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The Digital Pathology Association’s FDA Task Force prepared four questions for the Regulatory Panel session held at the Pathology Visions conference last week. The third, two part question was:
The regulatory panel consisted of representatives from the FDA, CAP, and CMS/CLIA and was moderated by Dr. Stephen Hewitt of NCI. The questions above are very important but the answers have different implications on the audience. Digital pathology manufacturers are overseen by the FDA, and laboratories are overseen by CMS and CLIA guidelines. However, the only clear answer given to these questions was by FDA representative Tremel Faison. She announced,
WSI are systems and are not considered, by definition, as Laboratory Developed Tests (LDT).
To date, the FDA’s oversight of LDTs has been very limited and LDTs have been enforced at the discretion of the Centers for Medicare and Medicaid Services (CMS) which governs CLIA. Although it is very clear the FDA plans to play a bigger role in the oversight of LDTs based on the public hearing held in July of 2010, and the fact that they tabled their final guideline on IVDMIAs to address the broader issue of LDT oversight. Dr. Bruce Friedman discusses this further and provides a very good background in his blog post, “FDA Shelves IVDMIA Regulatory Initiative; Will Focus on Laboratory Developed Tests” at Labsoftnews.com.
Also present at the regulatory panel last week was CLIA/CMS representative Debra Sydnor and Dr. Walter Hendricks who represented CAP as a CMS approved accreditation organization under CLIA. These two presentations were very important to pathologists and laboratories professionals and they should have provided a clear understanding of what is or is not available to them for clinical use of digital pathology for patient care.
Dr. Hendricks provided an overview of what CAP initiatives are currently underway to assist pathologists and laboratories with validation of digital pathology. For example, he discussed the soon to be issued CAP guidelines for Validation of WSI and Dr. Anil Parwani gave a presentation earlier in the week about the guidelines. The guidelines were created by the CAP Center Working Group as,
13 STATEMENTS developed to assist the pathology community with validating WSI for clinical diagnostic use.
based on an:
Down the road (although no plan is currently in place) some of these guidelines may become a CAP Checklist Requirement. However currently there are several CAP Checklists items that are applicable today to digital pathology. Dr. Hendricks outlined all of these in his other Visions CAP presentation titled “The CAP Laboratory Accreditation Program Practical World View on Digital Pathology from a CLIA Accreditation Provider.” Based on all of this it would be easy for pathologists and laboratories to assume that CAP is trying to provide guidance on self-validation of digital pathology/WSI systems.
What does CMS/CLIA have to say about all this? Honestly, I’m not too sure. I found the regulatory panel presentation by Ms. Sydnor to be very confusing. I reviewed my notes and her presentation again this morning but could not make any more sense of it. It appears by her powerpoint that she gave some background on CLIA and then highlighted CLIA requirements that are applicable to digital pathology. Ms. Sydnor never said that WSI was not an LDT like the FDA, but in an attempt to answer a question about the components of a digital pathology system she stated,
CLIA supports the FDA.
But was this statement made based on her (or CMS/CLIA’s) unfamiliarity with digital pathology? I did not come away with any confidence that CMS/CLIA have any real understanding of what laboratories currently face regarding digital pathology.
NOW WHAT? That’s really the big question for laboratories to try and answer. My best advice is to proceed with caution but PROCEED! There are a lot of ways to use digital pathology that will not impact compliancy with CLIA; remember the only major intended use up for debate right now is primary diagnosis. Examples include tumor boards, consultations, intra-operative, education, archival, decision support, peer review, quality assurance, and manual or automated image analysis. In a previous post on my blog about the regulation of digital pathology I stated,
Are you even ready for primary diagnosis with digital pathology? There are a TON of other areas that need to be addressed to make primary diagnosis with digital pathology work. Barcodes, laboratory workflow (before and after the scanner), data storage and management, and integration with your LIS, PACS, and EMR. Just to name a few. If you are serious about our digital pathology future then stop worrying about what the FDA is saying (or not saying) and get to work! Prepare the labs for change and start using digital pathology for all those applications you are sick of hearing about.
Are you even ready for primary diagnosis with digital pathology? There are a TON of other areas that need to be addressed to make primary diagnosis with digital pathology work. Barcodes, laboratory workflow (before and after the scanner), data storage and management, and integration with your LIS, PACS, and EMR. Just to name a few.
If you are serious about our digital pathology future then stop worrying about what the FDA is saying (or not saying) and get to work! Prepare the labs for change and start using digital pathology for all those applications you are sick of hearing about.
If you are one of those rare labs that has everything worked out and are ready for primary diagnosis, then set up a clinical trial collaboration with a manufacturer or use your own discretion on self-validation of digital pathology. As discussed above several resources are available for self validation of digital pathology. Use the CAP guidelines, CAP accreditation checklists, applicable CLIA requirements, and the newly release DPA white paper on validation to guide you. Ultimately the decision is up to you and what you are comfortable with.
In post USCAP Part 1: The BIG Players In Digital Pathology I said, “A shift in the mindset of pathologists could be felt throughout the meeting and left the digital pathology industry energized about what 2011 will bring. No more just looking and talking about digital pathology, pathologists were truly starting to plan and think about how to adapt to their digital future.” This is a big step toward the “tipping point” of digital pathology, however, we still have several barriers to work through including cost, regulatory, technical, and psychological.
COST
Cost justification is difficult in digital pathology, however, there are several options to help deal with this barrier. At USCAP two companies, MikroScan and Motic, showcased small, affordable, high-quality scanners for only $35,000.
Mikroscan's D2 Desktop Scanner
Mikroscan’s Victor Casas said “we are here to disrupt the workflow” by creating an affordable system that is outside the lab and on the pathologists desk. Mikroscan believes that they do not compete against the high-throughput systems created by other manufacturers, instead their systems are positioned to work with them. Mikroscan wants to focus on intra-operative/frozen section scanning; small, remote labs in rural areas; and the personal scanning needs of pathologists. The D2 scanner’s has a very nice “desktop” look and the paddle (aka slide holder) can load four 1×3 slides, two 2×3 slides, or one 2×3 and two 1×3 slides. Objectives include a 2.5x for the macro scan, 20x, and 40x for high resolution scanning.
Motic’s microscope based system can be configured for 1 or 25 slides, and offers microscope-like flexibility with slide acquisition up to 100x and of the z-axis. Scans average around 4 minutes for a 15 mm2 area (scan time only). Their system supports a server software and viewer, and has the capability for real-time remote telepathlogy of the microscope.
However, if your digital pathology needs include mid or high-throughput scanning the cost barrier will not be overcome simply with low cost equipment. Instead you need a business plan and strategy. My company, Digital Pathology Consultants, helps organizations of all sizes create a business plan that will ”cost justify” digital pathology and set you up for digital success now and in the future. Our 5WH program provides clients with a cost-effective, unbiased business case for digital pathology. The 5WH program is based on a common methodology for information gathering and the goal is simply to answer the who, what, where, when, why and how of digital pathology. Although the methodology is simple, discovering the best answers to these questions is not easy and that is why you need help.
REGULATORY
Some day (hopefully within the next 10 years…) I’ll be able to blog about the FDA’s plan on how to regulate digital pathology manufacturers. Until that day comes pathologists, and their labs, must determine ways to safe guard themselves but still move forward with the use of digital pathology. Remember the FDA regulates what digital pathology manufacturers can claim or say their technology is used for, not what a pathologist or a hospital does with digital pathology. CLIA is who regulates laboratory use of digital pathology. At USCAP, CAP announced that the Pathology and Laboratory Quality Center were developing guidelines for digital pathology titled “CAP Validation Principles for Whole Slide Imaging in Digital Pathology.” The goal of this document is to develop principles to assist pathologists in properly validation WSI digital imaging systems. The draft recommendations will be available for public review in Sring 2011.
TECHNICAL
In post USCAP Part 2: Innovation Trends in Digital Pathology I discussed technology trends and how these are helping to address technical barriers of adoption. However, our biggest initiative must be to educate others in the HIT world and share what we learn, and to not shy away from this very real component of digital pathology. Two white papers were published by the Digital Pathology Association in 2010 and are good examples of what we must do to prepare for the data wave and the level of integration necessary to ensure pathology departments are successful with digital pathology now and in the future.
PSYCHOLOGICAL
Psychological barriers is a “hot topic” for me. I firmly believe this is an area the digital pathology industry must have a plan to address or adoption may never truly succeed. At Digital Pathology Consultants we have developed a coaching program to help departments or individual pathologists overcome the psychological impacts of digital pathology. I also know this is a point of interest for Aperio, and their CMO Jared Schwartz, MD PhD. Dr. Schwartz recently did a webinar on the Psychological Barriers and how Aperio is working to address them.
Overall, USCAP 2011 was an amazing meeting with lots to see and discuss about digital pathology. What do you think- take the poll below:
Olympus CEO Mark Gumz announced some exciting news today in a blog article/interview written by Steve Tobak. Olympus is applying for FDA approval in digital pathology, and he also used digital pathology as an example to highlight “Enterprise Innovation” at Olympus. Every FDA approval gained in digital pathology is a huge step forward for our industry and it’s great to see that Olympus is applying to the FDA for approval. The blog post, titled “Enterprise Innovation: A Key to Untapped Business Growth“ summarized a recent interview with the CEO.
Enterprise innovation is defined as “Transformative business processes, practices, organizational planning and models that enable a business of any size to operate more effectively, profitably, and/or competitively,” according to this article and a Harris Interactive survey of Fortune 1000 executives. Mark Gumz states in the article,
…The status quo is the greatest inhibitor to growth. Enterprise innovation is something that’s within our control as an industry and as a nation.
The FDA quote from Mark Gumz is as follows:
We’re currently applying for FDA approval for clinical digital pathology, the ability to send a clinical slide over the Internet. During a surgical procedure, a surgeon could take a biopsy and send it to a pathologist anywhere in the world to get a second opinion – do I take out more or not? That will ultimately be a huge cost saver. Ultimately, enterprise innovation has to come down to return on investment.
So what do you get if you put Mr. Gumz’s vision of “Enterprise Innovation” together with an application for FDA approval of clinical digital pathology? My guess…not a whole lot in the near future! There are too many unanswered questions and likely a lot of work to be done. Some of these unanswered questions are:
I realize that all companies working toward FDA approval are faced with many questions and tough regulatory hurdles, especially since the FDA has not provided any clear guidance to manufacturers on this topic. However, based on the current public information out there about Olympus, their digital pathology product portfolio, and the information displayed on their website (which is 100% research and/or education focused) I have to imagine their FDA application is probably a rough draft and a long way off from being complete.
I attended Pathology Visions last week (more on that later…) which is organized by the Digital Pathology Association (DPA). The DPA released on Tuesday two white papers; 1) Interoperability between Anatomic Pathology Laboratory Information Systems (APLIS) and Digital Pathology Systems and 2) Archival and Retrieval in Digital Pathology Systems.
The white papers are good and provide vendor neutral information to help the digital pathology industry and consumers. Here are the abstracts and a few of my favorite points from each:
Archival and Retrieval in Digital Pathology Systems
This white paper frames the issues related to Archival and Retrieval of images and associated data as Anatomic Pathology laboratories adopt a digital imaging workflow in a research or clinical setting. This overview also includes a brief discussion of some of the solutions being developed and offered in digital pathology systems (DPS’s).
DPS’s start with creation of a whole slide image and provide an imaging workflow for pathologists by associating the images with a patient and case and furnishing the tools to review the cases digitally. Whole slide images (WSI) are very large and will drive the need for extensive storage and information life cycle management. Customers seek options for fast access to high quality and highly available data, when they use the DPS in a business critical application. Most importantly, since DPS’s are deployed in regulated environments, data reliability, privacy, and security need to be built into the solution and its management process.
Solutions that are being developed and deployed in digital pathology systems are also presented.
Favorite points:
Interoperability between Anatomic Pathology Laboratory Information Systems and Digital Pathology Systems
This white paper offers an overview of the current state of interoperability between Anatomical Pathology Laboratory Information Systems (APLIS’s) and Digital Pathology Systems (DPS’s). This overview also includes a brief discussion of future work that will impact interoperability.
Both systems rely on data from the other to efficiently deliver full digital imaging functionality to the healthcare provider. Anatomic Pathology (AP) departments and patients will benefit most from imaging workflow when there is a high degree of integration of Digital Pathology information within AP workflow. Implementations of such data sharing already exist via interfaces and standard communication protocols between APLIS’s and DPS’s, and work continues on these interface standards to improve the degree to which these systems can be used together.
The current state of interoperability provides Pathologists with access to images and image analysis data from within the APLIS or the DPS. This information is then available to the Patient Report.
Steve Potts, PhD CEO of Flagship Biosciences gave a great webinar last week on the right time to use image analysis in regulated pathology. Steve was faced with the challenge of trying to convey a meaningful message to a diverse audience from both the biopharma and clinical markets. He kept everyone engaged on this detailed, ever evolving topic which provided information on FDA, CLIA, CAP/ASCO, and GLP regulatory guidelines. Steve did this well, and kept us laughing throughout the presentation.
Navigating regulatory guidelines for image analysis and digital pathology will never be easy, however there are several ways you can effectively use these technologies today while safe guarding yourself. Steve provides a lot of information and resources in his powerpoint that can help organizations work through and understand just how to do this.
As for when is the “right time”? Well, you’ll have to download the recorded webinar and Steve’s powerpoint slides to find out! Thank you Steve for your time and for presenting on this important topic!
Download the Video
Download the presentation
Stay tuned to this blog and/or register for my newsletter to find out about our future webinars.
By Steve Potts, PhD
The formal training of pathologists has an impressive history, and pathology boards for both medical and veterinary pathologists are very difficult professional exams. As digital pathology slowly makes it way from a early adopter technology to mainstream, there will be an increased need for training of the “digital” pathologists, both in working remotely with digital slides (which is fairly quick to pick up) to image analysis (which takes more time and specialization). The vendors of digital pathology scanners generally offer basic and generic software training, and have done a good job of educating the pathologists in how to use the tools. However, much more work needs to be done across the industry in improving training opportunities for pathologists using quantitative analysis, both in the research and clinical markets.
The challenge of image analysis training in the clinical environment is illustrated by a question I had from the audience at a talk I gave recently on Validation of Image Analysis in GLP and CLIA environments. Someone asked,
We use the ER/PR algorithms from the manufacturer on Ki67 out of the box, and we want to know how to validate them?
The problem with this simplistic approach is that Ki-67 has a binary thresholding criteria rather than multilevel in ER/PR, and the Ki-67 staining patterns are generally much different in the nuclei than ER/PR and usually require tuning changes in how the software scores. And Ki-67 is a very simple marker! The best validation process is useless unless the pathologist knows how the algorithms work, and has a generally good understanding of image analysis concepts. While we are working actively on better validation approaches for image analysis for both clinical and GLP preclinical environments, real world training in image analysis must come first.
So prior to our plans for image analysis validation services, we first need to make training of image analysis more accessible to pathologists as well as imaging scientists and support personnel at pathology centers. This is a difficult activity for vendors to do, as it really should be taught by a combination of pathologists and image analysis experts. So many image analysis results heavily depend on the condition of the tissue in staining, fixation, or other histology steps, the pathologist needs to be involved in training to be able to point out some of these things. IHC overstaining is the precise reason that pathologists need to work closely with histotechnologists in determining the exact antibody dilution to use with each stain. Close communication avoids other artifact pitfalls that affect pathology endpoints and analytical consistencies. Some antibody vendors actually customize their IHC processes to make the antibody stains much darker, which might(?) be helpful to the human eye, but is poor for image analysis, where lighter staining is usually much better. If I had a dollar for every time someone has asked for an algorithm that will work on overstained IHC slides, well, I could buy a couple more slide scanners.
The other reason it is difficult for vendors is that under strict medical device manufacturing guidelines, particularly in the clinical environment, vendors need to stick to discussing and training on the markers for which they are cleared. This means training on the familiar three amigos ER/PR/HER2, and usually on only the subtype of breast cancer for which they have been validated and cleared. There is much more to this limitation than can be addressed here, but it clearly limits for good reason clinical IHC software vendors conducting broad training in image analysis.
The other challenge in training pathologists is time. Due to the heavy workload of many pathologists, there is often little time to devote to attendance at a two-day course either onsite or at the scanner vendor location. The histologist and the lab manager may go, but usually the pathologist simply cannot get the time free in his or her schedule.
To respond to this need, Flagship Biosciences is offering a once-a-week, six week image analysis course online, scheduled each Thursday. It is co-led by an image analysis expert and a board-certified pathologist, which makes for a fascinating interaction. Each session only lasts 2 hours (we may cut it to 90 minutes in the future, this is the limit that people can absorb information), and it gives a week in between for attendees to try out the concepts, see what worked and didn’t work, and come back with questions. We will start with basic cell and area measurement, and move toward more advanced, sophisticated software-aided approaches as the courses progress. We hope that after a pathologist and a pathology lab knows how the algorithms work and how to relook at their IHC approaches for quantitation, the next steps will be image analysis validation training.
It will be interesting to see if image analysis becomes something every pathologist is familiar with and can run, or will be the domain of pathology specialists. I hope for the former, but I am betting on the latter.
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