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The Situation
United States Army Medical Research and Development Command (USAMRDC), a pure R&D military organization which plays a vital role in the advancement of military medicine, engaged RQMIS with the objective of obtaining FDA’s clearance of their novel medical device software. The Army team designed a standalone medical device (SaMD) software Machine Learning (ML) developed algorithm, APPRAISE-HRI, operating on a smart phone to effectively triage soldiers with internal bleeding (internal hemorrhaging unseen) to save their lives.
As with many academic/government, R&D organization, and small startup companies the initial version of the SaMD was developed outside of a fully compliant Good Manufacturing Practice (GMP) Quality System. The ML developed algorithm was trained on an extensive dataset of patient monitoring data recorded at multiple clinical sites. When this milestone was achieved, they reached out to FDA through the Pre-Submission process to understand the regulatory requirements to gain commercial clearance of their APPRAISE-HRI software.
After the USAMRDC submitted and received feedback from the FDA through a Pre-Submission, they concluded that support from an outside consulting group, with experience in regulatory strategy and submissions, was necessary. The consulting group was also needed to understand the larger picture of product development and to address, not only regulatory questions and objectives and to design/manage the clinical validation study, but also to create the quality system the USAMRDC needed to develop the product and challenging the cybersecurity of the APPRAISE-HRI software to address all premarket cybersecurity testing and the post market cybersecurity monitoring plan. With this objective, the USAMRDC retained RQMIS to address all these requirements.
The Proposed solution
RQMIS reviewed the feedback from the FDA and developed an overall regulatory strategy plan to gain clearance. The strategy initially included the DeNovo classification request pathway, with the need for a clinical validation study. RQMIS also identified all of the software related documentation/testing, risk management documentation, and clinical validation data that would be required to support this strategy. We further recommended that the clinical validation data/study would not require the recruitment of patients, but would utilize hospital-based databases that captured the patient monitoring data and patient outcomes of trauma related emergencies.
FDA responded positively to our regulatory strategy and our proposed clinical validation study. FDA agreed that a DeNovo submission pathway was appropriate, agreed with the software risk classification, and that the noted clinical databases could be used to validate the APPRAISE-HRI software.
RQMIS designed a clinical validation study that did not require recruitment of patients but utilized large databases of patient monitoring data, collected by several hospitals during emergency transport of trauma patients. RQMIS authored the protocol, statistical analysis plan, and the Clinical Study Report.
As the project proceeded, FDA published its cybersecurity guidance and the Army reached out to a major supplier of patient monitoring equipment to allow for the Army, with RQMIS guidance, to perform software testing to demonstrate that the APPRAISE-HRI software could effectively gather the necessary data (wirelessly) from this company’s patient monitoring equipment and could calculate the patient’s likelihood of having an internal hemorrhage. With the new cybersecurity requirements, the Army requested that RQMIS’ partner TwinTech Labs create the necessary cybersecurity documentation and perform all cybersecurity testing.
Execution: Path to Success
After obtaining FDA’s consensus on the clinical study plan and the regulatory strategy from the 2nd Pre-sub (supplement), our regulatory/project manager began to execute the project plan in phases via ASANA (a cloud based project management tool) and coordinated multiple stakeholders within the Army (their software developers, senior scientist, statistician, project manager) and RQMIS team (our software design control expert, regulatory experts, cybersecurity expert, senior statistician).
Although the APPRAISE-HRI software had been developed/trained outside of a formal Quality Management System (QMS) process, RQMIS proposed designing a Quality Management System (QMS) focused on design control, risk management, and change control. The Army agreed and RQMIS designed/implemented this QMS in less than a month, with the design team providing guidance along the way. After the software was completed and ready for clinical study validation, the Army asked RQMIS to execute the clinical study validation plan and validate the APPRAISE-HRI software.
First Phase (development and verification testing)
During phase 1 of the project, the client and RQMIS developed and executed the software design and development plan within the design control and software life cycle process. We performed Failure mode effects analysis (FMEA) on each stage of software development, with design review, and released the final software version. With the final finished APPRAISE-HRI software, we performed clinical study, human factor study, unit, system, and integration verification testing, cybersecurity testing (including threat modeling, static and dynamic scan, fuzz testing, penetration testing), and laid cyber controls.
RQMIS regulatory experts gave constant regulatory updates to the US Army team on the FDA’s ongoing evolution of cybersecurity policies and guidance’s. We also made sure the cybersecurity documents contained all the necessary pre and post market cyber information.
Second Phase (validation & FDA regulatory submission)
Once the APPRAISE-HRI software was developed and verified, and the clinical study protocol was executed, our senior statistician generated data for statistical analysis. He then performed independent validation of the algorithm, performed statistical analysis of the results of the clinical study, and generated a clinical study report.
All the generated verification & validation documents, with the regulatory team’s input on preparing special control, including benefit – risk discussion, was included in the De Novo submission. RQMIS packaged it and send it to FDA.
Final Phase (addressing FDA’s concerns and negotiation)
Once the De Novo was submitted to FDA, we received a request to update the submission as Traditional 510(k) comparing to a similar predicate with different indication. RQMIS regulatory team reviewed FDA’s request and confirmed with FDA that the new substantial equivalence should not trigger any additional verification & validation testing for the APPRAISE-HRI software and re-packaged the De Novo file into a Traditional 510(k).
After FDA’s review, we received an Additional Information (AI) request from the FDA focusing on future hardware – software (APPRAISE-HRI) compatibility and clinical study inclusion data. The RQMIS team helped the US Army team and negotiated with FDA via SIR Q-sub process, regarding subject software – patient monitors compatibility issue. RQMIS helped to tackle these questions with our expertise, without requiring major changes to the software or additional clinical study data.
During the review process, the US Army development team had to make minor software updates. Since RQMIS already had the design control process in place, it was easy to create additional appropriate verification testing for the software updates and submit the Additional Information response, well before the due date.
The success: (FDA clearance)
On April 5, 2024, the APPRAISE-HRI was cleared by the FDA with a new product code, SAR.
With RQMIS providing full support on Regulatory, Quality, Clinical, Cybersecurity and Project Management, we were able to gain regulatory clearance for the APPRAISE-HRI software application. RQMIS was also available for consultation when questions arose outside of the primary objectives.
Overall, we completed the project within the estimated budget. One of the main reasons for the success was due to meticulous management of the project from the start to finish. RQMIS supported the medical device manufacturer (US Army) through the product development phases and tackled any questions from FDA.
RQMIS consultancy services
Are you a small start-up or small/medium sized medical product company that doesn’t have the internal resources to support commercial clearance of your product? The Army was very concerned about its organization and its ability to develop per regulatory requirements the necessary information to achieve market clearance. RQMIS is a leading force in the regulatory consulting field, with a glowing reputation among our medical device clients and consultant peers. RQMIS’s experience with regulatory strategy development and execution in the US puts RQMIS at an advantage when preparing regulatory documents for our medical device manufacturer base. We are particularly experienced with the small startup environment and have a deep appreciation of the challenges such organizations have in strategizing and executing in the regulatory space, whether this be the United States, EU, UK, Canada, Brazil, or elsewhere.
In the US, RQMIS has supported the development and negotiation of numerous FDA Pre-Submissions, 510(k)s, IDEs, and PMAs for the US, along with Clinical study management, for a wide range of medical devices containing novel or new technological features. This experience also includes taking many of these products through the regulatory processes in the EU, UK, Canada, Brazil, and elsewhere.
Disclaimer: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army, the U.S. Department of Defense, or The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. This [paper/abstract/poster] has been approved for public release with unlimited distribution.