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FDA Modernization Act

and the Opportunity for Microphysiological Systems (MPS) and ALine’s Contributions to this Pioneering Field

Leanna Levine, Ph.D. and Stefano Begolo, Ph.D.
October 13, 2023

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Insights into the Future of MPS

The purpose of this blog is to provide the context and links to resources that offer insights into the future for Microphysiological Systems (MPS).

It is an exciting and active time to realize the promise of these systems to vastly improve the safety and efficacy of new therapeutics, while creating opportunties to replace, reduce and refine (3Rs) the use of animal models.

FDA Modernization Act Changes

FDA Modernization Act Section 2 “New Approach Methodologies”

There has been a small but significant change to the language in the Act passed by Congress in 2021. Under Section 2 of the Bill, Titled “New Approach Methodologies”, a small but significant change in the language was made to Section 505 by striking reference to “Animal” and “preclinical tests (including tests on animals)” and inserting Non-clinical Tests or Studies.

The bill goes on to define what a “non-clinical test or study” is:

“…the term ‘nonclinical test or study’ means a test or study conducted in vitro, in silico, in chemico or in vivo that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug, and may include the following:

(1) Cell based assays
(2) Organ chips and microphysiological systems
(3) Computer models
(4) Other non-animal or human biology-based test methods
(5) Animal tests”

Incredible Advancement

The acknowledgement and support for the use of these new tools is an incredible advancement for the pharmaceutical discovery and development process. Research in the development of these systems will move beyond fundamental research into the realm of predictive science. This is the realization of a moonlanding in biological research.

Fundamental Science

Not only will these new methodologies reduce the use of animal testing in the future, it will improve the candidates that move forward to human clinical trials. It is a time where fundamental science begins to truly impact human society.

The Challenge

The challenge now is to advance the science toward the development of guidances and protocols that will enable the replacement, reduction, and refinement of animal models (3Rs) using these tools. The is a new and complex challenge for the FDA because each MPS, which organs and tissues are used, and how the device and tests are designed with each tissue/cell type, will impact how they can be validated.

FDA Modernization Act 2022 Amendment

In 2022, an amendment to the FDA Modernization Act includes the following under ‘Title VII – Research, Development, and Supply Chain Improvements, Subtitle A – In General’:

“Section 702

(a) Establishes a program to support the adoption and improve the development of, innovative approaches to drug product design and manufacture. And

(b) issue and update guidances to facilitate the adoption of innovative approaches to drug product design and manufacture.

To support this effort $20MM has been apropriated for each fiscal year 2023 through 2027.

The effort for the next five years, with $20MM in programmatic funding, is to work with companies and researchers to explore and develop guidances on the use of MPS.

Today’s Regulatory Environment

As of now, there are no specific regulatory guidelines solely dedicated to microphysiological systems (MPS). But the need for validation studies, data comparability, and regulatory acceptance of these methods has been highlighted.

While specific guidelines for MPS are still evolving, regulatory agencies are engaging with stakeholders, conducting pilot studies, and working towards establishing a framework for the acceptance and regulatory use of MPS data.

Collaboration between regulators, industry, and researchers is crucial in shaping future guidelines for MPS in drug development.

Sources of Interest

Taken together, these resources provide researchers an overview of the frameworks and agencies engaged in this important work.

Advancing New Alternative Methods at FDA

In June of 2023 at the MPS World Summit in Berlin, Dr. Donna Mendrick gave an overview presentation about the Working Groups and Center Activities for CDER, CBER, CFSPA, CVM, NCTR in her presentation titled “Advancing New Alternative Methods at FDA”.

One interesting highlight from The FDA’s Advancing Alternative Methods Working Group is the need for animal MPS for a variety of reasons including:

1) gaining confidence in human MPS by using in vivo to animal MPS to build confidence in performance and predictive capabiltiy of these systems (e.g. multispecies liver chips, and

2) for the development of animal drugs and being prepared to understand infectious diseases which zoonotic in nature.(e.g. bat, canine, and human MPS for SARS-Co-2.

Advancing New Alternative Methods Working Group

The Advancing Alternative Methods at FDA working group offers information links to Webinars, Roadmaps and Reports, engages with stakeholders and develops partnerships to explore regulatory science applications for ‘nonclinical tests or studies’.

IQ MPS Affiliate Working Group

Other interesting sources to review includes the meeting report from the IQ MPS Affiliate working group that is part of the International Consortium for Innovation & Quality in Pharmaceutical Development (IQ). Stakeholders include over 20 biomedical and pharmaceutical companies as well as participants from the FDA CBER, CDER, CFSAN, CVM, NCTR.

CDRH Guidance Document

A presentation that summarizes a guidance document published in 2017 by CDRH provides for a process for Qualification of Medical Device Development Tools, defined as a method, material, or measurement to assess effectiveness, safety, or performance of a medical device that has been scientifically validated and can be qualified for use in device evaluation and support regulatory decision-making.

NIH & FDA Memorandum of Understanding (MOU)

A final resource to review that is an important part of the MPS ecosystem is the MOU between the NIH (NCATS) and FDA whose purpose is to create a framework for their “…common interest and goal to accelerate the translational use ofMicrophsyiological Systems (MPS) as a New Approach Methodologies (NAMs), so that NAMs may help bring FDA-regulated products to market faster, with improved efficacy, or prevent products with increased harmful risk from reaching the market. Translation and adoption of NAMs could also contribute to advances to replace, reduce, and/or refine animal testing “.

Taken together, these resources provide researchers an overview of the frameworks and agencies engaged in this important work.

ALine's Contributions to This Exciting Process

We at ALine have been grateful to participate in this exciting process with several research and development groups, in particular supporting integration of porous membranes and transfer to processes and materials compatible with high volume manufacturing.

ALine Microfluidics Cartridges Video
Etched Membranes
  • ALine routinely integrates off the shelf track etched membranes in microfluidic devices. These membranes can be used to mimic the structure of organs and tissues, by acting as physical barriers between cell populations, while allowing exchange of chemical signals and nutrients. ALine demonstrated this approach by producing microfluidic devices for culture or rat Hepatocytes (https://pubmed.ncbi.nlm.nih.gov/26152452/), and now offers a customizable Two chamber Organ-on-Chip design as a standard product (https://www.alineinc.com/our-products/organ-on-chip/)
ALine Rapid Manufacture Process
Micro-SIMs
  • ALine has supported the development and manufacturing of the Micro-SIMs, microfluidic devices that integrate ultrathin silicon nanomembranes. This work has been performed in collaboration with Prof. James McGrath’s lab at the University of Rochester, and applied among others for modeling Blood-brain-barrier (https://pubmed.ncbi.nlm.nih.gov/36982697/), culture and alignment of endothelial cells (https://pubmed.ncbi.nlm.nih.gov/35953453/) and studying bacterial infection of bone tissues (https://pubmed.ncbi.nlm.nih.gov/34484165/). These modular devices are commercialized by SIMpore and can be assembled directly by the end users.
ALine Microfluidics in Cell Cultures
Thermoplastics
  • As part of an NIH funded program, ALine has also recently supported evaluation of thermoplastic materials to replace the silicones (PMDS) typically used in academic labs for producing Organ-on-Chip devices. The goal of this project was to identify alternative materials, characterize them for the relevant properties (e.g. biocompatibility, optical transparency, mechanical properties) and use the best candidates for producing existing organ on chip designs to test organ-on-chip applications with academic collaborators.

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