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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.
FDA representative Tremel Faison made it clear last week, during the Regulatory Panel at the Pathology Visions conference, that digital pathology systems will be classified as a class III medical device, requiring manufacturers seeking approval to follow a Pre Market Approval (PMA) process. If you have been following the regulation of digital pathology closely the news of a PMA should not be a shock. In fact this point was made by the same FDA representative in her presentation at the first FDA advisory panel meeting on digital pathology back in October 2009. In a previous blog post titled “The FDA States, WSI Systems are Not Class I Exempt” which I authored at www.tissuepathology.com I stated,
The initial presentation given by Tremel Faison, a Scientific Reviewer for the FDA, set the tone for the meeting whereby she informed the public and panel that WSI systems could not be Class I exempt, like a microscope, and are therefore subject to premarket requirements. The reason a WSI device will not be considered exempt is, as defined by21 CFR 864.9 limitations, a WSI device is considered to be different fundamental scientific technology and IVD intended for use in diagnosis.
However several manufacturers have pushed for this to be reconsidered over the past several years based on the extensive requirements and the enormous cost of the PMA process. A PMA submission to the FDA will cost a manufacturer $240K, and with extensive clinical trials needed to prepare for submission to the FDA, a manufacturer may have to invest at least $1M -$2M for a possible approval. If the approval is rejected, they will have to invest even more to redesign the trial and then resubmit. The only road map suggestion was for manufacturers to follow the path of cytology screening devices such as the ThinPrep Imaging System.
A submission to the FDA was made on January 7, 2002 for ThinPrep Imaging System and the PMA was finally awarded 17 months later on June 6, 2003. The Summary of Safety and Effectiveness Data for the ThinPrep Imaging System outlines the details of their extensive, multi-site clinical trial and it appears that the studies probably started some time in 2000, which estimates that this entire process probably took around 3 years.
The 510(k) process for clearance of quantitative IHC analysis as a class II device will remain unchanged, and will not be effected by the approval process for digital pathology systems. A 510(k) submission costs only $4K and the clinical trials are much smaller and focused. As a result a manufacturer may only have to spend between $50K-$100K to achieve a 510(k) clearance. This could be a stopgap for manufacturers. Manufacturers could focus on obtaining a portfolio of analysis algorithms that are reagent specific, and could even expand beyond the breast panel while working to obtain their PMA’s for primary diagnosis of H&E slides. Both types of clearances/approvals will be needed and they go hand in hand.
The most recent 510(k) clearance was awarded to Ventana for their Virtuoso System for HER2 using the iScan slide scanner. The clearance is for computer-assisted image analysis scoring and manual scoring of digital images of IHC stained (Ventana Pathway 4B5) HER2 slides. The FDA issued the 510(k) clearance in just over 4 months and the entire process including clinical trial work took approximately one year.
There is no doubt that manufacturers seeking FDA approval have their work cut out for them. Sadly this may be a game changer for some manufacturers. Manufacturers may have to pull back on the US market and focus their business strategies in other parts of the world or realign their market focus to research and education. This situation is not uncommon in the medical device market. A recent article in the Wall Street Journal titled “How the FDA Could Cost You Your Life” was written by Dr. Scott Gottlieb who was previously a deputy commissioner at the FDA. In the article he states,
This is an all too familiar story, the FDA impeding useful innovations in the U.S. Entrepreneurs here are forced to test promising medical devices in costly animal studies for years before they can advance their products into clinical trials. When clinical studies get started, the FDA is asking for longer and larger trials that increasingly mirror hurdles proposed for new drugs. In response, American device makers are moving their business overseas. Between 2004 and 2010, more than half of all innovative devices were first approved in Europe. Because more devices now launch in Europe, companies increasingly study the products there. In 2004, 86.9% of all medical-device studies listed in www.clinicaltrials.gov were being carried out in the U.S. By 2009, only 45% of clinical trials were run here.
This is an all too familiar story, the FDA impeding useful innovations in the U.S. Entrepreneurs here are forced to test promising medical devices in costly animal studies for years before they can advance their products into clinical trials. When clinical studies get started, the FDA is asking for longer and larger trials that increasingly mirror hurdles proposed for new drugs.
In response, American device makers are moving their business overseas. Between 2004 and 2010, more than half of all innovative devices were first approved in Europe. Because more devices now launch in Europe, companies increasingly study the products there. In 2004, 86.9% of all medical-device studies listed in www.clinicaltrials.gov were being carried out in the U.S. By 2009, only 45% of clinical trials were run here.
Furthermore he adds,
This is no way to run a regulatory process if the FDA is serious about promoting medical innovation and advancing the public health.
Digital pathology has the power to improve patient care, and there are a growing number of studies out which highlight how digital pathology may be better than the gold standard, a microscope. This point is articulated very well in a letter to digital pathology companies from a group of pathologists for digital pathology lead by Dr. Keith Kaplan. The pathology community is trying to help and to show the value. Now if only the FDA and its’ broken regulatory process would listen…
Stay tuned this week for blog post Part 2: Digital Pathology is not an LDT! Now what?
The second most popular question people ask me as a consultant in digital pathology is,
Have there been any updates to the FDA’s position on Digital Pathology?
No, but there are safe and effective ways to use digital pathology in a clinical setting today. 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. Safe and effective uses of digital pathology are available today that can benefit hospitals, labs, pathologists, medical students, residents, patients and more. Examples include tumor boards, consultations, intra-operative, education, archival, decision support, peer review, quality assurance, and manual or automated image analysis.
You are thinking…
Blah, blah, blah, blah.. and blah. I’ve heard all of this before! Tell me when will this be ready and safe for primary diagnosis?
Okay, but let me warn you… you asked for it! CLIA is who regulates laboratory use of digital pathology. So, let’s see what CLIA says:
Sec. 493.1253 Standard: Establishment and verification of performance specifications (a) Applicability. Laboratories are not required to verify or establish performance specifications for any test system used by the laboratory before April 24, 2003. (b)(1) Verification of performance specifications. Each laboratory that introduces an unmodified, FDA-cleared or approved test system must do the following before reporting patient test results: (i) Demonstrate that it can obtain performance specifications comparable to those established by the manufacturer for the following performance characteristics: (A) Accuracy. (B) Precision. (C) Reportable range of test results for the test system. (ii) Verify that the manufacturer's reference intervals (normal values) are appropriate for the laboratory's patient population. (2) Establishment of performance specifications. Each laboratory that modifies an FDA-cleared or approved test system, or introduces a test system not subject to FDA clearance or approval (including methods developed in-house and standardized methods such as text book procedures, Gram stain, or potassium hydroxide preparations), or uses a test system in which performance specifications are not provided by the manufacturer must, before reporting patient test results, establish for each test system the performance specifications for the following performance characteristics, as applicable: (i) Accuracy. (ii) Precision. (iii) Analytical sensitivity. (iv) Analytical specificity to include interfering substances. (v) Reportable range of test results for the test system. (vi) Reference intervals (normal values). (vii) Any other performance characteristic required for test performance. (3) Determination of calibration and control procedures. The laboratory must determine the test system's calibration procedures and control procedures based upon the performance specifications verified or established under paragraph (b)(1) or (b)(2) of this section. (c) Documentation. The laboratory must document all activities specified in this section.
The sentence highlight above “… or introduces a test system not subject to FDA clearance or approval” means that a laboratory should be able to validate a digital pathology solution on their own for clinical use. And although the FDA has not formally stated whether scanners will be “subject to FDA approval” it seems clear through they will. The background briefing document about the Advisory Panel Meeting held in October 2009 stated,
FDA hopes to gather information about how to evaluate and compare the performance characteristics of both the light microscope- the reference method- and the digital WSI method-…FDA follows the Code of Federal Regulation 21 CFR 860.7 for ensuring the safety and effectiveness of regulated medical devices…FDA believes the first requirement for adoption of digital whole slide imaging will be the maintenance of the diagnostic accuracy and reproducibility of current surgical pathology diagnostic performance using the conventional light microscope- the current reference method for the diagnosis of cancer and other histopathological entities.
At the Advisory Panel Meeting, Tremel Faison the Scientific Reviewer in the Office of In Vitro Diagnostic Device Evaluation and Safety, stated:
“…everything here at the FDA starts with an intended use. Intended use shapes how the device will be regulated, in what population and ultimately the study design. For the scope of this Panel meeting, the intended use is defined as the use of whole slide imaging for primary diagnosis of surgical pathology microscope slides in lieu of a microscope. This is not an adjunctive intended use, and for our purposes, we will be considering the use of whole slide imaging for all surgical pathology specimens. It will not be organ or disease specific… We recognize that the technological advances associated with whole slide imaging make its use a reality. Whole slide imaging systems are not Class I exempt and are therefore subject to premarket requirements.
“…everything here at the FDA starts with an intended use. Intended use shapes how the device will be regulated, in what population and ultimately the study design. For the scope of this Panel meeting, the intended use is defined as the use of whole slide imaging for primary diagnosis of surgical pathology microscope slides in lieu of a microscope. This is not an adjunctive intended use, and for our purposes, we will be considering the use of whole slide imaging for all surgical pathology specimens. It will not be organ or disease specific…
We recognize that the technological advances associated with whole slide imaging make its use a reality. Whole slide imaging systems are not Class I exempt and are therefore subject to premarket requirements.
As I said above, although the FDA has not formally stated whether scanners will be subject to FDA approval it seems clear they will. So, now what? You could try and go through CLIA for approval of your scanner within the lab or wait for direction from the FDA. Neither seems like that great of an option.
I started this post with the second most popular question asked of me and here is my response:
What does it matter! 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.
Digital Pathology Blog: The FDA States, WSI Systems Are Not Class I Exempt. This post was written by me as a guest author at tissuepathology.com. Tissuepathology.com is an educational and informative weblog for the digital pathology community, authored by Dr. Keith Kaplan.
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