A new notification from the FDA, issued last month, is likely to increase the questions related to the use of di-ethylhexyl phthalates (or DEHP), the softening chemical used to make a variety of medical devices and consumer products, and the its recommendations may suggest a stronger policy position by the agency in the future. While the agency previously has tended to raise a variety of issues concerning DEHP — without recommending against its use — the new statement appears to move closer to an anti-DEHP policy stance.The FDA's notice recommends substituting PVC devices that do not contain DEHP for high-risk patients. "Devices made of other materials, such as ethylene vinyl acetate, silicone, polyethylene or polyurethane can be used if available," the notice advised. "If PVC devices containing DEHP must be used, you may be able to minimize exposure to DEHP by using the freshest possible blood products stored at the lowest possible temperature or by using heparin-coated extracorporeal membrane oxygenation circuits."

But as with its previous statements on DEHP use, the agency followed its warnings with qualifications downplaying any serious health risks for most patients. In the new warning, it said there has been found to be little or no risk posed by patient exposure to the amount of DEHP released from PVC IV bags during the infusion of crystalloid fluids, such as normal saline. There is little risk, it said, posed by the amount of DEHP released from PVC bags used to store and administer drugs that require a pharmaceutical vehicle for solubilization, when label instructions are followed, the notice states.

The FDA said that the degree of risk is determined by two factors. First, the patient's sensitivity to DEHP determines risk. "Based on the evidence, the male fetus, male neonate, and peripubertal male would appear to be high-risk groups," the notice states. Secondly, risk is determined by the dose of DEHP the patient receives — largely a factor of the type of procedure performed and the frequency and duration of the procedure, according to the FDA.

In a sharp response to the FDA report, Charlotte Brody, RN, executive director of Healthcare Without Harm (HWH; Washington), criticized the warning because it failed to provide new labeling regulations. She said that the notification "falls far short of what is needed to protect patients from DEHP in medical devices. While FDA acknowledges that certain patients may be receiving unsafe doses of DEHP, and acknowledges that there are alternatives to DEHP-containing products, FDA does not give healthcare providers the one tool they need to protect their patients — a labeling requirement for all products that contain this harmful chemical."

HWH also offered a slant on the issue that was somewhat positive. Stacy Malkan, spokeswoman for the organization, told The BBI Newsletter that manufacturers actually may be ahead of the FDA in terms of developing medical products free of DEHP. "Using DEHP is an unnecessary risk," she said, but added: "Manufacturers are already moving in the direction of alternatives and offering DEHP-free products, and practitioners are asking for alternatives. As practitioners read about the notices and the articles in the press, the demands for DEHP-free alternatives are going to grow."

Malkan, however, pressed the current primary concern of Healthcare Without Harm: the need for more information provided to consumers about DEHP. Malkan said that labeling should be required by the FDA "because healthcare providers don't necessarily know which products have or do not have DEHP in them."

Like the FDA, the Advanced Medical Technology Association (AdvaMed; Washington) — though it has a clear interest in protecting the interests of its manufacturing members who use DEHP — appeared to be shifting its stance a bit on the issue. It has generally downplayed the reports of health risks alleged for DEHP-processed devices but it provided a balanced response to the new FDA report and expressed appreciation for the agency's "efforts to educate healthcare professionals" on the issue.

In its review of the report, AdvaMed states for consumers a key point, but coming as a rather mixed message: "As FDA cautions ... 'Most importantly, you should not avoid [certain high-risk procedures] simply because of the possibility of health risks associated with DEHP exposure. The risk of not doing a needed procedure is far greater than the risk associated with exposure to DEHP.'"

Procedures the FDA considers to have the highest risk of exposure to DEHP include:

• Exchange transfusion in neonates.
• Extracorporeal membrane oxygenation in neonates.
• Total parenteral nutrition in neonates with lipids in PVC bag.
• Multiple procedures in sick neonates.
• Hemodialysis in perpubertal males.
• Hemodialysis in pregnant or lactating women.
• Enteral nutrition in neonates and adults.
• Heart transplantation or coronary artery bypass graft surgery.
• Massive infusion of blood into trauma patient.
• Transfusion in adults undergoing extracorporeal membrane oxygenation.

Debate over value of GPOs continues

The debate on Capitol Hill concerning the pros and cons of group purchasing organizations (GPOs) heated up following the July 4th holiday with release of a new study arguing that GPOs have a significant anticompetitive effect on the medical device market. The report, titled "The Exclusion of Competition for Hospital Sales through Group Purchasing Organizations," was drafted by Einer Elhauge, a professor at Harvard Law School (Cambridge, Massachusetts) and a specialist in antitrust law and regulations.

The Medical Device Manufacturers Association (MDMA; Washington) was especially pleased with the report since it supported its own position on the issue. A week before release of Elhauge's study, MDMA had sent a proposed code of conduct to the Senate subcommittee that is investigating GPO contracting practices with hospitals. The report, said Larry Holden, MDMA president, "not only describes the specific market conditions that are excluding medical device manufacturers from bringing innovative products to market, but also endorses serious measures for reforming this environment."

The 54-page Elhauge analysis is divided into three sections — practices that exclude better or cheaper products, why GPOs and hospitals would agree, and possible reforms. It lists three possible reforms: Banning or restricting loyalty rebates; bundling and other exclusionary agreements; banning side-payments and special discounts; and requiring disclosure. "The report is particularly helpful as we work with the Senate Judiciary Antitrust Subcommittee, the Hospital Industry Group Purchasing Association (also Washington) and industry to determine an effective code of conduct for the GPOs," Holden said.

Elhauge's analysis argues that the device industry features economies of scale in production and that producing the first unit costs more than units that follow. Overhead costs also are involved in order to gain regulatory approval and to hire the necessary personnel to run the business, including maintaining a sterile environment, which can result in large payouts, a problem he terms as "relatively lumpy."

His conclusion: "By denying rivals access to the market share they would need to achieve their minimum efficient scale, exclusionary agreements can thus raise the costs required by rivals. Such a cost increase will prevent many rivals from offering their products at all, and we will never see them." Elhauge adds, "Other rivals may be so more efficient that they can overcome this barrier to offer their product, but the fact that their costs have been raised means they cannot offer as low a price as they otherwise would."

A real-life case study cited by Elhauge is that of Retractable Technologies (Little Elm, Texas). Its VanishPoint syringe reduces needlesticks, but the company's ability to market the syringe has been impeded by GPOs that have developed exclusionary agreements favoring other, more established syringe makers, Elhauge charges. "The company reports that the reason its prices are higher is that it cannot access enough of the hospital market to obtain the sales volume to lower its per-unit costs," the report states. Elhauge cites Becton Dickinson (BD; Franklin Lakes, New Jersey) as dominating the syringe sector, noting that leading group purchasing organization Premier (Chicago, Illinois) has a contract requiring hospitals to purchase 90% of their syringes from BD.

Asthma gene points to possible cures

A team of researchers reporting in the July 11 issue of Nature has identified a gene linked to asthma. Dr. Stephen T. Holgate, a medical professor at Britain's University of Southhampton, working with researchers from Genome Therapeutics (Waltham, Massachusetts), found that the gene controls the contractions of muscles lining the airway. The finding is particularly significant since much previous research has focused on what has been considered asthma's primary hallmark, the inflammation of the airways and lungs.

Asthma sufferers are known to have particularly "twitchy" muscles, which contract at the slightest stimulus and, when combined with the swelling caused by inflammation, cause victims to gasp for breath. The gene discovery, says Holgate, provides a new target for both drug treatments and diagnosis for the disease as alternatives to bronchodilators and inhaled steroids, which only provide symptom.

To locate a genetic cause, Holgate and his team recruited 352 families from the south coast of England and 98 from the U.S. in which two or more children had asthma. An additional 200 so-called "hypernormal" families, with no history of asthma for at least two generations, also were part of a control group. The gene the researchers found was dubbed ADAM33, and they identified it has having four different functions related to muscle contraction. The researchers also identified some 55 mutations in the gene, with eight to 10 of these associated with increased susceptibility to asthma.

Genome Therapeutics identified the gene in partnership with Schering-Plough (Kenilworth, New Jersey), which is now attempting to develop an asthma drug. Holgate estimates that will take at least eight years, but says a diagnostic test might soon be available for identifying those with greatest susceptibility to asthma so that preventive measures can be started before the disease develops.