BB&T Washington Editor, and Staff Reports

The arrival of new leadership at FDA was widely seen as an augur of a new era at the agency and recent developments have done little to dissuade observers of that perception. The agency's deputy commissioner, Joshua Sharfstein, MD, addressed the crowd at AdvaMed 2009 earlier this year, telling attendees that FDA is “very committed to public health.“ He also went out of his way to make the case that “it is very important that FDA not be using old standards for new technology.“

Sharfstein discussed the notion of “both incremental and transformative opportunities“ that lay in front of the agency and industry, but acknowledged that FDA is more interested the incremental variety. He said he was especially appreciative of devices made specifically for children. Despite efforts to bring such devices to market, “there is a huge gap“ in this area, and Sharfstein said he sees “so much more to be done“ to redesign existing devices for pediatric populations.

However, the bulk of Sharfstein's talk addressed the stewardship of the Center for Devices and Radiological Health by interim CDRH chief, Jeffrey Shuren, MD, who Sharfstein said has “a very clear mandate to move forward on clear priorities.“

Among those is an examination of and probable substantive changes to the 510(k) program, which Sharfstein said “could be improved,“ adding that such improvements could be imposed by regulations, administration or by a change in law. Sharfstein noted that one of the prevailing views among the agency's senior managers of the 510(k) program is that some of the relevant standards “are poorly defined,“ although he offered no details.

FDA announces review of QoL for LASIK

FDA reported that it has undertaken a collaborative study with the Department of Defense (DoD) and the National Eye Institute (NEI) to “examine the potential impact“ on quality of life (QoL) from laser-assisted in situ keratomileusis (LASIK), a procedure that is said to work exceedingly well for most patients, but which triggered a noisy advisory committee hearing last year.

The Oct. 15 statement also disclosed that FDA has issued warning letters to 17 outpatient facilities that offer the procedure “after inspections revealed inadequate adverse event reporting systems at all the centers.“ An FDA spokesperson told BB&T via e-mail that the letters were issued Oct. 9 and will be posted to the agency's web site on Oct. 27. The FDA statement notes that the inspections of the LASIK centers “did not identify problems with the use of the LASIK devices at these facilities.“

According to the FDA statement, the LASIK project will roll out in three phases, the first of which began in July. FDA, DoD and NEI will build and post “a web-based questionnaire to assess patient-reported outcomes and evaluate quality-of-life issues“ for patients who have had the procedure. Some of the responses, FDA indicates, “may relate to the safety of the lasers used in the ... procedure.“

The second phase will “evaluate the quality of life and satisfaction ... in a select, active duty population treated“ at the Navy Refractive Surgery Center in San Diego. The final phase “will be a national, multi-center clinical trial and will study the impact of the procedure on quality of life,“ FDA stated.

EMEA, FDA offer parallel advice

Firms that operate in more than one nation face a regulatory patchwork, but the European Medicines Agency (EMEA; Brussels) and FDA have opted to push a bit more toward a kind of harmonization – even if they disavow the concept in print – with a set of general principles on the subject of “parallel scientific advice.“ However, this function will apparently apply to only a limited set of therapeutic products, including nanotechnology.

According to the July 22 document, which EMEA posted to its web site toward the end of October, the objective is to exchange views “on scientific issues during the development phase of new medicinal products.“ The effort will hopefully lead to some regulatory clarity regarding breakthrough products as well as safety issues related to therapeutics for oncology and for pharmacogenomics. Also under consideration will be products such as vaccines, pediatric drugs and nanotechnology. EMEA said that a special emphasis is placed on products for which guidelines either do not exist or for which the two agencies' guidelines “differ significantly.“

Monitors an issue for FDA in digital pathology

FDA convened a two-day session recently with the hematology and pathology devices advisory committee to discuss how to reliably employ digital images of pathology slides in diagnostic workups. Not surprising is the impression that the agency is not “guidance-ready“ for this application of imaging technology, a fact which may be driven largely by FDA's concern that there is a lot of variance in how modern computer monitors display images.

Speaking for FDA at the October hearing was Aldo Badano, PhD, of the Office of Science and Engineering Labs at FDA's Center for Devices and Radiological Health. “Displays are components in the imaging chain,“ he noted, a chain which includes image acquisition, processing, storage and transmission. However, he informed the panel that FDA is of the view that “the display can be the weakest link in the chain.“

Badano said that poor display quality often leads to “incorrect or inconsistent diagnostic decisions.“ Display quality can also lead to increased variability in reads and longer image read times. He suggested that an application for a digital imaging system would have to specify the type of display with which the imaging system would be used.

“We can think of having a regulatory path that will go by component,“ Badano said, a paradigm that “allows us to model system improvement“ via plug-and-play of the various component types.

Most displays are based on liquid crystal technology, Badano remarked, and the image quality “depends on what comes out of the backlight and what is differentially absorbed by the layers“ of materials just behind the front of the screen. He made note of a comprehensive measurement test for LCDs promulgated by the American College of Radiology (ACR; Reston, Virginia), a standard he described as a “simplified version of requirements for practice in radiology.“ This is in reference to an ACR document published by ACR in the Journal of the American College of Radiology in August 2006.

Another standard, this one offered by the American Association of Physicists in Medicine (AAPM; College Park, Maryland), is a “very long document of testing procedures for characterizing display performance in radiology,“ Badano said. This document “has a variety of test patterns“ for initial checks of display quality, but “also a few clinical images“ for checks of display quality “before reading sessions,“ he said.

While these standards deal with imaging issues such as pixel defects, “what we do not have at the moment is an extension [of those standards] to color displays,“ Badano observed, which may be helped by standards from other applications of imaging technology. Among these, he said, is ISO 13655, a graphic arts standard, as well as the ASTM standards of E1336 and E1455. All the same, Badano noted, “we do not have a practical standard for measuring the physical characteristics“ of some color displays.

Other issues that have yet to be resolved include that image capture technology may be outrunning display technology. “We have detectors that could acquire two to nine megapixels, which are much larger“ than display capacities, which often run no higher than five megapixels. He also warned that he is of the impression that “display products with lower image quality are being considered based primarily on physical measurements.“

“Another aspect that is well understood is ambient light,“ Badano said, noting digital radiology reading rooms often require the use of only indirect lighting. Consequently, direct light exposure from one display to another is seen as problematic, something to bear in mind during bench testing and clinical trial design.

Badano recommended that when the panel is faced with a PMA for such a system, it should tread carefully where color gamut is concerned. “One of the questions ... is what fraction of color that exists in pathology slides would be outside of the camera and display gamut,“ he said. Some compression schemes could eliminate information because of inability to fully or accurately display certain colors.

The viewing angle issue for LCDs introduces an odd twist to the color shift issue, Badano observed. “The image you see changes as you move around,“ because while each color tends to shift, “not all the colors move in the same direction, which means it is possible to have color inversions“ at different viewing angles, he said.

Reader variability a key for whole slide images

FDA has decisions to make about clinical trials for digitized images of pathology slides, but the second-day session of the hematology and pathology devices advisory committee gave industry few hints about what the agency will require in those trials.

The panel heard plenty on the first day regarding the different types of monitors used to view whole slide images, but the panel seemed split on a couple of essential questions, including whether a trial should examine variability in interpretation between readers versus variability exhibited by one reader upon a second examination of a pathology slide.

Giving an overview of potential considerations for clinical trials was Tan Nguyen, MD, a medical officer at the Center for Devices and Radiological Health at FDA, who said that among FDA's chief concerns “is how we can reasonably demonstrate ... that any competent pathologist“ can use whole slide imaging (WSI) without compromising diagnosis. Another consideration for FDA, he said, is that “an out of focus or even partially out of focus“ image may miss “a single cell“ and result in misdiagnosis.

Nguyen said a prospective study can suppress bias caused by case selection and can be built around real-world practice, but that such a design will not eliminate the problems of non-uniform specimens and variability in the quality of glass slides. He also indicated that FDA is not utterly averse to the use of existing slides to bolster a PMA. “A retrospective study ... if thoughtfully designed, may allow the opportunity to use archival cases,“ he remarked.

A retrospective study intended to characterize receiver operator interpretation based on a multiple reader/multiple case data set “has been successfully deployed and proved its effectiveness,“ Nguyen said, and “can provide the practical ability“ to compare diagnoses across readers, so long as those readers have similar levels of training and experience.

The first question FDA posed to the panel was whether an application should be limited to image compression schemes that retain the full data set (non-lossy) or should allow compression schemes, such as jpegs, that filter out some data (lossy). Panel chairwoman Dorothy Adcock, MD, of Esoterix Labs (Englewood, Colorado), summarized, “the panel generally feels that this issue can't be answered with a yes or no and perhaps such a decision ... should be left to the manufacturer.“

The second question dealt with the idea of allowing a system's use to be validated for all organ systems by extrapolation from a single organ or organ system. Opinions dotted the chart on this question, with one panelist arguing that there is “too much difference to allow one to extrapolate“ while another made the case that “the issue is whether it can generate enough information“ to render a diagnosis and that “its not necessary“ to have organ-specific data. Adcock summarized that the panel “feels that is difficult or impossible to use an organ approach, or even a disease approach,“ but that such a specification might be necessary when designing a study.

The panel could not agree on whether a study should look at variability between readers versus variability within one reader, and was also hung on the verdict regarding the use of an expert panel for clinical trials.

FDA details financial ties in clinical summary

FDA has routinely published documents prior to advisory committee hearings, but documents published prior to the Nov. 4 meeting of the orthopedic and rehabilitation devices advisory committee included information that has not previously been a common feature of such documents, namely information regarding financial ties between the trial sponsor and participating clinical investigators (CIs).

In an executive summary published by the agency dated Nov. 4, the agency addressed the possibility that financial relations between CIs and the sponsor drove the results of the study toward a favorable finding for the sponsor, Zimmer Spine (Warsaw, Indiana).

The summary notes that 53 out of the 63 CIs participating in the trial comparing Zimmer's Dynesys to a control article acknowledged no financial ties to the firm outside the conduct of the study. However, the agency came up with an estimate of the total amount of reimbursement to the remaining 10 investigators as determined by study site. FDA calculated that compensation to CIs at 10 of the 26 study sites exceeded $100,000 each. Slightly more than half the study subjects – 53.8% of study subjects and 53.5% of controls – were enrolled in those 10 sites, FDA states.

If the count of CIs with financial ties is indeed 10 and the number of affected sites is also 10, the presumption is that one clinician at each of the 10 affected study sites had a six-figure financial interest in Zimmer. However, FDA does not state how many of the patients were treated by the CIs with those ties or how many CIs total worked at the sites in question.

The agency says Zimmer's analysis of the effect of financial ties using logistical regression discerned no connection between outcomes and financial relationships for the treatment group. A second analysis discerned a positive relationship for the study article and a negative relationship for the control device, Zimmer's Silhouette, but FDA acknowledged the findings “were far from being statistically significant.“

Zimmer's application for the Dynesys failed in the committee by a vote of 5-1, with one abstention. The two major issues for the panel were the use of conical-shaped pedicle screws in the spinal fixation device and what panelists saw as an unacceptable level of ambiguity in the proposed indication. However, the panel seemed open to the idea of using Zimmer's existing data set to apply again based on a more narrow indication.

China to lower barriers for device imports

Trade negotiations between the U.S. and China have been pockmarked with conflict, but the recently concluded round of negotiations have worked out well for the device industry. In an Oct. 30 statement, the Advanced Medical Technology Association (AdvaMed; Washington) welcomed “a series of commitments aimed at streamlining the regulatory process for medical devices“ announced by mainland China during negotiations conducted as part of the U.S.-China Joint Commission on Commerce and Trade.

The AdvaMed statement notes that Beijing has promised to drop the requirement that companies shipping devices to China “register their products in the country of export as a condition of registration in China.“ Beijing is said to have agreed to accept a product registration document issued by any nation “regardless of its exporting origin, country of manufacture or legal manufacture.“

Beijing is said to have also committed to consider clinical trials conducted in other nations as evidence toward device approvals, but will employ a risk-based approach in deciding which products can be approved via foreign-nation trials.

House passes medical isotope bill in landslide

The House of Representatives recently passed H.R. 3276 by a landslide vote of 400-17, putting a resounding stamp of approval to legislation that will authorize $163 million for a new program at the Department of Energy intended to encourage domestic production of a medical isotope that has recently been in short supply.

The American Medical Isotopes Production Act of 2009 was introduced to a subcommittee this summer and serves the dual purpose of encouraging domestic development of radioisotopes for medical use and discouraging the use of high-enriched uranium (HEU) for energy production as part of an overall strategy for reducing nuclear weapons proliferation.

H.R. 3276 passed through the Energy and Commerce Committee in October and authorizes the funding between fiscal years 2011 and 2014. The Senate will likely take up the House bill as is.

The House is responding to a persistent shortage of technetium-99, which is processed from molybdenum-99. Molybdenum is in turn a byproduct of uranium, which is widely used in energy production across the globe. However, several plant shutdowns in production facilities in Canada and the Netherlands have crimped supplies sharply of technetium of late, leading hospitals and radiology clinics to suspend needed radio-imaging procedures.