A Medical Device Daily

As we reported in the April 8 edition of Medical Device Daily, an analysis of PMAs showed that FDA takes substantially longer than European authorities to render a decision on such applications. However, author Ralph Jugo, a senior technical specialist with Quality First International (London) has penned another in the series, this time looking at whether the concerns expressed by FDA and its advisory committees are warranted. Jugo looked at outcomes for seven PMAs, and found fault with all but one.

In the August edition of the Journal of Medical Device Regulation, Jugo says that his review of transcripts of an advisory committee hearing for an implantable hemodynamic monitor suggests that "the panel was generally not comfortable with recommending approval because the primary endpoint did not achieve statistical significance despite demonstrating that the device reduced heart-failure related events ... by 21%." Jugo writes that the reasons for the panel's 9-2 vote for non-approval "were not product-safety related and were not because the device did not produce accurate measurements." He faulted the panel for making the decision "based on a statistical technicality."

In his analysis of an application for an excimer laser for peripheral vascular ischemia, Jugo points out that "FDA had previously agreed to the use of the historical control group, which was later a reason for PMA disapproval." He also states "the disapproval was probably not warranted because the sponsor did achieve statistical support for the pivotal study's primary safety and efficacy endpoints."

The article states that Jugo also looked at safety-related data for five of the seven devices under analysis and he concluded that the analysis "revealed an absence of any product-related safety problems." He describes the U.S. device approval regime as "overly strict, burdensome [and] overly academic in nature (due to the academic versus industrial orientation of the advisory panel members)." Jugo also points out that "it is the patients who may suffer the most as a result of not having had the opportunity to receive the benefits of these potentially important medical devices."

Hypothalamic overeating gene pegged

The chemistry of obesity is of great interest given the impact of the condition on the nation's healthcare tab, and a recent announcement at the NIH web site points the finger at neurochemistry as a contributing factor.

According to the Aug. 27 announcement, the chemical compound in question, known as brain derived neurotrophic factor (BDNF), is also involved in the transition of recall from short-term to long-term memory, and animal studies have hinted at a role for BDNF in appetite regulation. In 2002, researchers in France observed that immobilization stress in rodents increased BDNF expression in the region of the rat hypothalamus that also governs the release of other hormones, including as the stress-response steroid cortisol.

The current study, however, is not of healthy patients, but those who suffer from WAGR syndrome, which is described as a rare genetic syndrome giving children a predisposition to development Wilms kidney tumors, an absence of the colored part of the eye known as aniridia, abnormalities of the genitourinary tract, and mental retardation.

A team led by Joan Han, MD, of the National Institute of Child Health and Human Development at NIH analyzed the chromosomes of 33 patients with WAGR and determined that 19 "had deletions of all or a major proportion of one copy of the gene for BDNF." Each of the 19 was obese by the age of 10 and demonstrated a propensity to overeat, and "all of the 19 had blood levels of BDNF that were roughly 50% lower than those of patients who had two working copies of the BDNF gene." The statement also noted that the remaining patients with "two working copies of the BDNF gene were no more likely to develop childhood onset obesity than the general population, and did not report unusually high levels of overeating."

Whether the results of this study, which appeared in the Aug. 28 edition of the New England Journal of Medicine, can be extrapolated to anyone with a less damaged set of genes is difficult to say, but the authors note that the subjects in the study "have large, heterozygous ... deletions" of the genes in question, and a further analysis of other gene samples hints that a more restricted set of damages to those genes might have a similar effect on appetite control.

NICHD director Duane Alexander, MD, described the study as "a promising new lead in the search for biological pathways that contribute to obesity," expressing the hope that it will "eventually lead to the development of new drugs to regulate appetite in people who have not had success with other treatments."

NIH offers technologies for licensing

NIH reported last week that it is offering two new technologies for licensing to interested parties. The Federal Register announcement says that the agency has a diagnostic that can identify those at "an increased risk for developing renal cancer, spontaneous pneumothorax and lung cysts" by detecting the folliculin-interacting protein 2 (FNIP-2). This technology "could facilitate the development of therapeutic drugs to treat the skin lesions and renal tumors that develop" in patients with Birt-Hogg-Dube's syndrome, which is said by NIH to have been diagnosed in more than 60 families. Previous analyses of those patients indicate a mutation of the FNIP-2 gene is present in 84% of those with the syndrome.

Also available for licensing is "a novel immunotoxin" based on a truncated cholera exotoxin that can be used to target cancer cells. NIH says that previous experience with Pseudomonas exotoxins (Pe) suggests that patients can tolerate only one administration of the substance as a targeted therapy because of "the development of neutralizing antibodies." The truncated cholera variant does not trigger the development of neutralizing antibodies, but because it has a "strong functional and structural similarity" to Pe, patients may be able to receive a second round of anticarcinogenic therapy.

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