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Why modernize 21 CFR 820 to ISO 13485?

The FDA patches the regulations with guidance documents, but there is a desperate need to modernize 21 CFR 820 to ISO 13485.

FDA Proposed Amendment to 21 CFR 820

On February 23, 2022, the FDA published a proposed rule for medical device quality system regulation amendments. The FDA planned to implement amended regulations within 12 months, but the consensus of the device industry is that a transition of several years would be necessary. In the proposed rule, the FDA justifies the need for amended regulations based on the “redundancy of effort to comply with two substantially similar requirements,” creating inefficiencies. In public presentations, the FDA supporting arguments for the proposed quality system rule change relies heavily upon comparing similarities between 21 CFR 820 and ISO 13485. However, the comparison table provided is quite vague (see the table from page 2 of FDA’s presentation reproduced below). The FDA also provided estimates of projected cost savings resulting from the proposed rule. What is completely absent from the discussion of the proposed rule is any mention of the need to modernize 21 CFR 820.

Overview of Similarities and Differences between QSR and ISO 13485 1006x1024 Why modernize 21 CFR 820 to ISO 13485?

Are the requirements “substantively similar”?

The above table provided by the FDA claims that the requirements of 21 CFR 820 are substantively similar to the requirements of ISO 13485. However, there are some some aspects of ISO 13485 that will modernize 21 CFR 820. The areas of impact are: 1) software, 2) risk management, 3) human factors or usability engineering, and 4) post-market surveillance. The paragraphs below identify the applicable clauses of ISO 13485 where each of the four areas are covered.

Modernize 21 CFR 820 to include software and software security

Despite the limited proliferation of software in medical devices during the 1990s, 21 CFR 820 includes seven references to software. However there are some Clauses of ISO 13485 that reference software that are not covered in the QSR. Modernizing 21 CFR 820 to reference ISO 13485 will incorporate these additional areas of applicability. Clause 4.1.6 includes a requirement for validation of quality system software. Clause 7.6 includes a requirement for validation of software used to manage calibrated devices used for monitoring and measurement. Clause 7.3 includes a requirement for validation of software embedded in devices, but that requirement was already included in 21 CFR 820.30. The FDA can modernize 21 CFR 820 further by defining Software as a Medical Device (SaMD), referencing IEC 62304 for management of the software development lifecycle, referencing IEC/TR 80002-1 for hazard analysis of software, referencing AAMI TIR57 for cybersecurity, and referencing ISO 27001 for network security. Currently the FDA strategy is to implement guidance documents for cybersecurity and software validation requirements, but ISO 13485 only references IEC 62304. Then only aspect of 21 CFR 820 that appears to be adequate with regard to software is validation of software used for automation in 21 CFR 820.75. This requirement is similar to Clause 7.5.6 (i.e., validation of processes for production and service provisions).

Does 21 CFR 820 adequately cover risk management?

The FDA already recognizes ISO 14971:2019 as the standard for risk management of medical devices. However, risk is only mentioned once in 21 CFR 820. In order to modernize 21 CFR 820, it will be necessary for the FDA to identify how risk should be integrated throughout the quality system requirements. The FDA recently conducted two webinars related to risk management of medical devices, but implementing a risk-based approach to quality systems is a struggle for companies that already have ISO 13485 certification. Therefore, a guidance document with examples of how to implement a risk-based approach to quality system implementation would be very helpful to the medical device industry. 

Modernize 21 CFR 820 to include Human Factors and Usability Engineering

ISO 13485 references IEC 62366-1 as the applicable standard for usability engineering requirements, but there is no similar requirement found in 21 CFR 820. Therefore, human factors is an area where 21 CFR 820 needs to be modernized. The FDA has released guidance documents for the human factors content to be included in a 510k pre-market notification, but the guidance was released in 2016 and the guidance does not reflect the FDA’s current thoughts on human factors / usability engineering best practices. The FDA recently released a draft guidance for the format and content of human factors testing in a pre-market 510k submission, but that document is not a final guidance document and there is no mention of human factors, usability engineering, or even use errors in 21 CFR 820. Device manufacturers should be creating work instructions for use-related risk analysis (URRA) and fault-tree analysis to estimate the risks associated with use errors as identified the draft guidance. These work instructions will also need to be linked with the design and development process and the post-market surveillance process.

Modernize 21 CFR 820 to include Post-Market Surveillance

ISO/TR 20416:2020 is a new standard specific to post-market surveillance, but it is not recognized by the FDA. There is also no section of 21 CFR 820 that includes a post-market surveillance requirement. The FDA QSR focuses on reactive elements such as:

  • 21 CFR 820.100 – CAPA
  • 21 CFR 820.198 – Complaint Handling
  • 21 CFR 803 – Medical Device Reporting
  • 21 CFR 820.200 – Servicing
  • 21 CFR 820.250 – Statistical Techniques

The FDA does occasionally require 522 Post-Market Surveillance Studies for devices that demonstrate risks that require post-market safety studies. In addition, most Class 3 devices are required to conduct post-approval studies (PAS). For Class 3 devices, the FDA requires the submitter provide a plan for a post-market study. Once the study plan is accepted by the FDA, the manufacturer must report on the progress of the study. Upon completion of the study, most manufacturers are not required to continue PMS.

How will the FDA enforce compliance with ISO 13485?

It is not clear how the FDA would enforce compliance with Clause 8.2.1 in ISO 13485, because there is no substantively equivalent requirement in the current 21 CFR 820 regulations. The QSR is 26 years old, and the regulation does not mention cybersecurity, human factors, or post-market surveillance. Risk is only mentioned once by the regulation, and software is only mentioned seven times. The FDA has “patched” the regulations through guidance documents, but there is a desperate need for new regulations that include critical elements. The transition of quality system requirements for the USA from 21 CFR 820 to ISO 13485:2016 will force regulators to establish policies for compliance with all of the quality system elements that are not in 21 CFR 820.

Companies that do not already have ISO 13485 certification should be proactive by 1) updating their quality system to comply with the ISO 13485 standard and 2) adopting the best practices outlined in the following related standards:

  • AAMI/TIR57:2016 – Principles For Medical Device Security – Risk Management
  • IEC 62366-1:2015 – Medical devices — Part 1: Application of usability engineering to medical devices
  • ISO/TR 20416:2020 – Medical devices — Post-market surveillance for manufacturers
  • ISO 14971:2019 – Medical Devices – Application Of Risk Management To Medical Devices
  • IEC 62304:2015 – Medical Device Software – Software Life Cycle Processes
  • ISO/TR 80002-1:2009 – Medical device software — Part 1: Guidance on the application of ISO 14971 to medical device software
  • ISO/TR 80002-2:2017 – Medical device software — Part 2: Validation of software for medical device quality systems

What is the potential impact of the US FDA requiring software, risk management, cybersecurity, human factors, and post-market surveillance as part of a medical device company’s quality system?

Posted in: FDA, Human Factors, ISO 13485:2016, Post-Market Surveillance, Quality Management System, Software Verification and Validation

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The best human factors questions in every successful FDA meeting are?

What are the best human factors questions to ask the FDA during a pre-submission meeting, and what information content do you need in a 510k?

Talk to the FDA before human factors validation

The FDA did not start enforcing the requirement to apply human factors and usability engineering to medical device design until 2017 because the final version of the human factors guidance document was not released until February 3, 2016. Approximately ninety percent of the human factors testing reports submitted to the FDA in 510k pre-market submissions are deficient because the 510k submission content only includes the final summative testing report. The FDA needs a complete usability engineering file, and the human factors information needs to comply with FDA guidelines for the format and content of a 510k pre-market submission–not just IEC 62366-1:2015.

What human factors information does the FDA want?

For several years, FDA submission deficiency letters indicated that you should not include the frequency of occurrence in your estimation of use-related risks, but the FDA never provided this information in a guidance document. On December 9, 2022, the FDA finally released a draft human factors guidance regarding the format and content of a 510k pre-market submission. The new draft guidance includes the requirement for a use-related risk analysis (URRA) in table 2 (copied below).

Table 2 example of tabular format for the URRA 1024x354 The best human factors questions in every successful FDA meeting are?

In this new draft FDA guidance, the FDA identifies three different human factors submission categories. For the first category, only a conclusion and high-level summary are needed. For the second category, a user specification is also needed. For the third category, you need a comprehensive human factors engineering report with the following elements described in Section IV of the draft FDA guidance:

Submission Category 1, 2, and 3

  • Conclusion and high-level summary

Submission Category 2 and 3

  • Descriptions of intended device users, uses, use environments, and training
  • Description of the device-user interface
  • Summary of known use problems

Submission Category 3 only

  • Summary of preliminary analyses and evaluations
  • Use-related risk analysis to analyze hazards and risks associated with the use of the device
  • Identification and description of critical tasks
  • Details of validation testing of the final design

Before you spend tens of thousands or hundreds of thousands of dollars on human factors testing, you want to make sure the FDA agrees with your human factors testing plan. Otherwise, you will pay for the testing twice: once for your initial submission and a second time in your response to the FDA request for additional information to address deficiencies. Testing can cost more than your electrical safety testing. The facility needs to have the right equipment and space for the testing, you need support personnel to set up the equipment, you need to recruit participants, you need to compensate participants, and you need device samples.

When can you ask the FDA human factors questions?

The FDA cannot provide consulting advice on a submission, and the agency will not review data during pre-submission meetings. The FDA can provide feedback on protocols, specifications, and scientific justifications. Therefore, you should submit questions to the FDA in a pre-submission when you have a draft protocol, a draft specification, or a draft justification for why a task is not critical. Pre-submissions are “non-binding.” You can change your design and approach to human factors. Therefore, don’t wait until your information is 100% finalized. Share your documentation at the draft stage during the development phase and before your design freeze. You need these answers when you are planning a study and obtaining quotes. 

What are the best human factors questions to ask in a pre-sub?

In the FDA guidance for pre-submission meetings, the FDA provides suggested questions to ask:

  • Does the Agency have comments on our proposed human factors engineering process?
  • Is the attached use-related risk analysis plan adequate? Does the Agency agree that we have identified all the critical tasks?
  • Does the Agency agree with our proposed test participant recruitment plan for the human factors validation testing?

The above examples are only suggestions, but the best approach is to provide a brief example of what the human factors information will look like and ask the FDA to comment on the examples. The FDA does not have time to review data during a pre-sub meeting, but the FDA can review a few rows extracted from your URRA and comment on your proposed approach to the human factors process.

Human factors questions that are not appropriate

The FDA pre-submission guidance cautions you only to ask 3-4 questions for each meeting request because the FDA has difficulty answering more questions in a 60-minute teleconference. Therefore, you should not ask questions already answered in the FDA guidance. The new draft guidance includes examples of when a device modification can leverage existing human factors information and when new information is needed to support a premarket submission. Instead of asking a question specific to leveraging existing human factors information, instead, provide your rationale for leveraging existing data and ask if the FDA has any concerns with your overall approach to human factors.

Recommended human factors action items

Create a procedure for your human factors process that includes detailed instructions for creating the information required in a usability engineering report and templates for each document.

Posted in: 510(k), FDA, Human Factors, Usability

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