Bryan Brosseau, Founder and Principal Consultant, Brosseau Consulting LLC09.14.21
Planning for a regulatory submission entails consideration of numerous requirements beyond simply the content and required elements of the application. Planning and careful coordination between regulatory representation and other functional areas are crucial. From the onset of design and development, design control principles must be applied to ensure the medical device meets the required needs and to ensure proper verification and validation. Regulatory requirements are incorporated as design inputs to inform the test strategy and ensure final design compliance and testing support. In addition, quality system and compliance requirements must be met to ensure the cleared or approved product can be manufactured and distributed. Whether you are submitting for FDA clearance or approval, clinical trial approval, CE-marking, or approval in any other jurisdiction, the likelihood of a delay will be reduced by planning for all regulatory requirements at the onset.
In general, assess the following in developing a regulatory strategy as part of the development plan at the earliest development stages:
In planning for a development project, assess all desired markets and determine the regulatory requirements for each one. The project should have a representative specifically dedicated to regulatory directives. Identify all applicable recognized U.S. consensus standards or all applicable harmonized EU standards. For the European Union, plan to ensure the device will meet state-of-the-art requirements as well as performance and safety mandates outlined in Annex 1 Regulation (EU) 2017/745 (the EU MDR). Other regulatory jurisdictions also have general safety and performance requirements. This is the first step in planning for a submission and it is critical to have a seasoned regulatory team member on board. If a required standard or regulation is dismissed in this preliminary stage, a significant delay may result later in the process.
Ensuring the correct device classification at the inception of design controls will ensure the development process is appropriate for the device. The device classification will influence submission type, the necessary data for the submission, required QMS processes, and review time. For novel devices, communication with the regulatory agency may be needed to determine the appropriate classification. In some cases, clinical data may be required with a clinical study performed before the application is submitted. Determine if clinical data from one jurisdiction may be used to support a marketing application in others and plan accordingly. Proper site selection may result in a reduced clinical trial approval timeline and data that may support regulatory applications in multiple jurisdictions.
Technical Requirements
The technical requirements help ensure a device is safe, effective, and performs as intended. In some cases, technical and regulatory requirements are the same thing—performance standards include technical requirements and are sometimes recommended or mandated by regulators. As described previously, there are FDA recognized consensus standards and EU harmonized standards for specific medical devices and device categories. For example, ISO 152231 is recognized by the FDA and EU Commission for symbols used in medical device labeling. This standard can help device manufacturers minimize SKUs or model numbers for universal labeling. Similar principles apply for performance and safety testing, and other aspects of verification and validation.
For novel devices, consider how existing testing standards may be adapted to suit unique device aspects. This approach provides a testing framework that is familiar to regulators. Consider seeking feedback from the regulatory body through a pre-submission (FDA) or other formal mechanisms where existing test standards are not sufficient to evaluate safety and performance.
Conflicting Inputs
In some cases, different regulatory jurisdictions recognize different standards or dissimilar versions of the same standard. Identifying and addressing these differences early will enable companies to assess conflicting requirements. In some cases, testing may be performed to one version of a standard with a justification of equivalence to another version for demonstrating compliance to both versions. There are also situations where input from regulators will drive differences in testing strategies, labeling, or other device aspects. These discrepancies are less predictable, usually occur later in development, and are often more challenging; however, by minimizing other variables through thorough planning, it may be easier to address conflicting regulatory feedback to prevent multiple product configurations for different geographies.
While common symbology may be used for a product intended for U.S. and European distribution, the FDA and EU Notified Body may disagree on labeling content. This situation may require different product versions for these locations or additional coordination with regulators to reach a single configuration for distribution in both locations.
Regulatory Submission Content
Many regulatory agencies provide guidance on the content of regulatory applications. It is important to note that general guidance documents do not address all the required information for a particular device type. In some cases, regulators publish device-specific guidance that provides more content detail for a pre-market application. For example, FDA Guidance document “510(k) Information Needed for Hydroxyapatite Coated Orthopedic Implants” (February 1997) describes the necessary details for a 510(k) application regarding the composition, process, and performance of hydroxyapatite coating on orthopedic implants. In this case, such required information will inform the verification test plan and possibly the device’s design.
A thorough review of submission content—preferably involving subject matter experts from the development team—is critical to ensure all elements are addressed and the submission is accurate and cogent.
Quality Management System
A common mistake for startups or newcomers to the medical device industry is to focus on the product only without thoroughly understanding the Quality Management System (QMS) requirements. While some submissions require little to no information about the QMS, such data is necessary for development and to begin marketing the device upon clearance or approval. QMS documentation outlines the design control process to be followed during development, the risk management process, post-market surveillance requirements, and all regulatory requirements for the pre-market application. Product purchasing, manufacturing, packaging, inspection, and testing (in-process or final) will be governed by documented QMS elements.
Regulatory approval is often misconstrued as the “end zone” for product development. However, there are usually many remaining elements to address after approval is granted. Closing remaining design control phases often happens after regulatory approval. After an approval, a registration and/or device listing process is required in several jurisdictions; this process may require annual renewal. Unique device identifiers must also be registered with the appropriate regulatory agencies. In some geographies, local representation is required either as a marketing authorization holder, authorized representative, or importer. Depending of the jurisdiction and device classification, a regulatory inspection may also be required before or shortly after approval.
Post-Marketing Requirements
An increasing focus on post-market surveillance by regulators has resulted in the need for more robust post-market surveillance processes. A passive complaint handling system alone is not adequate to meet regulatory requirements, particularly for medical devices marketed in the European Union. QMS processes are required for intaking complaints and feedback, evaluating such information, performing root cause investigations, and reporting to regulatory authorities. Post-market surveillance data is an input to the risk management process, which is conducted throughout the device lifecycle to ensure product risks are analyzed and mitigated. There are also administrative requirements for post-market reporting that must be planned and arranged well in advance of filing a report for a reportable event. For example, adverse event reports must be submitted electronically to FDA and the process for obtaining an account for electronic reporting is cumbersome and time consuming, particularly for first-time users.
Post-market surveillance processes are intertwined with clinical evaluation and risk management processes. Many “templated” QMS systems lack the detail and instructions to adequately perform these functions, particularly as the device risk classification increases. Allow time to fine-tune QMS processes for your specific device and organizational structure. Revisions to the QMS during the development of different products or products in a different classification is not uncommon.
Summary
Adopt a holistic view in planning product development with an early emphasis on regulatory requirements. Identify all requirements for the QMS, product development under design controls, and administrative requirements. Identify the resources you’ll need for these elements and for continued operations after clearance or approval. For novel devices or devices in a higher risk classification, use formal communication methods to get feedback from regulators (e.g., FDA pre-submission and EU consultation for clinical evaluation) to ensure a robust regulatory application that meets their expectations. Lastly, prepare for the post-market requirements and understand your obligations as a medical device manufacturer distributing products. While these requirements may initially seem daunting, your organization will be more adept at this process with each subsequent project.
Reference
Bryan Brosseau’s experience has been forged in 20 years in the medical device and biologics industries. With a varied and in-depth knowledge of quality and regulatory requirements, he drives quality and compliance without impeding progress. Bryan implements, manages, and improves quality management systems for numerous companies and has obtained regulatory approvals for products across a wide range of therapy areas. Bryan received his bachelor’s degree in biology from the University of Georgia, maintains a Regulatory Affairs Certification (U.S.) from the Regulatory Affairs Professionals Society, and is a certified ISO 13485:2016 and MDSAP Lead Auditor.
In general, assess the following in developing a regulatory strategy as part of the development plan at the earliest development stages:
- Identify the regulatory requirements for all desired markets including regulation, guidance, applicable standards, and any feedback from regulatory agencies from previous related interactions
- Identify the technical requirements for the product performance, safety, and usability; include and incorporate them as design inputs
- Identify any conflicts or necessary coordination between the aforementioned requirements
- Determine the information needed for the regulatory submissions and the information that is not required but supportive of the desired indications for use
- Determine the supporting Quality Management System (QMS) elements and the associated resources for pre-market requirements beyond the regulatory application
- Plan for post-market requirements
In planning for a development project, assess all desired markets and determine the regulatory requirements for each one. The project should have a representative specifically dedicated to regulatory directives. Identify all applicable recognized U.S. consensus standards or all applicable harmonized EU standards. For the European Union, plan to ensure the device will meet state-of-the-art requirements as well as performance and safety mandates outlined in Annex 1 Regulation (EU) 2017/745 (the EU MDR). Other regulatory jurisdictions also have general safety and performance requirements. This is the first step in planning for a submission and it is critical to have a seasoned regulatory team member on board. If a required standard or regulation is dismissed in this preliminary stage, a significant delay may result later in the process.
Ensuring the correct device classification at the inception of design controls will ensure the development process is appropriate for the device. The device classification will influence submission type, the necessary data for the submission, required QMS processes, and review time. For novel devices, communication with the regulatory agency may be needed to determine the appropriate classification. In some cases, clinical data may be required with a clinical study performed before the application is submitted. Determine if clinical data from one jurisdiction may be used to support a marketing application in others and plan accordingly. Proper site selection may result in a reduced clinical trial approval timeline and data that may support regulatory applications in multiple jurisdictions.
Technical Requirements
The technical requirements help ensure a device is safe, effective, and performs as intended. In some cases, technical and regulatory requirements are the same thing—performance standards include technical requirements and are sometimes recommended or mandated by regulators. As described previously, there are FDA recognized consensus standards and EU harmonized standards for specific medical devices and device categories. For example, ISO 152231 is recognized by the FDA and EU Commission for symbols used in medical device labeling. This standard can help device manufacturers minimize SKUs or model numbers for universal labeling. Similar principles apply for performance and safety testing, and other aspects of verification and validation.
For novel devices, consider how existing testing standards may be adapted to suit unique device aspects. This approach provides a testing framework that is familiar to regulators. Consider seeking feedback from the regulatory body through a pre-submission (FDA) or other formal mechanisms where existing test standards are not sufficient to evaluate safety and performance.
Conflicting Inputs
In some cases, different regulatory jurisdictions recognize different standards or dissimilar versions of the same standard. Identifying and addressing these differences early will enable companies to assess conflicting requirements. In some cases, testing may be performed to one version of a standard with a justification of equivalence to another version for demonstrating compliance to both versions. There are also situations where input from regulators will drive differences in testing strategies, labeling, or other device aspects. These discrepancies are less predictable, usually occur later in development, and are often more challenging; however, by minimizing other variables through thorough planning, it may be easier to address conflicting regulatory feedback to prevent multiple product configurations for different geographies.
While common symbology may be used for a product intended for U.S. and European distribution, the FDA and EU Notified Body may disagree on labeling content. This situation may require different product versions for these locations or additional coordination with regulators to reach a single configuration for distribution in both locations.
Regulatory Submission Content
Many regulatory agencies provide guidance on the content of regulatory applications. It is important to note that general guidance documents do not address all the required information for a particular device type. In some cases, regulators publish device-specific guidance that provides more content detail for a pre-market application. For example, FDA Guidance document “510(k) Information Needed for Hydroxyapatite Coated Orthopedic Implants” (February 1997) describes the necessary details for a 510(k) application regarding the composition, process, and performance of hydroxyapatite coating on orthopedic implants. In this case, such required information will inform the verification test plan and possibly the device’s design.
A thorough review of submission content—preferably involving subject matter experts from the development team—is critical to ensure all elements are addressed and the submission is accurate and cogent.
Quality Management System
A common mistake for startups or newcomers to the medical device industry is to focus on the product only without thoroughly understanding the Quality Management System (QMS) requirements. While some submissions require little to no information about the QMS, such data is necessary for development and to begin marketing the device upon clearance or approval. QMS documentation outlines the design control process to be followed during development, the risk management process, post-market surveillance requirements, and all regulatory requirements for the pre-market application. Product purchasing, manufacturing, packaging, inspection, and testing (in-process or final) will be governed by documented QMS elements.
Regulatory approval is often misconstrued as the “end zone” for product development. However, there are usually many remaining elements to address after approval is granted. Closing remaining design control phases often happens after regulatory approval. After an approval, a registration and/or device listing process is required in several jurisdictions; this process may require annual renewal. Unique device identifiers must also be registered with the appropriate regulatory agencies. In some geographies, local representation is required either as a marketing authorization holder, authorized representative, or importer. Depending of the jurisdiction and device classification, a regulatory inspection may also be required before or shortly after approval.
Post-Marketing Requirements
An increasing focus on post-market surveillance by regulators has resulted in the need for more robust post-market surveillance processes. A passive complaint handling system alone is not adequate to meet regulatory requirements, particularly for medical devices marketed in the European Union. QMS processes are required for intaking complaints and feedback, evaluating such information, performing root cause investigations, and reporting to regulatory authorities. Post-market surveillance data is an input to the risk management process, which is conducted throughout the device lifecycle to ensure product risks are analyzed and mitigated. There are also administrative requirements for post-market reporting that must be planned and arranged well in advance of filing a report for a reportable event. For example, adverse event reports must be submitted electronically to FDA and the process for obtaining an account for electronic reporting is cumbersome and time consuming, particularly for first-time users.
Post-market surveillance processes are intertwined with clinical evaluation and risk management processes. Many “templated” QMS systems lack the detail and instructions to adequately perform these functions, particularly as the device risk classification increases. Allow time to fine-tune QMS processes for your specific device and organizational structure. Revisions to the QMS during the development of different products or products in a different classification is not uncommon.
Summary
Adopt a holistic view in planning product development with an early emphasis on regulatory requirements. Identify all requirements for the QMS, product development under design controls, and administrative requirements. Identify the resources you’ll need for these elements and for continued operations after clearance or approval. For novel devices or devices in a higher risk classification, use formal communication methods to get feedback from regulators (e.g., FDA pre-submission and EU consultation for clinical evaluation) to ensure a robust regulatory application that meets their expectations. Lastly, prepare for the post-market requirements and understand your obligations as a medical device manufacturer distributing products. While these requirements may initially seem daunting, your organization will be more adept at this process with each subsequent project.
Reference
- ISO 15223-1:2016, Medical devices—Symbols to be used with medical device labels, labelling and information to be supplied—Part 1: General requirements
Bryan Brosseau’s experience has been forged in 20 years in the medical device and biologics industries. With a varied and in-depth knowledge of quality and regulatory requirements, he drives quality and compliance without impeding progress. Bryan implements, manages, and improves quality management systems for numerous companies and has obtained regulatory approvals for products across a wide range of therapy areas. Bryan received his bachelor’s degree in biology from the University of Georgia, maintains a Regulatory Affairs Certification (U.S.) from the Regulatory Affairs Professionals Society, and is a certified ISO 13485:2016 and MDSAP Lead Auditor.