The FDA's Outlook on Microphysiological systems (MPS)

By Vijayalakshmidevi

Abstract

FDA seeks to promote new advancements in tissue engineering that enable predicting human and animal responses in artificial systems, saving time, money, increasing efficiency and reducing vivisection. FDA has provided regulatory guidelines that support the Micro-Physiological systems (MPS) for determining the efficacy of the new drug.


Background

In a survey of 14 large pharmaceutical companies, it was found that 24 candidate drugs were needed to yield one commercial product. More than 45% of failures occurred in the three clinical phases of drug development, highlighting the need for better systems for preclinical testing (Ku, et al.,2015).

Figure 1: Success rate by development stage for new drugs (reproduced from Ku etal.2015)


Advances in systems biology, stem cells, tissue engineering, and mathematical modeling are creating unique opportunities to improve FDA's predictive ability, potentially enhancing our ability to predict risk and efficacy. The FDA-regulated products for these innovative technologies help to market faster, with improved efficacy, or prevent products with increased toxicological risk from reaching the market. These advanced technologies aid to replace, reduce, and/or refine animal testing. 


Role of FDA in Supporting New In Vitro and In Vivo Methods

FDA has provided  FDA Predictive Toxicology Roadmap, and have its Alternative Methods Working Group (Alternative Methods Group) to discuss new FDA-wide new in vitro, in vivo, and silico methods, by providing research support, and communication by interacting with FDA stakeholders to explore regulatory science applications for these new technologies. Microphysiological systems, organs-on-chip, organoids, and physiological cellular microsystems are different classes of micro-engineered cellular systems that are fabricated miniature structures at micrometer scales or smaller. FDA also helps to identify the performance criteria of microphysiological systems/organ-o-chip models by engaging with FDA experts and stakeholders through public-private partnerships.

Figure 2: Reproduced from Advancing Alternative Methods at FDA


FDA's Alternative Methods Group support information for alternative methods instead of routine toxicity and efficacy testing by supporting alternative systems (in vitro, in vivo, in silico, and systems toxicology modeling) to bring new insights into regulatory toxicology. They undergo a regulatory review of the risk, safety, and efficacy of FDA-regulated products.


In 2021, the FDA has approved Human Intestinal Organoids/Colonoids Cell Line FDA_SS_1238931 (The John Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218) to provide their services per FAR part 6.302‐1. Human Intestinal Organoids/Colonoids Cell Line is capable of long-term primary intestinal epithelial cell culture recapitulating the structure and function of intestinal physiology after multiple passages.

The approval of organoids by the FDA was suvject to the following requirements:
  • To provide Human organoid/colonoids cultures derived from male and/or female adult healthy donors that recapitulate the normal organ physiology, with limited genetic or physiologic alterations, even after many generations. 
  • Shall provide three (3) separate colonoids to ensure consistency 
  • Shall provide cells from the distal colon.
  • Shall not have a cell line that results in a significant change in physiology and structure upon long‐term propagation of the intestinal colonoid/organoid
  • Shall have intestinal colonoids/organoids to be grown undifferentiated to mimic intestinal epithelial cells (IECs) in the crypt or differentiated to mimic villus cells composed of mature colonocytes, enteroendocrine cells, and goblet cells.
  • Shall have colonic organoids that can create a mucus layer.
  • Shall have colonoids to be grown as monolayers with apical and basolateral surfaces. 
  • Shall have the ability to withstand fluid shear stress and repetitive mechanical deformation (2‐10% cell strain, 0.1‐0.2Hz frequency) in monolayer culture form.
  • Shall have the colonoids be free from any contamination.
  • Shall provide a cell line previously demonstrated on the Emulate system.
  • Shall have a lab that has Institutional Review Board (IRB) approval for the organoids and provide documentation
  •  Shall provide information for proper delivery and storage.
  • Shall provide storage temperature recommendations.
  • Shall provide virtual training on the handling of the cell line for up to three (3) End Users.
  • Shall have the ability to replace colonoids that do not meet the requirements within three (3) weeks of notification.
  • Shall provide one (1) year warranty from date of acceptance.
When an organoid meets these requirements may submit a written capability statement to FDA that supports and demonstrates their ability to perform the requirements which will be reviewed by FDA for approval.

Conclusion

FDA support in evaluating cellular microsystems platforms that replicate human physiology and can advance drug development and evaluation by detecting drug liabilities early in preclinical drug testing which will hasten the clinical trials studies, develop medical countermeasures to public health emergencies, and enable therapies to treat rare diseases.

References:
  1. Ku, MS, 2015, Recent Trends in Specialty Pharma Business Model, J Food Drug Anal, 23 (4):595-608.
  2. https://www.fda.gov/science-research/about-science-research-fda/advancing-alternative-methods-fda
  3. https://www.fda.gov/science-research/about-science-research-fda/publications-co-authored-fda-alternative-methods
  4. https://www.fda.gov/drugs/regulatory-science-action/impact-story-evaluating-potential-microengineered-human-cellular-systems-predict-drug-effects-clinic
  5. https://www.fda.gov/media/146018/download