Digital Pathology Blog

http://tissuepathology.typepad.com/weblog/

An earlier post

January 25, 2011

Standardization and Validation of Digital Pathology in Clinical Laboratories

The following post was submitted by Dr. Holger Lange, CTO of Flagship Biosciences, who is working with a number of pharmaceutical partners on regulatory companion diagnostics development.

Digital Pathology is a new technology, a new industry, where organizations like CLIA, CAP and the FDA provide limited guidance, and the manufacturers still have to learn what it means to provide instruments into a clinical laboratory.

With Digital Pathology now entering the clinical laboratories, it is crucial for physicians and laboratory professionals to understand the regulatory requirements and how to best implement Digital Pathology in their clinical laboratories.

For the past 4-5 years I have worked for a leading Digital Pathology manufacturer. I was responsible for their first product in the clinical market – a digital IHC workflow solution, and their portfolio of FDA clearances. Now I have put together a presentation that summarizes my experience in the clinical market. I hope it will help many physicians and laboratory professionals to quickly get up to speed on how to deal with the implementation of Digital Pathology in their clinical laboratories.

These are the subjects that are covered in the presentation:

Clinical Laboratory Regulations

A discussion on how the CLIA standard and the CAP checklist apply to Digital Pathology. A review of the new ASCO/CAP guidelines for HER2 and ER/PgR for the latest thoughts on standardization and validation in clinical laboratories.

Medical Device Manufacturer Regulations

An overview of the existing US Food and Drug Administration (FDA) clearances for Digital Pathology with an example of a successful study design. A discussion on the FDA advisory panel meeting on Digital Pathology Whole Slide Imaging (WSI) for the latest thoughts on what it takes to validate Digital Pathology systems for primary diagnosis.

Digital Pathology Systems

Practical tips on how to implement a digital pathology system in a clinical laboratory and how digital pathology manufacturers could make it easier. A demo of how a digital pathology system can help with the logistics of its own validation. A discussion on how going digital could be a game changer for the standardization of pathology, looking at the example of the automatic standardization of staining, using standard controls and automatic image analysis.

Go to the Flagship Biosciences product page for digital pathology regulatory products.

You get an 1½ hour video presentation on a DVD and the presentation transcript.

Save yourself many hours of research and reading! Get the insights you need by viewing this video presentation. Get access to material that cannot be found anywhere else.

FDA approves first 3-D mammography imaging system

 

FDA NEWS RELEASE

For Immediate Release: Feb. 11, 2011
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA approves first 3-D mammography imaging system

Selenia Dimensions System may boost accuracy in breast cancer detection, diagnosis

The U.S. Food and Drug Administration today approved the Selenia Dimensions System, the first X-ray mammography device that provides three-dimensional (3-D) images of the breast for breast cancer screening and diagnosis.

A mammogram is a safe, low-dose X-ray of the breast that is the best tool for early detection of breast cancer. However, with the limitations of conventional two-dimensional (2-D) imaging, about 10 percent of women undergo additional testing after the initial screening exam for abnormalities that are later determined to be noncancerous.

The Selenia Dimensions System, an upgrade to Hologic’s existing FDA-approved 2-D system, can provide 2-D and 3-D X-ray images of the breasts. The 3-D images may help physicians more accurately detect and diagnose breast cancer.
“Physicians can now access this unique and innovative 3-D technology that could significantly enhance existing diagnosis and treatment approaches,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health.

The National Cancer Institute recommends women ages 40 and older have a mammogram every one to two years. Nearly 40 million mammograms are performed each year in the United States.

As part of the approval process, the FDA reviewed results from two studies where board-certified radiologists were asked to review 2-D and 3-D images from more than 300 mammography exams.  In both studies, radiologists viewing both the 2-D and 3-D images obtained a 7 percent improvement in their ability to distinguish between cancerous and non-cancerous cases as compared to viewing 2-D images alone.

While the combination of the Selenia’s 2-D and 3-D images approximately doubled the radiation dose the patient received, it improved the accuracy with which radiologists detected cancers, decreasing the number of women recalled for a diagnostic workup. There is uncertainty for radiation risk estimates; however, the increase in cancer risk from having both a 2-D and 3-D exam is expected to be less than 1.5 percent compared to the natural cancer incidence, and less than 1 percent compared to the risk from conventional 2-D mammography.

The Mammography Quality Standards Act requires that all health care professionals obtain eight hours of training prior to using new mammography technology on patients. The FDA also requires that the manufacturer provide each facility with a manual clearly defining the tests required for initial, periodic, and yearly quality control measures.

According to the NCI, nearly 200,000 women will be diagnosed with breast cancer this year. And 1 in 8 women will be diagnosed with breast cancer during their lifetime. There is a 98 percent survival rate when breast cancer is detected early and still localized to the breast.

The Selenia Dimensions System is marketed by Bedford, Mass.-based Hologic Inc.

Medical Treatment, Out of Reach - NY Times article

Received this article by e-mail and am passing it on.

From
Brendan Benner
Vice President of Public Affairs
Medical Device Manufacturers Association (MDMA)

 I wanted to make sure you saw the front page story in yesterday’s New York Times' Business section detailing the challenges patients and innovators are having with FDA.

MDMA and others have been working on this story for several weeks, and we believe this story turned out well to show the real-world impact of unnecessary delays.

This is a very compelling piece and has received widespread attention in Congress and Washington media.

I would encourage you to pass this along to the local business and health care reporters in your community to ensure this important topic gets more exposure.

In addition, if your company utilizes social media, this would also be a great item to post and increase its visibility.

All the best,

Brendan

http://www.nytimes.com/2011/02/10/business/10device.html?_r=1&ref=business
Medical Treatment, Out of Reach
By ANDREW POLLACK

Late last year, Biosensors International, a medical device company, shut down its operation in Southern California, which had once housed 90 people, including the company’s top executives and researchers.

The reason, executives say, was that it would take too long to get its new cardiac stent approved by the Food and Drug Administration.

“It’s available all over the world, including Mexico and Canada, but not in the United States,” said the chief executive, Jeffrey B. Jump, an American who runs the company from Switzerland. “We decided, let’s spend our money in China, Brazil, India, Europe.”

Medical device industry executives and investors are complaining vociferously these days that the industry’s competitive edge in the United States and overseas is being jeopardized by a heightened regulatory scrutiny.

The F.D.A., they and others say, appears to be reacting to criticism that its approvals for some products had been lax, leading to a spate of recalls of some unsafe medical devices, like implanted defibrillators and hip replacements.

Now, executives of device companies say the F.D.A. has gone too far in flexing its regulatory muscle, and they worry that a slower, tougher approval process in a weakened economy could chill investments and cripple innovation.

In addition, they say that American patients are being deprived of the latest technology because companies routinely seek approval for new devices in Europe first. For instance, heart valves that can be installed through a catheter instead of open-heart surgery have been available in Europe since 2007 but will not be available in the United States until late this year at the earliest.

“Ten years from now, we’ll all get on planes and fly somewhere to get treated,” said Jonathan MacQuitty, a Silicon Valley venture capitalist with Abingworth Management.

Marti Conger, a business consultant in Benicia, Calif., already has. She went to England in October 2009 to get an implant of a new artificial disk for her spine developed by Spinal Kinetics of Sunnyvale, Calif.

“Sunnyvale is 40 miles south of my house,” said Ms. Conger, who has become an advocate for faster device approvals in the United States. “I had to go to England to get my surgery.”

Stenum Spine Hospital in Germany has performed disk surgery on 1,000 Americans over the last eight years, said Jim Rider, the hospital’s American marketing agent.

Acknowledging industry concerns, the F.D.A. on Tuesday proposed creating an “innovation pathway” aimed at speeding regulatory reviews of a small number of groundbreaking devices. And last month the agency announced measures it said would make the regulatory process more predictable for the vast majority of devices.

“A consistent and predictable review process will stimulate investment here at home and keep jobs from going overseas,” Dr. Jeffery Shuren, the director of the agency’s medical device division, told reporters.

But Dr. Shuren said the F.D.A. would not relax its standards, arguing that Europe’s system might be too lax. He said that a breast implant, a lung sealant and an implant for elbow fractures were approved in Europe but not in the United States, and then had to be taken off the market in Europe for safety reasons.

“We don’t use our people as guinea pigs in the U.S.,” he said

Medical device executives said they welcomed the steps, but continued to express concerns. Consumer advocates, like Dr. Sidney Wolfe of Public Citizen, however, said that device regulation was already much less stringent than for drugs and that the F.D.A. was caving in to industry demands rather than ensuring consumer safety.

Dr. Charles Rosen, a spine surgeon who is also president of the Association for Medical Ethics, said that the newest devices were not always best. He said he had at least 50 patients who had suffered serious problems from an older artificial disk. Many of those patients, he said, had gone to Europe to get them before they were available in the United States.

Just since November, three reports — two sponsored by device industry trade groups and one conducted by the consulting firm PricewaterhouseCoopers — have raised concerns about the F.D.A. approval process. One report found that the rate of recalls in Europe was similar to that in the United States, suggesting faster approvals overseas were not hurting patients.

The complaints are driven in part by financial pressures. Venture capitalists, because of the financial crisis and their own poor returns, have less money and need quicker returns on their investments from the companies they back.

Bigger device companies also complain about the F.D.A., but not as much as struggling start-ups. “The F.D.A. is asking for larger trials, more thoughtful trials, all in the interest of the American public,” said Dr. Stephen N. Oesterle, senior vice president for medicine and technology at Medtronic.

To be sure, the United States remains the clear world leader in medical device innovation, according to the report by PricewaterhouseCoopers. Some 32 of the 46 medical technology companies with annual sales exceeding $1 billion are based in the United States, the report said.

Still, the report said the United States’ lead was slipping.

Device companies have been seeking early approval in Europe for years because it is easier. In Europe, a device must be shown to be safe, while in the United States it must also be shown to be effective in treating a disease or condition. And European approvals are handled by third parties, not a powerful central agency like the F.D.A.

But numerous device executives and venture capitalists said the F.D.A. has tightened regulatory oversight in the last couple of years. Not only does it take longer to get approval but it can take months or years to even begin a clinical trial necessary to gain approval.

Disc Dynamics made seven proposals over three years but could not get clearance from the F.D.A. to conduct a trial of its gel for spine repair, said David Stassen, managing partner of Split Rock Partners, a venture firm that backed the company. “It got to the point where the company just ran out of cash,” Mr. Stassen said. Disc Dynamics was shut down last year after an investment of about $65 million.

Dr. Shuren of the F.D.A. said the agency had concerns from preliminary studies that the material in the gel could cause cancer and that the gel would come out of the disk, requiring a new operation.

Some companies and investors are even contemplating forgoing the American market completely.

“We never intend to spend a nickel in the United States for clinical trials,” said William Starling, a venture capitalist who also runs Synecor, a device company incubator in North Carolina.

Mr. Starling is an investor in Spinal Kinetics, whose artificial disk was implanted in Ms. Conger in England.

The company began working with both the F.D.A. and European regulators in early 2005. It won approval in Europe in 2007 after testing its device in 30 patients and spending $4 million. Since then, thousands of the disks have been implanted.

Only last May did it receive approval for a final trial for F.D.A. approval that would involve about 250 patients. But hard-pressed investors are not willing for now to put up the $50 million or so the trial would cost, Mr. Starling said.

In the meantime, Spinal Kinetics is moving its manufacturing to Germany and has already laid off 20 people in Silicon Valley. One reason for the move, Mr. Starling said, was that some countries in Asia and Latin America allowed use of devices that have been approved in the country in which they are made. So moving manufacturing out of the United States opens up those markets.

Totally forsaking the lucrative American market could be difficult. While approval in Europe is easier, health care systems there tend to spend less on medical devices. Even if a device were approved, doctors in Europe might not use it if there was not enough data proving it really works.

Some companies, however, are trying to generate some sales in Europe in an effort to be acquired by a bigger company, which could then afford to deal with the F.D.A.

Dr. Shuren of the F.D.A. said in an interview that there had been “no conscious effort” to make device approvals tougher. “We are dealing with increasingly more complex devices coming to market,” he said.

But numerous executives say agency reviewers seem to be more cautious as Congress and others criticize the agency for being too lenient. Critics cited two recent examples: the DePuy hip implant recalled last year and an instance in which top agency officials approved a knee repair implant, made by ReGen Biologics, over the strenuous objections of their scientific reviewers.

Pharmaceutical executives are also complaining about how tough the F.D.A. has become. But they are not forsaking the American market, in part because there is not a big disparity in the regulatory system for drugs between the United States and Europe.

Some figures bear out a toughening in devices. The F.D.A. last year granted 19 premarket approvals — the type of clearance required for the most highly regulated devices — down from 48 in 2000.

The average time to win an approval through the less stringent 510(k) pathway, which is used for most devices, rose to 116 days in fiscal year 2008 from 97 days in fiscal year 2002. Agency figures show there have been increases in the proportion of applications sent back for questioning.

Investment by American venture capitalists in the medical device sector has fallen 37 percent since 2007 to $2.3 billion last year, according to the MoneyTree survey from PwC, the National Venture Capital Association and Thomson Reuters. That is steeper than the 27 percent drop for all venture capital investing.

Last year, total venture capital investing increased 19 percent while investment in medical devices fell 9 percent.

--
Brendan Benner
Vice President of Public Affairs
Medical Device Manufacturers Association
1350 I St, Suite 540
Washington, DC 20005
202.354.7172
http://www.medicaldevices.org/

CDRH Seeks Comments on 510(k) Device Process

GenomeWeb Daily News

CDRH Seeks Comments on 510(k) Device Process

February 11, 2011

By a GenomeWeb staff reporter
NEW YORK (GenomeWeb News) – The US Food and Drug Administration's Center for Devices and Radiological Health is reaching out to industry and the public for input on its plans to change the process for handling 510(k) submissions by collecting public meeting in March.

As GenomeWeb Daily News reported in January, CDRH has issued a 25-point plan aimed at streamlining the review process, clarifying when clinical data should be submitted, and establishing a council of FDA experts to assist applicants in making decisions.

CDRH Director Jeffrey Shuren said at the time that the changes will result in "a smarter medical device program that supports innovation, keeps jobs here at home, and brings important, safe, and effective technologies to patients quickly."

These steps are being considered in order to "strengthen" the review process and to "improve the predictability, consistency, and transparency of its decision-making," CDRH said in a Federal Register posting this week.

"These actions will not only improve the safety of medical devices but also increase the ability of innovating companies to attract investors, estimate costs, and more quickly bring products to market," according to CDRH.

The Center plans to hold is public meeting on March 15 in Silver Spring, Md., at FDA's White Oak Campus.

CDRH is seeking comments on its report in general, as well as in certain areas, such as the eligibility criteria for the new programs; how CDRH should determine what types of technologies will be included in some of these new innovation initiatives; how time frames for the program should work; what criteria should be used for clinical test center certification; how candidates for inter-agency or public-private partnerships will be defined; and other actions CDRH should take to facilitate the development, assessment, and regulatory review of innovative medical devices.

Public Docket for comments on Array-Based Cytogenetic Tests

Thought it wold be interesting to see the public comments submitted tot he docket for this item.  See previous posts where FDA (CDRH) had projected issuing a framework for the validation and review of array CGH assays.

Here is a link to the docket at regulations.gov.

http://www.regulations.gov/#!searchResults;rpp=10;so=DESC;sb=postedDate;po=0;s=FDA-2010-N-0259


There have really only been 2 comments posted from the public.

The College of American Pathologists (http://www.regulations.gov/#!documentDetail;D=FDA-2010-N-0259-0003.1) and
The Cleveland Clinic (http://www.regulations.gov/#!documentDetail;D=FDA-2010-N-0259-0002.1)

The only other items posted are the original Federal Register notice announcing the June 30, 2010 public meeting (http://www.regulations.gov/#!documentDetail;D=FDA-2010-N-0259-0001) and the actual transcript of the public meeting (http://www.regulations.gov/#!documentDetail;D=FDA-2010-N-0259-0004).

Interestingly, FDA does not even seem to have posted the various presentations given at the public meeting to the docket.

Public Docket for FDA/CDRH Medical Device Innovation Initiative

If you are interested in following the comments posted to the Public Docket (FDA-2011-N-0062) for this FDA activity, here is a direct link.
http://www.regulations.gov/#!searchResults;rpp=10;so=DESC;sb=postedDate;po=0;s=FDA-2011-N-0062


http://www.regulations.gov/#!home

FDA/CDRH's External Expertise Partnerships (EEP) Program

External Expertise and Partnerships (EEP)

The Center for Devices and Radiological Health (CDRH) regulates a wide array of medical devices. To keep pace with the rapid development of new technology, and to make decisions based on the best scientific information and knowledge available, CDRH routinely collaborates with experts in the academic community, government entities, clinical practice, and industry. External Expertise and Partnerships is located in the Office of the Center Director in CDRH.

• EEP's Mission
• Three Components of EEP
• The Medical Device Fellowship Program (MDFP)
• Partnerships and Technology Transfer
• The Critical Path Initiative

EEP's Mission

EEP's mission is to advance public health by acquiring specialized expertise and material resources that support scientific and clinical evaluations conducted in the offices of CDRH. By filling gaps in expertise for a finite period of time, EEP enhances the efficiency and effectiveness of CDRH operations. EEP is the focal point of all CDRH fellowships and interorganizational partnerships. EEP also fosters scientific innovation by helping offices form partnerships with academia, private sector organizations, and government agencies. The consulting and oversight services facilitate project success and ensure that CDRH employees operate within the context of all legal obligations.

Three Components of EEP

EEP is divided into three general components:

1. The Medical Device Fellowship Program (MDFP)
2. Partnerships and Technology Transfer
3. The Critical Path Initiative

The Medical Device Fellowship Program (MDFP)

The Medical Device Fellowship Program began at CDRH in 2003 with the goal of advancing public health by acquiring specialized expertise and material resources for a finite period of time in support of scientific and clinical evaluations conducted in the offices of CDRH. The Fellowship Program addresses how to place external expertise for targeted projects.

Fellows are full-time or part-time Food and Drug Administration (FDA) employees. Qualified individuals, including clinicians, scientists, researchers, academics, and students in appropriate fields, enjoy unique experiences working with world-class scientists, physicians, and engineers, while helping bring innovative technologies to market. There are opportunities to present research results through publications and presentations.

EEP coordinates MDFP fellows and projects, as well as the CDRH fellowship projects for the FDA Commissioner’s Fellowship Program (CFP) and the FDA-NCI Interagency Oncology Task Force (IOTF) Fellowship.

Related Links

• Medical Device Fellowship Program
• Commissioner's Fellowship Program
•  FDA-NCI Interagency Oncology Task Force (IOTF)

Partnerships and Technology Transfer

Partnership and Technology Transfer refers to the processes involved in facilitating the transfer of expertise, technology, materials, equipment, and intellectual property. The activities in this area include: advising and consulting with appropriate staff and principal investigators (PIs), determining partnership mechanisms, guiding collaborations, developing and executing partnership tools, fostering communication, and providing oversight through the many phases of collaborations. EEP is the contact point for CDRH Technology Transfer and partnership activities.

Technology transfer has been defined by the Federal Laboratory Consortium for Technology Transfer as follows:

“Technology transfer is the process by which existing knowledge, facilities, or capabilities, developed under federal research and development (R&D) funding, are used to fulfill public and private needs.”

This list is a general overview of technology transfer mechanisms that serve as partnership tools:

Confidential Disclosure Agreements (CDAs)

• Provide protection against disclosure of proprietary information

Material Transfer Agreements (MTAs)

• Are simple agreements between government, academic, or private sector partners (industry or professional societies)
• Permit the transfer of disposable equipment, supplies, materials, or proprietary data or information that is trade secret
• Involve no interactive collaboration

Cooperative Research and Development Agreements (CRADAs)

• Provide mutually beneficial collaboration and cooperation between FDA and government, academic, or private sector partners (industry or professional societies)
• Enable collaborator to contribute personnel, equipment, materials, or funds
• Enable government to contribute personnel, equipment, or materials, but NOT funds

Grants

• Are funding provided from the government or private sector for a specific project by an application process

Interagency Agreements (IAAs), or IAGs

• Are formal agreements between FDA and other Federal agencies
• Concern transfer of funds, provision of services, loan of staff, or use of property, facilities, or equipment, or exchange of information (costly)

Memorandums of Understanding (MOUs), also known as Memorandums of Agreement (MOAs)

• Represent agreement between two or more government, academic, or private sector partners (including nonprofits, professional societies, etc.)
• Establish organizational links in Technology Transfer
• Are announced by publication in the Federal Register

Related Links

• CDRH Cooperative Research and Development Agreements (CRADAs)
• FDA CRADAs

The Critical Path Initiative

The Critical Path Initiative facilitates a national effort to modernize the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery or “proof of concept” into a medical product. The initiative was launched in 2004 after the release of a report titled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. The report highlighted the difficulty and unpredictability of medical product development and called for a concerted effort to modernize the scientific tools (e.g., in vitro tests, computer models, qualified biomarkers, innovative study designs) and harness the potential of bioinformation used to evaluate and predict safety, effectiveness, and manufacturability of candidate medical products.


The Critical Path Initiative holds potential to improve the tools FDA uses to evaluate the safety and efficacy of human and veterinarian products and the safety and nutrition of food and food ingredients. In another area, new bioinformatics approaches could greatly enhance the interoperability of information tracking systems in the healthcare environment for all regulated products (e.g., adverse events reporting). As resources allow, FDA will initiate partnerships to address some of these scientific hurdles. EEP coordinates CDRH's Critical Path projects.

Related Links

• CDRH Critical Path Projects FY2009
• CDRH Critical Path Projects FY2010
• Critical Path Initiative