RQM+ sponsored both RAPS U.S. and Euro Convergence conferences in 2020 and we also led and provided subject matter experts for two panel discussions. Our experts pulled together the highlights from both conferences and summarized them by category for our readers.
- Notified Bodies (NBs) are working on a technical documentation format in alignment with IMDRF TOC (see IMDRF notes below).
- Might see the actor module of EUDAMED for registration (get your SRN here) by fourth quarter 2020.
- BSI has finished technical documentation reviews for 30-40 devices to date.
- About 50% of applications are rejected the first time they are received.
- The application and review process are taking longer than the NB anticipated. We can attest to that one!
- MIR using IMDRF codes. CAUTION: Competent Authorities are focusing on use error and design error as two areas that are generating additional questions from the CAs. If you use these IMDRF codes in your vigilance reporting (per the 2020 form), then be prepared to respond to questions about redesigning to address the root cause of design issue or use error.
- For spine device companies: classification of intervertebral body fusion devices (cages) has been sent for borderline classification ruling.
- QMS/ISO 13485: Some NBs are utilizing short-term renewals but it isn’t clear what happens at the end of the short-term renewal.
- Consider statistical approach to trending and select the right tool and understand what types of shifts may be detected using the various models (consider p-chart, CUSUM, EWMA) and select one that reflects what you are monitoring and the specific shape of the curve (e.g. skewed distribution).
- Team NB is working on a guidance for combination products and when they might need a new assessment.
- Medicinal substance dossiers most common errors are in analytical method, critical process variables and stability data. Clinical data is usually not a common cause for questions with CA review.
- NBs are requesting compliance or a short-term plan for ISO 14971 compliance; one NB is also requesting compliance with ISO/TR 24971. Hint: a three year plan is too long!
EU IVDR/US IVD
- Reference laboratories may not be ready until May 2022.
- There has been some success utilizing IMDRF TOC as technical documentation format for IVDR NBs.
- If you have a swab as part of an IVD test kit, the swab is an invasive sampling device and classified as part of the MDR. The whole kit including the swab is CE marked under the IVDR.
- In the European Union, greater oversight on what are LDTs (much more narrow allowance requiring CA oversight) and Research Use Only (RUO) reagents expected forcing more IVD products under the IVDR than were under IVDD.
- Pending legislation (VALID Act) in United States could impact LDT activities (potentially in 2021) bringing them back under FDA’s jurisdiction.
- Update: Shortly after the RAPS Convergence conferences ended, the Medical Device Coordination Group (MDCG) publish the new Guidance on Classification Rules for in vitro Diagnostic Medical Devices under Regulation (EU) 2017/746, which can be found here.
Emergency Use Authorization (EUA) Updates
- FDA is feeling the burden of doubling their workload and pulling people to new areas to support Pre-EUA and EUA submissions; people working overtime and weekends (Be kind to your FDA reviewer as they are probably tired.) Pre-submission meetings deprioritized from workload, especially in OHT1, OHT4, and OHT7. FDA has stated that they have over 1,200 EUAs still in the queue so response can take several days to several weeks, depending on the urgency. In total, FDA has received over 4,500 pEUAs!
- There is no date or timeline for when FDA will be returning to the office (most likely not until 2021) so no in-person meetings in sight.
- FDA is unaware of when the EUAs will be terminated. Like what happened with the Zika EUAs, revocation may be unpredictable and sudden. As the scale of the COVID-19 pandemic is much larger (56 EUAs for all other pandemics vs. 366 EUAs for COVID-19 as of July 2020), the termination and transition will be different. FDA expects to publish policy that will outline what the transition will look like but in the meantime, FDA encourages companies to start thinking about future plans now.
- The eSTAR pilot was originally launched on February 27, 2020 with nine participants. While the pilot is still on-going, FDA has made the Non-In Vitro Diagnostic and IVD eSTAR PDF for 510(k)s available for everyone to use. While still in testing, the future benefits of using the eSTAR include:
- Models Reviewer SMART Template
- Fewer expected AI requests (less/no stock deficiencies sent)
- Integration of the content of guidance documents (e.g. device specific testing requirements) and elimination of the need of others (e.g. RTA Guidance, eCopy)
- No RTA process, no eCopy
- No special software needed
- Field auto-population and integrated databases
- Currently, only the eSTAR PDFs for 510(k)s are available. Looking forward, FDA expects to create an eSTAR template for De Novos, PMAs, 513(g), IDE, and Q-subs (in that relative order). The De Novo eSTAR pilot was approved on June 9, 2020 and will begin with nine submissions.
- Later this summer, the eSTAR PDF is intended to replace the eSubmitter template used in the Quality in 510(k) Pilot. The Quality in 510(k) FDA program pilot is currently available for only some devices. See the list here. The goal of this pilot is for FDA to make a final decision at day 60. Fortunately for us we have a client with one of these product codes getting ready for a 510k submission, so we hope we can try this program out!
- Pro-Tip: Even if you are not submitting one of these select product codes, it is worth looking at the templates and filling out basic information for your device. It is really cool – you select the type of device and some key features and the template auto-populates sections you need to complete.
Real World Evidence
- Use of ICD-10 codes can be used to gather richer information (e.g. type of fractures associated with orthopedic implants).
- NEST has 21 test cases underway.
- Working on natural language data capture to reduce burden for physicians that have to do too many selections in current system.
- Anticipating use of RWE for post EUA COVID products.
- RWE can also be a very useful way to address Post-Approval Study Conditions.
- While many large databases exist, there are still many challenges with applying RWE for every submission:
Challenges: Too few devices used each year; devices are too new so no long term data; inconsistent terminology between databases; missing data; and incorrect reporting, etc.
- Finding linkages between databases can help fill information gaps to strengthen RWE for use in submissions.
Patient Reported Outcomes (PROs)
- PROs are moving from a ‘nice-to-have’ to a ‘must-have’ with more emphasis placed on PROs and Patient engagement by FDA. PROs play a large part in the Benefit-Risk determination for FDA.
- Patient input can also help bridge the gap between clinical trial data and RWE.
- Incorporating patient input and understanding the patient/caregiver perspective throughout the development process can lead to many benefits such as more successful clinical trial design, decreased loss to follow-up, and clearer outcome measures.
Shifting Regulatory Framework
- There is a need for a new regulatory framework to evaluate SaMD and AI due to the current regulatory paradigm not being agile enough to accommodate the faster rate of development of Software, especially with AI. Comparatively to hardware devices, software/AI versions can be more rapidly iterated which requires a more flexible, fluid regulatory pathway. FDA believes this can be accomplished by shifting to a TPLC approach by increasing post-market oversight and decreasing pre-market burden. Here are two useful documents helpful to understand the new regulatory framework:
- This was not discussed at RAPS but there is a revised biocompatibility guidance issued September 4 that can be found here.
- A new draft guidance was issued in October for biocompatibility of certain devices in contact with intact skin that can be found here.
- Safety and Performance Pathway now available for cutaneous electrodes and conventional foley catheters (August Guidance)
- Increasing de novo submissions, especially with the increasing popularity of SaMDs (63 so far this year).
- Throwing the “least burdensome flag” is one way to get management attention at FDA.
- Pro-Tip: Be cautious, sometimes getting management attention at FDA is not a good thing. If things get too heated, don’t forget that the Agency’s Ombudsman can act as an independent, impartial, and confidential third-party to help resolve disputes!
- If you have not seen it, take a look at the multiple function device guidance and do not be afraid to exclude information on exempt or enforcement discretion wellness portions of your device.
- Just a reminder that the Special 510(k) program eligibility has been expanded to allow manufacturers to make changes to the indications as well as review minimal test reports. The full details can be found in the Special 510(k) Guidance Document here.
- The NBs put together their guidance in advance of the latest version of the Regulated Product Submission (RPS) Table of Contents (TOC) but that does not mean they will not accept that format. Worth requesting if you want to leverage TOC for global submissions.
- MDSAP Non-conformity scoring – balancing defining it for consistency while still allowing auditor on site to make determination based on what they see. We encourage companies to push back if scoring does not seem aligned.
Favorite Regulatory Portrayal
- Regulatory is not the people of “No,” but rather the people that “KNOW how to solve problems.”
- Survey shows that most companies are planning to hire at least one regulatory person in 2021.
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