Computer-Based Modeling & Simulation: Not Just a Tool for Quicker Product Approval

b) Modeling and simulation in other industries

The use of computer models and simulation is widespread in other industries:

• Car manufacturers simulate crash tests. They use crash tests with real cars primarily for the validation and enhancement of computer models.
• The development of aircraft and the testing of their flight characteristics is initially carried out exclusively on computers.
• The weather forecast is based on computer models.
• Manufacturers calculate the mechanical properties of new products using methods such as the finite element method.

2. Application of computer-based modeling in medical technology

Computer-based modeling and simulation can be used by medical device manufacturers in all phases of a device's life cycle.

a) Development of medical devices

Manufacturers must justify the “solution chosen”

Laws such as the MDR and the IVDR require manufacturers to comply with the general safety and performance requirements. These include requirements for

• The mechanical, electrical, electromagnetic and biological safety of the devices
• Reliability and first-failure safety
• Compliance with the performance characteristics

Manufactures must justify why they have chosen a particular solution, e.g. a specific design:

“The documentation shall […] include a justification […] of the solutions adopted to meet those [general safety and performance] requirements.

MDR, Annex II, Chapter 4.

This justification will be particularly successful if manufacturers can demonstrate that other solutions are inferior to the chosen solution.

Modeling and simulation can be used for this

A very efficient way of doing this is to simulate alternative solutions on a computer and select the best option. These options involve the:

• Selection of materials
• Design of components, e.g., shape, material thickness
• Design and positioning of antennas
• Design of user interfaces

However, it’s not just the device itself that is modeled, the people using the device, including their anatomy and physiology, are also modeled.

b) Production

Some manufacturers use computer-based modeling to simulate production processes, e.g.:

• Filling of products
• Sterilization and disinfection
• Design of measuring systems

c) Verification, validation and authorization

The evidence that a medical device is safe and effective and provides the promised clinical benefits can be generated in part or in full using computer models.

In some cases, the FDA has even made a decision on the authorization of medical devices based exclusively on such models and simulations. This includes a device whose “MRI compatibility” had to be proven.

In addition, the FDA has authorized a device for “3D mammography” whose diagnostic performance was evaluated using synthetic(!) images. For this, the manufacturer simulated both the breast (e.g. size, fat content, geometry, mammary ducts, vessels, lesions) and the medical device itself.

As a result, a large part of the clinical investigation was performed by simulation with in-silico clinical trials.

d) Post-market phase

Simulation can also help manufacturers in the post-market phase:

• Error patterns in the field can be simulated using computer models and the causes identified
• Manufacturers can quickly try different troubleshooting measures and select the best option.
• Models can also be used to verify and validate these measures and prove their effectiveness to authorities.
• Models help to predict future errors. They also allow manufacturers to simulate extreme situations.

e) Summary

There is hardly a phase in the device life cycle in which modeling and simulation cannot be used. The FDA agrees.

4. Regulatory requirements for computer-based modeling & simulation

a) Europe

Even up-to-date laws, such as the MDR and IVDR, do not contain specific requirements for the use of computer models for the development of medical devices. However, they explicitly provide for their use and simulation.

where appropriate, the results of biophysical or modelling research the validity of which has been demonstrated beforehand; (Annex I, 10.1a))
results of tests, such as engineering, laboratory, simulated use and animal tests [...]; (Annex II, 6.1.a))
the pre-clinical testing, for example laboratory testing, simulated use testing, computer modelling, the use of animal models (Annex VII, 4.5.4.a))

ISO 13485 requires manufacturers to:

• Validate their computerized systems
• Validate their processes
• Validate measuring equipment
• Plan monitoring and measuring processes
• Use appropriate statistical methods

b) USA/FDA

The FDA was mandated by the US Congress to promote and regulate the use of computer-based modeling and simulation. It had already published the document “Advancing Regulatory Science at FDA” in August 2011. In it, the authority chose to focus on the “use and develop computational methods and in silico modeling.”

In 2018, Tina Morrison, who is driving the issue forward at the FDA, explained in an article in “Frontiers in Medicine” the possibilities offered by “computational modeling for medical devices” and the required “regulatory science.”

Even before that, she had played a key role in the development of the guidance document “Reporting of Computational Modeling Studies in Medical Devices Submission”, a final version of which has been available since 2016.

As the name suggests, this document describes what documentation the FDA expects. But it does not contain very specific guidelines for the validation of the models.

c) ASME V&V 40

For this, the FDA relies on the “V&V 40” published by the American Society for Mechanical Engineering (ASME) with the title “Verification and Validation of Computational Modeling of Medical Devices”.

The document describes the steps manufacturers should take when validating computer models.

These steps include:

1. Formulating the question of interest
   Specify exactly what the question to be answered by the model is. For example, how much fluid should I remove from dialysis patients?
2. Describing the context of use (COU)
   The COU describes what role the computer model has in answering the question and what the specific object of the computer model is. For example, it will simulate the human fluid compartment of a patient in order to estimate the hydrogenation.
3. Analyzing the risks
   The risks are determined by the influence of the model on the manufacturer's decision and the consequences of this decision. For example, the influence of the model would be greater if the manufacturer relied solely on the model.
4. Establishing the “credibility goals”
   Here, the ASME document describes numerous aspects (see Fig. 7) for which manufacturers must define criteria. These range from the analysis of discretization errors to the adequacy of the model and its formulas and constants through to the verification of the comparator used to validate the model.