BB&T Washington Editor

WASHINGTON — The development and use of nanoscale materials is hardly new, and nanoscience promises to play a much larger role in devices and drugs in the decades to come. Hence, the Food and Drug Law Institute (FDLI; Washington) last week sponsored its first of what is planned to be an annual symposium on nanotechnology.

While attendees may have expected to hear about different FDA approaches to device and drug applications that incorporate nanomaterials, the consensus among panelists from the agency and the private sector was that the agency has the expertise it needs to review nano-products and requires no new regulatory apparatus to ensure nanotech product safety.

Additionally, the phrase "case-by-case basis" was employed routinely when specific regulatory questions were posed.

Ralph Hall, PhD, of the law firm of Baker and Daniels (Minneapolis), said "one of the key regulatory issues is whether nanotechnology is just another new technology." Assuming it is new, he said, "the core issue is FDA's scientific expertise." But Hall went on to make the case that nanotechnology "is not new to FDA" because the agency already has reviewed a number of products employing nanoscale materials, including silver nanoparticles, engineered calcium phosphate, liposomes and albumin-bound nanoparticles.

As for the novelty of yet-to-come devices and drugs, Hall said the agency has dealt with novel product lines in the past • such as pacemakers and other high-risk implantable devices • without creating new mechanisms.

"If this is not new, why all the fuss?" Hall asked — answering that despite generic concerns about nanotechnology, the public "has not perceived any issues" with specific products.

"If you want to regulate it, you have to define it," he said, but that the FDA nanotechnology task force "declined to define it" for what he said were good reasons. Hewing to the definition of objects smaller than 100 nanometers (nm) can be arbitrary because "I may try to design all my products to be 101 nm and get out of your definition."

Hall said that those who make the case for a new regulatory paradigm run the risk of creating new requirements at considerable expense but no benefit.

"No unique safety issues have emerged" in all these applications, Hall said. He made the case that many FDA scientists are familiar with this scale of matter because most pharmaceuticals "act at their site of action as individual molecules that are in the nanosize range."

Bernie Liebler, director of technology and regulatory affairs at the Advanced Medical Technology Association (AdvaMed; Washington), discussed the application of nanotechnology to medical devices and hinted at a need to demystify nanotechnology.

Does nanotechnology constitute a new way of making devices?

"It's a question that constantly comes up and we need to address it," Liebler said.

"When people think about our industry, they think of" high-risk medical devices, he said, but pointed out that hospital gowns and drapes are also devices, and these "will be affected by nanotech" first.

"We'll have high-tech coatings on low-tech products," which "will have a significant impact" on healthcare, he said. "For example, you could probably see anti-friction coatings for catheters, making them easier to get into the body."

"We are in an era of implants," Liebler said, such as hip implants. "You're always looking for longer life in that hip," and that the durability of implants will improve with the addition of nanoscale materials.

Liebler predicted that FDA will not hire nanotech specialists. "I think we're going to see specialists in biocompatibility" and other areas with a focus on nanotechnology, he said, adding that "it's a little hard to foresee someone sitting at a desk as the nanotechnology expert" because of the subject's breadth.

"The one burning question that has come up before and will come up again: Will the current paradigm work?" Liebler asked.

"Yes it has, and it will continue to," he said, noting that a pre-market application requires that "you show from ground zero [that the device] is reasonably safe and effective."

Liebler said if the concern is additional assurances of safety, "there are ways to approach it that require no new regulations or new statutes." Safety assurance cases, a method for validating the use of products in other industries, "could easily be applied to medical devices." By adding this technique to risk management, he said, "you would be looking at a way to formally demonstrate" safety in a more rigorous way, should that prove necessary.

Norris Alderson, PhD, associate commissioner for science at FDA and co-chair of the agency's nanotech task force, said the nanotech report from July 2007 "represents our current thinking" on "nano-engineered materials, not nanotechnology," calling these different issues. He said that the task force was designed to create a consistent and transparent approach to regulation, acknowledging that "nano-engineered materials may become a part of all the products" regulated by FDA at some point.

FDA discussed the National Nanotechnology Initiative's definition of nanotechnology, essentially anything between 1 and 100 nm in size, but the agency has concluded: "We don't need a [fixed] definition because we're regulating the products, not the technology," Alderson said. "We're more concerned about the information that comes available about these materials than about defining" the prefix "nano."

Alderson indicated that the science suggests that due to the interplay between the construct of materials and scale, "we may have to start thinking about surface area" in order to grapple with the physical/chemical properties of a drug or device, but he also acknowledged that "in many cases, we may not even have standards" for some of the materials that will hit FDA's reviewers.

"We recognize that in any new technology, we may have to get new expertise ... but our staff is undergoing training on these issues."

Alderson echoed Liebler's earlier remarks on competence areas, saying: "we're not looking for a nano-expert — we're looking for an expert" with sufficient background in nanomaterials.

Guidance generates debate over off-label device and drug uses

The line between providing information about a healthcare product and promoting and marketing that product is rather difficult to define. And the FDA appears, to some, to be moving that line in a way that could expand greater off-label uses of drugs and devices. However, the agency says that the availability of information about such uses will mean that they are applied more effectively.

The agency last month issued a draft guidance defining the types of information that a company can provide to physicians – essentially reprints of articles concerning the unapproved, off-label uses of a product, but already FDA cleared/approved by the FDA.

The draft guidance on "Good Reprint Practices" supports the use of "medical or scientific journal articles and reference publications" providing information use in the distribution of medical or scientific journal articles and reference publications" that involve these unapproved uses.

The draft guidance says that the FDA's policy on the issue "has not changed" – though several news reports concerning the document interpreted it as "softening" the use of information concerning unapproved uses. And the draft guidance came under fire as providing too much leeway to manufacturers because tending to encourage marketing of these unapproved uses.

Rep. Henry Waxman (D-California) had written to the agency, asking it to delay issuance of the guidance, arguing that it would create a "large loophole" in the law against off-label promotion. "It's a conflict of interest for the company to be promoting sales when they haven't been able to establish that a drug is safe and effective through the rigorous FDA process," Waxman said.

The FDA has long warned companies against marketing unapproved uses of drugs and devices, and it says that the new guidance also does not allow broader marketing and promotion, but specifically warns against it. Randall Lutter, FDA deputy commissioner for policy, in an agency statement, said that dissemination of information concerning unapproved uses of drugs and devices "can contribute to the practice of medicine and may even constitute a medically recognized standard of care." The guidance, he said, "safeguards against off-label promotion."

The guidance supplants guidelines concerning the dissemination of information on unapproved uses of FDA-approved products that expired in late 2006, thus probably leaving companies considerably unsure as to what the agency's current stance is.

The guidance provides considerable detail concerning:

• the kinds of materials that can be provided to physicians: only from organizations with editorial boards and peer-review, rather than being distributed or in any way influenced by the product manufacturer. And the information should constitute "the weight of credible evidence derived from adequate and well-controlled investigations."

• the format of these materials; essentially unaltered, unabridged reprints, and not "marked, highlighted, summarized, or characterized by the manufacturer in anyway."

• and the "manner" of dissemination: materials as are to be accompanied by other supplementary information, including the approved labeling of the drug or device, "a comprehensive bibliography" of publications covering similar uses of the drug or device"; and any contradictory information about the use of the drug or device if contrary conclusions about the off-label use have been published elsewhere.

In addition, the draft guidance recommends against distribution of special supplements or publications that have been funded by one or more of the manufacturers of the product in the article.

The guidance says that there are "important public policy reasons for allowing manufacturers to disseminate truthful and non-misleading journal articles and medical or scientific reference publications on unapproved uses" of approved products.

Thermal intradiscal therapy procedure to get CMS review

The Centers for Medicare & Medicaid Services last month reported that it has opened a national coverage determination (NCD) for a minimally invasive low back pain treatment that it says costs about 10 times less than spinal fusion surgery. Thermal intradiscal therapy for patients with chronic discogenic lower back pain has been around for almost 10 years, but has failed to catch on with surgeons, either because the insurance companies seem more willing to pay for more invasive treatments or because surgeons stand to lose income with a less costly, minimally invasive procedure alternative.

That was the finding of an expert panel that reviewed the issue two years ago.

In an unusual move, CMS said that it initiated the NCD internally, rather than following its usual protocol of responding to an outside requestor. "We decided to open it up ourselves," Marcel Salive, MD, MPH, director, Division of Medical & Surgical Services, in the CMS' Coverage and Analysis Group, told Biomedical Business & Technology. "We were hearing about the technology and had some information about it and thought it was a good topic to review. Some of the contractors had looked at it and raised some questions, and we wanted to take a closer look at it."

Thermal intradiscal therapy — such as intradiscal electrothermal annuloplasty (IDET), percutaneous intradiscal radiofrequency thermocoagulation (PIRFT), or disc biacuplasty — is a minimally invasive treatment for patients with low back pain believed to originate in the disc. The procedure involves the insertion of a wire or probes into the disc, under imaging guidance through a small incision in the back. Heat is applied to the disc through the use of various energy sources, such as electrical or radiofrequency.

Spinal fusion surgery can cost $50,000 to $70,000, depending on how many levels of the spine are fused, compared to IDET, costing an average $7,000. From 7,000 to 10,000 IDET procedures are performed annually in the U.S. The American Academy of Orthopaedic Surgeons (Rosemont, Illinois) reports that there were 324,000 spinal fusion surgeries in 2005, the latest year for which data were reported.

If the NCD is approved, one company especially stands to gain from the reimbursement coverage: Smith & Nephew (S&N, Andover, Massachusetts).

"CMS has grouped three or four distinct procedures under the umbrella of thermal intradiscal therapies," said Barbara Rohan, VP of government relations for S&N's Clinical Therapies Division (Memphis, Tennessee). "S&N manufacturers the Spinecath Intradiscal Catheter, which is used to perform IDET," she said. "Currently, the Spinecath Intradiscal Catheter is the only device on the market that generates electrothermal energy for thermal intradiscal therapy. Any physician who is properly trained may perform this procedure. The term IDET, though, is a Smith & Nephew trademark."

IDET is one of the few interventional spinal procedures that has ever been studied in several randomized controlled trials, which is one reason why the American Medical Association (Chicago) created separate, distinct CPT IDET codes. Those codes, according to S&N, were intended to distinguish IDET from similar procedures.

"Since the clinical evidence and clinical acceptance of each procedure differs, it is important that CMS consider each one according to its unique merits," Rohan said. "We feel that the evidence supporting a positive decision for IDET is very strong."

IDET has been discussed favorably in multiple evidence-based practice guidelines.

A panel that reviewed treatment options for chronic discogenic lower back pain, conducted by MedPanel (Cambridge, Massachusetts) in 2006, agreed that the first course of treatment for these patients should always be physical therapy and/or chiropractic, muscle relaxants and non-steroidal anti-inflammatory drugs.

If a patient doesn't respond to these treatments in four to six weeks, most of the panelists agreed that minimally invasive procedures should be considered and spinal fusion surgery should be used as a last resort.

CMS is expected to issue an opinion by July 15.

Patient Safety Organization guidelines rolled out by HHS

The Department of Health and Human Services has proposed to establish a series of patient safety organizations (PSOs, in response to the need to reduce medical errors and save lives.

The proposed regulation conforms to the requirements of the Patient Safety and Quality Improvement Act (Patient Safety Act) of 2005, which was, in turn, prompted to some extent by the well-known report on patient safety published in 1999 by the Institute of Medicine (IOM; Washington), "To Err is Human." The IOM report estimated that from 44,000 to 98,000 patients die in hospitals each year due to medical errors.

PSOs, the Feb. 15 HHS announcement said, would be separate from any existing entities that address healthcare quality. It said that one of the advantages of PSOs is that they provide a shield of confidentiality with regard to such reports and so allow providers to sidestep legal liability.

This protection was encoded in the Patient Safety Act by according the status of privileged legal communication to such reports. IOM recommended this protection, as well as the establishment of PSOs, in its 1999 report.

AHRQ Director Carolyn Clancy, MD, said the government is aware that providers want to "participate in efforts to improve patient care, but they often are inhibited by fears of liability and sanctions." She said that the liability provisions will "make the right thing to do the easy thing to do."

Those provisions, however, are not ironclad, and one exception would allow a breach of confidentiality for legal proceedings that might not be able to obtain the information in question by other means.

HHS Secretary Mike Leavitt said in the statement that PSOs "will help make healthcare safer for all Americans," and that "[b]y making it easier for patient safety events to be reported and the lessons learned from them to be shared more broadly, patients will ultimately receive safer healthcare."

According to the HHS statement, AHRQ will be tasked with administering the rules for accrediting PSOs, and the HHS Office for Civil Rights will enforce the confidentiality provisions.

The proposed regulation provides specifics on how providers will report information to PSOs as well as on how entities can become PSOs.

The legislation mandates that a PSO must be primarily engaged in patient safety data activities, which should suppress conflicts of interest by keeping hospitals from participating directly in the PSO business. The comment period ends April 1.

Study; PET found superior to CT for detection of lung nodules

A large, multi-institutional study comparing the accuracy of positron emission tomography (PET) and computed tomography (CT) in the characterization of lung nodules found that PET was far more reliable in detecting whether or not a nodule was malignant. "CT and PET have been widely used to characterize solitary pulmonary nodules (SPNs) as benign or malignant," said James Fletcher, professor of radiology at Indiana University School of Medicine (Indianapolis).

"Almost all previous studies examining the accuracy of CT for characterizing lung nodules, however, were performed more than 15 years ago, with outdated technology and methods, and previous PET studies were limited by small sample sizes.

"Detecting and characterizing SPNs is important because malignant nodules represent a potentially curable form of lung cancer. Identifying which SPNs are most likely to be malignant enables physicians to initiate the proper therapy before local or distant metastases develop," said Fletcher.

In a head-to-head study addressing the limitations of previous studies, PET and CT images on 344 patients were independently interpreted by a panel of experts in each imaging modality, and their determination of benign and malignant nodules was compared to pathologic findings or changes in SPN size over the next two years.

The researchers found that when PET and CT results were interpreted as "probably" or "definitely" benign, the results were "strongly associated with a benign final diagnosis" — in other words, they judged the modalities equally good at making this determination.

PET's superior specificity (accuracy in characterizing a nodule as benign or malignant), however, resulted in correctly classifying 58% of the benign nodules that had been incorrectly classified as malignant on CT. Furthermore, when PET interpreted SPNs as definitely malignant, a malignant final diagnosis was 10 times more likely than a benign.
SPNs are commonly encountered in both primary and specialty settings, often showing up on chest X-rays obtained for some other purpose than cancer screening and are often the first manifestation of lung cancer.

The question for these patients then becomes whether to undergo surgery, undergo a needle biopsy or "watch and wait" to find out if the nodule is benign or malignant but treatable.

"In patients with an untreated and undiagnosed SPN between 7 and 30 mm, PET provides better identification of malignant nodules that require a more aggressive treatment approach," said Fletcher. "PET, in combination with CT, can also provide good identification of those nodules that are most likely to be benign, suggesting that a 'watch and wait' strategy can be adopted in lieu of unnecessary invasive — and expensive — procedures such as needle biopsy or surgery."