diseases, facilitating and accelerating drug screening, or gaining insights and results in mechanistic exploration.。"Using scientific research as a breakthrough point has broadened our horizons. If this can be achieved, I believe it will help more people understand organoids and promote their subsequent standardized and industrialized applications."

Hua Guoqiang | Danwang Medical:Compared with the organoid industry abroad, China’s primary advantage lies in its patient resources; due to its large population, there is a substantial and diverse supply of samples, constituting an excellent resource for biological specimens.

The second is cost advantage. Whether in terms of labor or the substitution of upstream products with domestically produced alternatives, the overall supply chain costs will be reduced.

Third, as the potentially largest market in the biopharmaceutical sector, China enjoys the advantage of scale. In clinical practice alone, there are millions of new cancer patients each year, representing an extremely large patient population, and the pharmaceutical market is growing at a very rapid pace.

Of course, policy aspects should not be overlooked either.The CDE’s Acceptance of Non-Animal Models, Such as Organoids, Is Increasing. Additionally,Due to restrictions under China’s human genetic resource regulations, it is difficult for companies with foreign investment backgrounds to collect patient samples and establish organoid model libraries. As a result, this sample repository remains relatively protected, which actually presents a favorable opportunity for domestic companies.