Designing for Regulatory Approval: What is Important to Regulators in the Approval Process?

Giving attention to regulatory considerations at the earliest stages of product design and development can create a smoother and more successful pathway to approval. It’s also very important to understand how regulators “think” and what they consider to be of the greatest importance during the approval process.

What follows are some key points that those involved in product design and development need to consider at the earliest possible stage of the design process.

Does the Product Offer Potential Risks?

Regulators view products in terms of the potential and actual risks they pose to users, patients, other persons, and the environment. The ISO 14971 risk management standard provides a framework by which manufacturers can plan, analyze, estimate, and evaluate product risks throughout the product lifecycle. This standard is widely recognized and is adopted in the major geographies, including US, EU, Canada, Japan, and Australia.

In general, the higher the risks associated with the product, the more regulatory requirements need to be fulfilled, and the higher the burden of proof is on the designer and manufacturer. Any risks identified in the design phase must be documented and reduced, as far as possible, prior to product launch. Users, and patients, if applicable, need to be informed of any residual product risks by providing specific information on the product label and/or accompanying documentation.

A complete assessment of the benefits and risks of the product must be conducted. A medical device can only be placed on the market if the riskbenefit analysis concludes that the benefits outweigh the risks. Additionally, any new risks identified after the product has been placed on the market need to be addressed and mitigated. Product safety is absolutely paramount in the thought process of regulators.

Profile the User and the Environment

The profile of the intended user of the product, and the environment in which the product is used must be considered when designing the product. For example, if a product will be used by a member of the public in a home environment, the education and agegroup of the user as well as the storage and operating conditions of the product in the home environment must be taken into account by the product designer. The design requirements for products intended to be used by professionals, for example, a doctor in a hospital environment, are often quite different from products to be used by the general public. (See Figure 1)

Regulatory authorities are putting an increased focus on ensuring that designers consider the requirements and preferences of end-users and patients, both in the design of the device and the product labeling. It is widely acknowledged that user errors are a major contributor to serious injuries associated with medical devices.

Human factors and usability engineering principles should be applied in the design process. The IEC 62366 standard describes the application of usability engineering to medical devices. The onus is on the design team to develop an inherently safe product, designed in such a way as to minimize the likelihood of use errors, and, where necessary, incorporate protective features such as alarms.

Information supplied with the product must be written at a level, and in language that can be easily understood by the intended audience. Use of simple drawings and diagrams rather than complex technical descriptions is often preferable and more appropriate, particularly for lay users. Training must be provided where necessary, to enable the user to use the product correctly. The product designer must consider, and mitigate against, any reasonably foreseeable misuse of the product by the user.

How Does the Product Work?

This sounds like a rather obvious question, but it’s a key factor to consider at the earliest design stages. Medical devices are regulated by the FDA in the US and thus are subject to the regulatory controls outlined in 21 CFR Parts 1-58, 800-1299. In the EU, the requirements of the Medical Device directive 93/42/EC must be met and the product must be CE Marked.

Additional regulatory requirements may apply in certain instances. For example, if the device incorporates wireless technology, it needs to comply with FCC standards (US) and the Radio and Telecommunications directive 1999/5/EC (EU). If the device has electrical components it will need to be EMC (electromagnetic compatibility)-tested. With increased dependency on automation and software driven systems within healthcare, software validation is critical and must be conducted on products that incorporate software. Personal data protection regulations must be considered where patient information is stored or processed. It is important to consider all legislation and standards that may be relevant when designing complex systems.

What Are the Components of the Product?

The composition of the product also needs to be reviewed at the early design stage. Use of hazardous substances must be carefully considered. For example, in the EU, the Restriction of Hazardous Substances (RoHS) directive 2011/65/EU applies to electrical and electronic medical devices. The composition of liquid mixtures must be reviewed in respect of labeling with appropriate chemical hazard symbols and also consideration must be given to local environmental laws for chemical disposal. Particular attention must also be given to medical devices that contain animal-derived substances. Most countries have specific safety requirements and restriction on use of such components in order to mitigate against risk of spreading infectious disease. It is, therefore, important to scope out all the applicable regulations at the initial stages of the design project.

Is the Device Re-usable?

Reprocessing of re-usable medical devices has come under the spotlight of regulators in recent times. In the US, the infection of seven patients with a socalled “superbug,” carbapenem-resistant enterobacteriaceae (CRE), at UCLA hospital between October 2014 and January 2015 was linked to use of a duodenoscope manufactured by the Olympus Corporation. Two of the patients subsequently died as a result of the bacterial infection. Although the duodenoscope was reprocessed by the hospital following the manufacturer’s instructions, the cleaning and decontamination procedure was ineffective, forcing Olympus Corporation to issue new instructions on the cleaning and decontamination steps to be followed. This example serves to highlight the importance of ensuring that where a device is re-usable, the device design must facilitate cleaning and decontamination. A comprehensive cleaning validation study must be conducted by the manufacturer. Clear instructions and training, if necessary, on the reprocessing procedure must be provided to the user. The manufacturer must ensure that the cleaning procedure is robust and effective. (See Figure 2)

Achieving Performance Claims

Regulators expect that products are designed and manufactured in a way to ensure that the product fulfills its intended purpose for the expected lifetime of the product. Medical devices must be durable and achieve the performances claimed by the manufacturer. Design verification and validation testing must be performed at the design stage in line with product-related standards and state of the art. Test protocols and records need to be documented and available for regulatory authorities to review when required. Products must be manufactured under an appropriately controlled manufacturing environment and validation of critical processes must be conducted.

Biocompatibility

It is also important to give due consideration to the potential for toxicity of components that come into contact with patients at the early stages of design. Medical devices that come into contact with the body need to be tested to determine if there is potential toxicity from any of the component materials. This is particularly important for devices incorporating novel constituent materials, implants, and devices used in higher risk anatomical locations. Biocompatibility testing should be based on risk assessment, with factors such as frequency, nature, and duration of contact, and product composition used to determine the testing plan.

The ISO 10993 series of standards describes a suite of in vitro and in vivo biocompatibility tests. The tests include in vitro cytotoxicity; acute, sub chronic, and chronic toxicity; irritation; sensitization; genotoxicity; hemocompatibility; implantation; and effects on reproduction. Where the manufacturer decides to omit a test, the rationale must be documented.

Assessing the Clinical Evidence

Regulators need to know that your medical device is not only safe but effective, and fulfills its intended medical purpose in real life situations. Lower risk medical devices that are well-established and have a long history of safe and effective use will not require a new clinical study to demonstrate effectiveness. In these cases, clinical evidence can generally be obtained by review of published clinical data from a similar marketed or competitor device, once the manufacturer can demonstrate that the devices are equivalent.

Higher risk devices and novel devices will normally require a clinical study in order to demonstrate that the device fulfills its intended purpose in a real-life situation, while ensuring that any previously unidentified safety issues are addressed.

Defining the Markets

Regulations vary from region to region and are constantly changing. It is imperative that the markets for which the product is intended are defined at an early stage, so that any particular requirements are captured before embarking on a verification and validation program. Conducting a comprehensive risk assessment of the device, and considering all of the points outlined above, will provide a framework for the testing that will need to be conducted to provide assurance that the product design is safe and effective.

This article was written by Paula McCarthy, Senior Regulatory Affairs Advisor, Acorn Regulatory, Clonmel, Ireland. For more information, Click Here  .

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