Tag Archive for Regulatory

Part 1: An Update on the FDA’s Regulation of Digital Pathology

November 9, 2011 Clinical Trials, Digital Pathology, FDA, Pathology Comments Off

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.

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? 

 

Stop Worrying About What The FDA Is Saying (or Not Saying) About Digital Pathology

March 16, 2011 CLIA, FDA, Regulatory 2 comments

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.

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.

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.


USCAP Part 3: Break Down Adoption Barriers

March 14, 2011 CAP, Coaching, Digital Pathology, Meetings, Regulatory, USCAP, Validation Comments Off

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:

QuestionsView Results

Olympus Applying for FDA Approval in Digital Pathology

November 18, 2010 Clinical Trials, DICOM, Digital Pathology, Interoperability, Regulatory, Validation Comments Off

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:

  • What instrument, software, algorithm, technique, etc are being used in the application to the FDA? This is very confusing since Olympus America offers their own VS110 microscope-based slide scanner and software, distributes the NanoZoomer and it’s software from Hamamatsu, distributes image analysis software from Visiopharm on both hardware platforms, and still has server and viewer software from Bacus Laboratories, Inc (a company  they acquired in 2006).
  • With whom are the clinical trials being conducted and what type of data is being gathered for application to the FDA? Several  competitors of Olympus have publicly announced and or have discussed details of their clinical trials.  For example, Aperio’s Project Pink is a primary diagnosis concordance study focused on breast tissue with four sites in the United States, and one of those sites is MD Anderson.  Omnyx announced in a recent press release the start of their clinical trials with three sites in the Unites States and one in Canada.  However, I have never seen or heard anything about clinical trials with Olympus.
  • What is going to or has changed within the Olympus digital pathology product line to be more clinically oriented? They primarily sell hardware with a data management/viewer software solution that typically functions in a stand-alone research environment.  Clinically oriented hardware and software products from their competitors are very different and are designed with consideration for the histology lab and the diagnostic routine of a pathologist.
  • What is being done to support laboratory workflow and interoperability within the pathology department and hospital? At Pathology Visions a Pathologist and I spoke with marketing staff at Olympus about this.  As of a few weeks ago Olympus did not have integration with any LIS vendors.  Also, they explained to the pathologist I was with that they do not support the DICOM format (WG-26 Supplement 145) recently approved for digital pathology.
  • What about that ROI mentioned in the FDA quote above? I have not seen or heard of any marketed or published data showing Olympus’s efforts to create an ROI business model in digital pathology.  Maybe that’s in the works??

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.

The DPA Issues Two White Papers

November 3, 2010 CDSS, Cloud, Data Storage, DICOM, Digital Pathology, Interoperability, IT, Laboratory Automation, LIS, Regulatory, Validation Comments Off

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:

  • WSI are about 10x that of Radiology images.  The white paper talks about an average, compressed image size and the storage and network requirements needed to support a DPS for different size programs.
  • The importance of data integrity, reliability, and audit trails for HIPAA, CLIA, and FDA compliance.
  • An overview of Image Life Cycle Management (ILM) and important decision criteria.

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.

Favorite points:

  • In depth analysis and information about digital pathology and the AP Lab workflow
  • Examples of current interoperability implementations between the APLIS and DPS
  • Dealing with network and security issues for outside consultations
  • The importance of barcodes
  • Understanding the difference between compatibility and Interoperability
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