Introducing VarSeq Dx as a Medical Device in the European Union
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A transition period regarding in vitro medical device (IVD) regulation in the European Union (EU) is upon us. The former IVDD regulations are phasing out and IVDR 2017/746 has already taken its place as the acting regulation for IVD manufacturers but also lab developed tests (LDTs) and health institutions. In our upcoming webcast we will talk about the roles and significance of IVDR and ISO 13485 certification for clinical labs and for Golden Helix as a medical device manufacturer. Join us as we will introduce VarSeq 2.6.1 complete with Dx Mode, which offers the use of VarSeq as CE marked medical device. Even more we will also present strategies to facilitate the transition of Golden Helix customers to operate in accordance with IVDR.
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Introducing VarSeq Dx as a Medical Device in the European Union
- 1. May 22, 2024 Presented by Julia Love Introducing VarSeq Dx as a Medical Device in the European Union
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- 3. May 22, 2024 Presented by Julia Love Introducing VarSeq Dx as a Medical Device in the European Union
- 4. Today’s Presenter 4 Rana Smalling, PhD Gabe Rudy VP Product & Engineering Introducing VarSeq Dx as a Medical Device in the European Union Julia Love Associate Director of Product Quality
- 5. NIH Grant Funding Acknowledgments 5 • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: o Award Number R43GM128485-01 o Award Number R43GM128485-02 o Award Number 2R44 GM125432-01 o Award Number 2R44 GM125432-02 o Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 o NIH SBIR Grant 1R43HG013456-01 • PI is Dr. Andreas Scherer, CEO of Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- 6. Golden Helix at-a-Glance 6 Company Snapshot: Leading SaaS provider of tertiary genomic analysis solutions for NGS labs Golden Helix is a SaaS bioinformatics solution provider specializing in next-gen sequencing (“NGS”) data analysis The Company’s software enables automated workflows and variant analysis for gene panels, exomes, and whole genomes Key Clinical Applications Prenatal testing Hereditary disease testing Reproductive testing Oncology Marquee Global Clients Golden Helix’s solutions allow clients to increase throughput, ensure consistent quality, maximize revenue, and save time 1998 Company Founded Bozeman, Montana Headquarters Recognitions Government Research Pharmaceuticals Agrigenomics Testing Labs Translational Labs Human Genetics Research Hospitals Academia Publications Content & Resources Pharmacogenetics testing
- 7. NGS Clinical Workflow Golden Helix provides comprehensive data analytics software that scales across gene panels, whole exomes, and whole genomes DNA Extraction in Wet Lab and Sequence Generation Interpretation and Result Reporting Primary Read Processing and Quality Filtering Alignment and Variant Calling Secondary *Golden Helix provides Secondary Analysis through a reseller agreement Tertiary Golden Helix’s software and primary focus Comprehensive secondary and tertiary analysis solutions for primary data aggregated by all commercially available sequencers Type Size Gene Panel Small (100MB) Whole Exome Medium (1GB) Whole Genome Large (100GB) Cancer use case Hereditary use case Process Analysis … and scales across multiple data set sizes for cancer and hereditary use cases Filtering and Annotation Data Warehousing Workflow Automation Golden Helix works with all major sequencers and testing kit providers…
- 8. NGS Clinical Workflow Golden Helix provides comprehensive data analytics software that scales across gene panels, whole exomes, and whole genomes DNA Extraction in Wet Lab and Sequence Generation VSClinical Primary Sentieon PLOT & UMI Sentieon DNAseq Secondary *Golden Helix provides Secondary Analysis through a reseller agreement Tertiary Golden Helix’s software and primary focus Comprehensive secondary and tertiary analysis solutions for primary data aggregated by all commercially available sequencers Type Size Gene Panel Small (100MB) Whole Exome Medium (1GB) Whole Genome Large (100GB) Cancer use case Hereditary use case Process Analysis … and scales across multiple data set sizes for cancer and hereditary use cases VarSeq VSWarehouse VSPipeline Golden Helix works with all major sequencers…
- 9. ISO Certification 13485:2016 9 • ISO 13485:2016 from TÜV SÜD • ISO 13485:2016 is an international standard that specifies requirements for a quality management system (QMS) for organizations involved in the design, development, production, and servicing of medical devices. o maintain a quality management system o demonstrate sufficient risk management o show consistent tracking of customer satisfaction and safety in the market o demonstrate continued improvement efforts on the product and system level. • ISO 13485:2016 is designed to objectively document that we are holding ourselves to the highest quality standards as we are providing innovative solutions to hospitals, testing labs, and research institutions globally.
- 10. In vitro Medical Device Regulation (IVDR) 10 • The purpose of IVDR is to ensure consistency in safety and performance for in vitro diagnostic medical devices (IVDs). • Lab developed tests may incorporate one or more IVDs • Key incidents led to the need for stricter IVD regulation and IVDR was created • Labs need to update their quality management system which is expected to be ISO 13485 compliant under IVDR.
- 11. IVDR Transition Timeline 11 2022 2030 2027 2028 2029 IVDR Valid All new devices must comply with IVDR IVDD Class D Devices IVDD certified devices must comply with IVDR IVDD Class A sterile and Class B Devices IVDD certified devices must comply with IVDR IVDD Class C Devices IVDD certified devices must comply with IVDR IVDD Invalid Sell-off period is complete
- 12. ISO 13485 for Labs and Health Institutions 12 • Proof to customers that the organization follows high-quality standards • ISO 15189 compliant labs should make changes to existing quality management systems to comply with ISO 13485 • Building based on IVDR compliant devices and ISO 13485 certified manufacturers simplifies LDT development
- 13. Golden Helix Solution 13 Golden helix is an ISO 13485 device manufacturer as of January 2024 VarSeq is a CE marked Medical Device under IVDR as of April 2024 VarSeq is CE marked in version 2.6.1 when Dx Mode is activated
- 14. VarSeq Dx Mode Requirements 14 Reviewed Installation Verification Test (IVT) • Confirmation that VarSeq was correctly installed • Confirmation that standard VarSeq features function as expected 1 Golden Helix User Certification Program • Tiered approach to certification based on licensed VarSeq features • Declaration of proficiency certificate earned when certification program is completed 2
- 17. Summary of VarSeq as a Medical Device 17 • It is essential for clinical labs in the EU to leverage IVDR-compliant devices and work with ISO 13485- certified manufacturers • VarSeq 2.6.1 introduces VarSeq Dx Mode and will be offered for all future VarSeq releases • To use VarSeq as a medical device customers need to confirm acceptable VarSeq installation and user certification.
- 18. NIH Grant Funding Acknowledgments 18 • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: o Award Number R43GM128485-01 o Award Number R43GM128485-02 o Award Number 2R44 GM125432-01 o Award Number 2R44 GM125432-02 o Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 o NIH SBIR Grant 1R43HG013456-01 • PI is Dr. Andreas Scherer, CEO of Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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- 20. eBook Library 20 • Prenatal Genetics – Learn the Following o Existing approaches to prenatal WES, along with clinical indications for its use o How VarSeq and VSClinical can be utilized for its use o A few interesting cases of variants and their classifications • Pharmacogenetics – Learn the Following o Foundations of Pharmacogenomics o Genetic variability and drug response o Pharmacogenomic test reporting nomenclature and terminology o The Pharmacogenomic eco-system o VSPGx - A pharmacogenomics application
- 21. 21 Discover the Latest at Golden Helix's Booth at booth 428! • In-Booth software demos. • Famous t-shirts for demo attendees. • EBooks, engaging discussions, and more! Corporate Satellite Talk Golden Helix – A Clinical Interpretation Solution for Next Generation Sequencing Labs Monday, June 3rd, 12:00-13:00, Room: New York 1 Presented by: Dr. Andreas Scherer, Golden Helix President & CEO Nathan Fortier, PhD, Golden Helix Director of Research Jennifer Dankoff, PhD, Field Application Scientist Guest Speakers: Tina Han, Director of Applications & Business Development, Twist BioSciences David Stucki, Field Application Support Manager, PacBio ESHG 2024: What to Expect Dr. Andreas Scherer Nathan Fortier Jennifer Dankoff Tina Han David Stucki
- 22. ESHG Booth #428 Demo Schedule 22 Saturday, June 1st Sunday, June 2nd Monday, June 3rd • 10:10 - PGx: Pharmacogenomics Workflow • 12:10 - VarSeq Dx: Using the VarSeq Suite as a Medical Device Under IVDR • 12:40 - Whole Genome Analysis with Long Read Data • 13:10 - Calling CNV with Twist Exome 2.0 • 13:30 - NGS Enterprise Capabilities - Automation, Warehousing, Continuous Improvement 16:10 - Carrier Status Analysis in VarSeq • 18:10 - Somatic NGS Workflow with VarSeq - Streamlining Tertiary Analysis with Oncogenicity Classifier and CancerKB • 10:10 - Somatic NGS Workflow with VarSeq - Streamlining Tertiary Analysis with Oncogenicity Classifier and CancerKB • 12:10 - PGx: Pharmacogenomics Workflow • 12:40 - VarSeq Dx: Using the VarSeq Suite as a Medical Device Under IVDR 13:10 - Whole Genome Analysis with Long Read Data • 13:40 - Carrier Status Analysis in VarSeq • 15:40 - NGS Enterprise Capabilities - Automation, Warehousing, Continuous Improvement • 16:40 - Calling CNV with Twist Exome 2.0 • 10:10 - Carrier Status Analysis in VarSeq • 12:00 - 13:00 Corporate Satellite Talk (Room: New York 1): Golden Helix: A Clinical Interpretation Solution for Next-Generation Sequencing • 13:30 - VarSeq Dx: Using the VarSeq Suite as a Medical Device Under IVDR • 15:40 - PGx: Pharmacogenomics Workflow • 16:10 - Calling CNV with Twist Exome 2.0 • 16:40 - NGS Enterprise Capabilities - Automation, Warehousing, Continuous Improvement
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Editor's Notes
- Thanks Casey! We can’t wait to dive in to this subject
- Thanks Casey! We can’t wait to dive in to this subject
- Before we start diving into the subject, I wanted mention our appreciation for our grant funding from NIH. The research reported in this publication was supported by the National institute of general medical sciences of the national institutes of health under the listed awards. We are also grateful to have received local grant funding from the state of Montana. Our PI is Dr. Andreas Scherer who is also the CEO at Golden Helix and the content described today is the responsibility of the authors and does not officially represent the views of the NIH. So with that covered, Before diving into today's topic, I'd like to offer some background and context on what Golden Helix brings to the table as a company
- Since1998, we have been supporting research and vital clinical applications across various industries worldwide. Among our key applications are oncology, where we facilitate clinical analysis through specialized databases and empower precision medicine with targeted molecular therapy. Additionally, we cater to a diverse range of hereditary use cases, from diagnostic disease testing to prenatal and reproductive reporting for couples. More recently, we've introduced pharmacogenomic testing, which holds particular value for healthy individuals. By analyzing their genetic information, they can preemptively steer clear of potential adverse effects from prescribed medications in the future. Beyond our extensive capabilities, we also have a diverse user base encompassing government labs, renowned institutions like UCLA conducting both research and clinical practices, high-throughput clinical testing labs, and research hospitals, among others. And in working with such varied labs, we encounter diverse workflows, specialized data requirements, and the need for tailored bioinformatic pipelines along with end-to-end automation solutions. Ultimately, by working closely with our customers we can discern the evolving needs in the genetic analysis domain, and subsequently integrate them into our product roadmap. Over our 25 years in operation, this collaborative effort has yielded thousands of customer publications. We take pride in delivering systems that prioritize automation, facilitate nuanced data interpretation, and seamlessly translate insights into actionable clinical endpoints. Ultimately, our goal is to streamline the adoption of genetic tests, making the process efficient and economical, while significantly impacting patient care and clinical outcomes.
- What does the Golden Helix full-stack workflow entail? Our system is holistically designed, starting with secondary analysis for sequence alignment and variant calling. It's crucial to highlight that we support multiple upstream next-generation sequencing (NGS) platforms, including Illumina and Thermo Fisher also we accommodate long-read technologies such as Nanopore and PacBio, as well as emerging sources like MGI. Within these NGS platforms, users can opt for a targeted approach using gene panels or escalate to whole exomes or, increasingly cost-effective, whole genomes. Notably, there are few platforms that can transition from gene panels to whole genomes on the analysis front. The data scale amplifies significantly at each stage, with a surge in the number of variants analyzed, which is accompanied by heightened computational and storage demands. Moving into tertiary analysis, our platform has exceptional annotation and filtering capabilities, alongside clinical report interpretations for variants, CNVs (Copy Number Variations), and fusions. Furthermore, we offer automation functionalities for each component of tertiary analysis. Lastly, we provide robust data warehousing solutions to streamline data management and accessibility.
- On a product level, we have different solutions that work together and cater to each stage of this process. We've partnered with Sentieon for upstream preparation and secondary analysis, VarSeq handles variant annotation and filtering, VSCLinical manages clinical workflows, VSPipeline ensures automation across the board, while our warehouse serves as an intuitive repository for aggregating and storing variant frequency data from your own cohorts over time. This comprehensive infrastructure not only facilitates efficient data management but also enables easy retrieval of clinical interpretation work that can be applied to new samples as they undergo analysis.
- Each of the applications we've just discussed has been meticulously crafted by our in-house team here at Golden Helix. Our team adheres to a highly structured manufacturing process, one that we've diligently documented and embraced. This commitment has earned Golden Helix an ISO 13485 certification as a medical device manufacturer. For laboratories, especially those within the European Union, this certification holds significant importance and labs developing in-house tests would benefit from seeking ISO 13485 certification as it aligns with the expectations outlined in the In Vitro Device Regulation (IVDR). But essentially, upstream venders can more easily to be incorporated into your own quality management systems and processes if they themselves are 13485 certified. With our certification, we offer labs the assurance of easy reproducibility of our quality specifications and manuals, thus simplifying the validation processes. Furthermore, labs can trust that both our current and future versions of our products are developed using this robust quality management system, ensuring the delivery of high-quality products.
- IVDR establishes standardization for medical devices and their manufacturers that market and sell these devices or products in the EU. The goal is to ensure that in vtiro medical devices are safe and have reliable performance. IVDR applies to any device that is used directly on humans or to monitor humans. Lab developed tests may concatenate any number of the devices together but these devices range from reagents to software used in clinical labs, calibrators, diagnostic assays, test kits digital systems for analysis, and implanted devices. Prior to IVDR there were a few other directives that regulated in vitro medical devices including the in vitro medical devices directive or IVDD, medical devices directives (MDD) and the active implantable medical devices directive (AIMDD) but they weren’t keeping up new advancements in genetic testing and other modern devices. And in 2010 the shortfalls in these directives came to light with the PIP Scandal. The manufacturer poly implant prothese (protheys) manfucatured breast implants- they switched from using medical grade silicone to industrial grade silicone to cut manufacturing costs but the impurities in the silicone increased the risk of rupture by 500%! 10 years after the silicone switch there were several deaths due to toxicity or breast cancer. The problem in this case was associated with poor post marketing surveillance which was a big aspect that IVDR and ISO 13485 certification focused on improving. With IVDR stepping in and the other directives phasing out, lets take a look what this transition period will look like.
- IVDR replaced IVDD on 5/26/2022 so all new devices since 2022 must be IVDR compliant. However devices previously compliant with IVDD have a sell off period and transition period to become compliant with IVDR. High patient risk devices with high public risk (class D devices) have a shorter grace period to transition to IVDR than Class B or A devices as they pose less risk to patient health. Outside of these critical deadlines to transition to IVDR it is important to note that if IVDD CE marked devices are being used in the interim they still must maintain their IVDD certification so even before these deadlines arrive its worth verifying that the IVDD certification has not expired and then when the deadlines do arrive you may need to still be diligent about confirming the device is now CE marked and valid under IVDR. In addition these IVDD devices are limited in the changes they can undergo while in the sell off period. The approved changes are primarily for minor bug fixes or subtle adjustments to existing functionality, but new feature development is halted until IVDR compliance is achieved. Right now we are in the middle of this changeover period but now let’s talk about what can labs do now to get a jump start on this process.
- We talked about the importance of ISO 13485 already but what does this really mean for labs and health institutions with new IVD regulation. The ISO 13485 certification communicates to your customers assurance that products are manufactured according to industry-accepted best practices. Many labs and or health institutions providing lab developed tests likely already have a quality management system in place under ISO 15189, which is a requirement stated by IVDR. At the same time, the IVD regulations also clarify that an ISO 15189 compliant quality management system are not sufficient for manufacturing Lab Ddeveloped Tests and it is expected for these labs to update or augment their current QMS to comply with ISO 13485. This whole process becomes easier for labs when the LDTs are built by integrating IVDR compliant devices with ISO 13485 certified manufactures.
- Now Golden Helix is proud to announce that we can offer ourselves as not only an ISO 13485 certified device manufacturer since January of this year, but now VarSeq is a CE marked medical device under IVDR as of April! That being said, by default VarSeq is not CE marked. However, If you want to use VarSeq as CE marked medical device, we have developed VarSeq Dx Mode which is available in 2.6.1 and will be available in all future versions of VarSeq As well. To use VarSeq in Dx Mode, there are a few requirements and steps that need to be taken to unlock this capability.
- The first requirement is to verify VarSeq’s installation is correct and working proficiently. To achieve this, we will provide an installation verification test to any customer that would like to use VarSeq Dx Mode. This is a straightforward test that is carried out by the user and confirms 2 important concepts, first that VarSeq was installed correctly meaning we want to make sure VarSeq is installed in a location that users have stable connections to golden helix servers, there is appropriate read and write access to files and folders required by VarSeq to run proficiently, there is optimal space on the machine to store data, among other metrics. And Second is to verify that the most standard VarSeq features function as expected, so this means you can create a project, import data, annotate variants, build a filtering workflow, run algorithms and VarSeq performs all of these actions without a hitch. The second requirement is that golden helix can offer a User Certification Program. The certification program verifies that at least one user in the lab or institution has sufficient knowledge and understanding of the program to carry out variant analysis using VarSeq. The level or extent of the certification depends on the which licensed VarSeq features are active for your lab or institution. The Golden Helix User Certification program is synergistic with what a lab must do to obtain and maintain accreditation.
- Alright now let’s take a look at what VarSeq Dx Mode like from the software perspective! VarSeq functionality does not change when in DX Mode, so it’s the same old software you know and love. But then how can you tell if you are using VarSeq in Dx Mode or not? There are some key places to look that you can confirm that you are using Dx Mode. First is the login screen, so straight away you can note the VarSeq Dx Mode logo here but also the Title bar will show the version of VarSeq you are using- 2.6.1 and the Dx signifies that you are in Dx Mode, and this DX in the title bar sticks around while you are within a project, or VSClinical as well not just at the start screen. Of course in the Help menu you can select About VarSeq and this dialog on the right pops up and you can see the Dx here by the VarSeq build and you can see in the Features list that Dx Mode is turned on for the license.
- The last place you can look is the project log. The project log will log the user and indicate that each action within the project was carried out in Dx Mode.
- So in summary, IVDR is already in place and the transition for non IVDR compliant devices is upon us. It is essential that Clinical labs in EU leverage IVDR-compliant devices and for ease of compliance, and work with ISO 13485 certified manufacturers. This year, Golden Helix and VarSeq can now check both of these boxes with the ISO 13485 certification and the CE mark for VarSeq as medical device under IDVR. The latest VarSeq 2.6.1 release introduces Dx Mode so VarSeq can be used as a medical device and In order to activate Dx Mode customers will need to show that VarSeq is installed correctly and certify at least one person in the lab/institution as a VarSeq user. Our area directors are happy to talk about this process whether you are an existing VarSeq customer or a new one!
- Before wrapping up, we'd like to again state our appreciation for the grants included here. In addition, we’d also like to thank our European customers for their feedback and just mention how we are excited to support our European customer base by offering VarSeq Dx Mode and simplifying the IVDR compliance process. Look for us at ESHG where we would love to talk to you more about VarSeq Dx . And with that, I'll hand things back to Casey and he will give you more details on visting us at ESHG along with other exciting marketing updates and then also take us through a Q&A session.
- Join us for an insightful discussion on our latest advancements in the clinical interpretation of next-generation sequencing data. Discover our high quality variant analysis and interpretation capabilities that scale efficiently. Implement ACMG and AMP guidelines for variant interpretation, directly call CNVs in target regions, exomes and whole genomes, and utilize repeatable clinical interpretation workflows. Recently, we unveiled our pharmacogenomics solution VSPGx, based on the CPIC guidelines. We will share some of the VSPGx capabilities in further detail. Talk about a variety of capabilities that we have for hereditary diseases pgx and cancer, excited for guest speakers from twist and pacbio that talk about specific aspects of our partnership at eshg.
- PGx: Pharmacogenomics Workflow VarSeq Dx: Using the VarSeq Suite as a Medical Device Under IVDR Whole Genome Analysis with Long Read Data Calling CNV with Twist Exome 2.0 NGS Enterprise Capabilities - Automation, Warehousing, Continuous Improvement Carrier Status Analysis in VarSeq Somatic NGS Workflow with VarSeq - Streamlining Tertiary Analysis with Oncogenicity Classifier and CancerKB
- Questions: Are we limited to TSO500 data for somatic analysis or can we build our own panel and include any number of customer genomic signatures? Answer: No limitations at all. User can build any somatic panel or workflow overall and include any specific sample level data either in the variant tables or from the sample manifest. TSO data is just one example among any physical or virtual panel your lab would run 2. Can the CNV calling in the whole exome example be automated with pipeline too? A: Yes! When you build the original workflow template, you can include CNV calling, or importing externally called CNVs and SVs. These will also go through the annotation process. 3. How to save time and effort in variant interpretation if you or a teammate need to sequence the whole genome for a sample already analyzed in VarSeq as a gene panel?A: You can save already assessed variant interpretations to assessment catalogs and reuse to avoid rework.