Originally Published MDDI November 2001

WASHINGTON WRAP-UP

Unanimous vote calls device center review process into question.

James G. Dickinson

DEHP Poses Risk to Children | Cracking Hip Implants Recalled | Should FDA Ban These Devices? | Needle Destructor Needs 510(k) | Ortho Development Cited for MDR Failures | Cooper Companies Also Cited

A striking echo of the flawed decision making by FDA's device center staff in the TMJ Implants case was heard in a milestone decision against the center on September 6, 2001. Benefiting from the first-ever meeting of FDA's new Medical Devices Dispute Resolution Panel was Lifecore Biomedical Inc. (Chaska, MN).

The fresh eyes of incoming Office of Device Evaluation director Bernard Statland were able to see something wrong in the staff work on TMJ Implants' PMA review, and Statland reversed its effect. The fresh eyes of the new panel members also saw something wrong in CDRH's reliance on arcane statistical analyses to disapprove Lifecore's device. The four-member panel unanimously recommended reversing the staff decision against the company's postsurgical adhesion prevention product, Intergel. CDRH director David Feigal watched in apparent discomfort as his staff's recommendations unraveled. No outside speakers defended the CDRH position.

The dispute resolution panel was established under the 1997 FDA Modernization Act to resolve scientific disputes between manufacturers and the agency. Lifecore had sought appeal to the panel following earlier unsuccessful efforts to persuade an FDA medical devices advisory committee, and the agency, to approve a PMA application for Intergel. Lifecore describes the product as an "intraperitoneal instillate for reduction of adhesion formation following gynecologic pelvic surgery."

Speaking for Lifecore, Karen Becker, PhD, emphasized the importance of developing interventions to prevent or mitigate the occurrence of adhesions in gynecologic pelvic surgeries. "More than three million gynecologic surgeries are performed annually in the United States," she said. "Of these, 60% to 90% result in adhesions, which can lead to infertility, bowel obstruction, and chronic pain." She pointed out that Intergel is now approved for use in Canada and Europe, with favorable results.

The initial PMA application for Intergel was submitted by Lifecore in March 1999, with a subsequent amendment in June 2000. Both were denied by FDA. The agency based its decisions on recommendations of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee. In a "not approvable" letter issued on November 15, 2000, FDA concurred with the advisory panel's opinion that data from Intergel-treated patients did not show a clinically significant benefit over control patients. The letter also expressed concern over a "higher infection rate," allegedly inferred from data submitted by Lifecore in support of its application.

CDRH statistician Richard Kotz presented FDA's interpretation of data from a double-blinded, randomized clinical trial of Intergel. More than 200 patients were enrolled at multiple clinical centers in the United States and Europe. Kotz contended that the data showed no statistical difference between the incidence or severity of adhesions in patients on Intergel and control patients. In particular, he said that data from the U.S. and European clinical centers were "not combinable." From a statistical standpoint, he concluded, pooling the data would tend to "skew results of the trial toward success and away from failure."

CDRH clinical reviewer Roxi Horbowyj, MD, also expressed skepticism about the efficacy of Intergel, because there was "a statistical difference of less than one adhesion between patients on Intergel and controls." Further, she expressed concern over data indicating a 4.9% infection rate for patients treated with Intergel compared with 2.0% for patients who did not receive the product.

The dispute resolution panel heard from a number of witnesses in support of the product. Theodore Colton, ScD, of Boston University's School of Public Health, described the trial as "well designed and scientifically sound." According to his interpretation of the clinical trial data, there appears to be "a five-fold lower risk of adhesions" for patients who received Intergel.

Lifecore's Becker took special issue with the CDRH contention that trial data cast doubt on the safety of Intergel. "The number of patients who suffered postoperative infections was very small (a total of five) and, of these, one had a head cold and the other was diagnosed with chicken pox," she pointed out. "Clearly, neither infection could be associated with the use of Intergel."

Several practicing physicians also spoke in support of the PMA application for Intergel. Melvin Thornton, MD, assistant professor at Columbia University School of Medicine, said the gel form of the Lifecore product is easier for surgeons to employ than competing products. He said this fact constitutes encouragement to its use, and would thus likely benefit larger numbers of patients.

Mark Martens, MD, a physician practicing in Baltimore and a self-described patient advocate, gave especially moving testimony on his experience with Intergel, which he said he has been able to employ on a "compassionate use" basis. Martens said his advice to patients suffering chronic pelvic pain related to adhesions who are denied the use of Intergel in the United States is that they should go to Canada, where it is both legal and available.

Panel members agreed that there were some weaknesses in the design of the clinical trial. Gerald Shirk, MD, of OB/GYN Associates in Cedar Rapids, IA, pointed out that there were no controls on surgical techniques and materials used in surgeries in the trial. Ralph D'Agostino, PhD, professor of mathematics/statistics and public health at Boston University, noted the relatively small number of patients enrolled in the trial. On balance, however, panel members found no reason to vote against premarket approval.

Perhaps the most unusual testimony came from Bess Weatherman, representing the National Venture Capital Association. The organization represents more than 400 of the nation's largest venture capital firms, including those providing financial support for the development of new drugs and medical devices. Weatherman, a medical device specialist for Warburg Pincus (New York City), said the availability of venture capital depends on the "consistency and predictability" of regulatory decisions. For this reason, she said, FDA's opposition to the Intergel PMA was "very disturbing," given that it seemed to discount the successful results of a randomized, double-blinded Level I clinical trial. She told the panel that its actions would be scrutinized and widely noted within the investment community.

The panel's decision against the center's disapproval decision now is before director Feigal. According to FDA's July 2, 2001, final guidance on dispute resolution, he has 10 days after receiving the official transcript of the meeting (usually about a month after the panel meeting) to take one of the following actions:

DEHP Poses Risk to Children

Children, particularly neonates, and other subpopulations undergoing certain medical procedures may be at risk from DEHP, a plasticizer used in polyvinyl chloride (PVC) medical devices. This warning was given by CDRH on September 5, 2001, in a document titled "Safety Assessment of Di(2-ethylhexyl)phthalate (DEHP) Released from PVC Medical Devices."

The center's report says the available reproductive and developmental toxicity data are limited but suggestive. Human exposures in some situations approach toxic doses in rodents, raising concerns about the possibility of harmful side effects, particularly on the developing reproductive tract of young boys.

The report notes three findings that supported its conclusion:

The report also says its conclusion is consistent with that of an expert panel recently convened by the Center for the Evaluation of Risks to Human Reproduction of the National Toxicology Program.

Neonates undergoing extracorporeal membrane oxygenation (ECMO) in particular may be exposed to more than 20 times the safe-exposure limit, but other groups may be at risk as well, the report says. "Lipid in enteral nutrition solutions can leach out considerable doses of DEHP from PVC bags and tubing," it states. Patients may be put "at an increased risk of developing DEHP-mediated effects if PVC bags and tubing are used to deliver the enteral nutrition solutions."

Also at possible risk are infants undergoing exchange transfusions and adults undergoing ECMO and cardiopulmonary bypass. Furthermore, the report points out, DEHP dose estimates typically do not take into account exposure of patients to multiple PVC devices, such as neonates in the NICU environment who are typically exposed to the substance from multiple sources.

A spokesperson for industry association AdvaMed said it is reviewing the report, but expressed disappointment that CDRH released the assessment without first obtaining public comment on a draft version.

The full report is available at http://www.fda.gov/cdrh/ost/dehp-pvc.pdf.

Cracking Hip Implants Recalled

St. Gobain Desmarquest zirconia ceramic femoral head hip implants are experiencing a higher fracture rate than expected 13 to 27 months after implant, according to an FDA talk paper issued September 14, 2001. The paper said the problem component is the ball portion of the hip prosthesis that connects the femoral stem to the pelvis. Eight American companies are involved in the recall: Apex Surgical (Lakeville, MA), Biomet (Warsaw, IN), DePuy Orthopedics (Warsaw, IN), Encore Orthopedics (Austin, TX), Osteoimplant Technology (Hunt Valley, MD), Smith & Nephew (Memphis), Stryker Howmedica Osteonics (Allendale, NJ), and Zimmer (Warsaw, IN).

The FDA paper said there are no tests that can predict which patients will experience failure of their hip implants because of defective femoral heads. According to the document, "Fracture of implants with this component is usually signaled by a sudden pain in the implanted hip joint, sometimes preceded by an audible 'pop' from the hip just before the onset of pain. If a hip implant fractures, surgery to replace it will be necessary."

The current recall is the second major hip implant recall this fiscal year, FDA said. Sulzer Medica announced last December that it was recalling certain of its hip implants because the presence of a lubricant residue prevented the devices from bonding with a hipbone. The paper says that problem also was related to manufacturing.

The talk paper may be accessed at http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01102.html.

Should FDA Ban These Devices?

FDA intends to issue an advance notice of proposed rulemaking to solicit industry comments on whether a ban on unsafe blood devices is necessary. In denying a Public Citizen petition requesting an immediate ban on the devices, the agency also said it will ask if labeling changes are needed and whether the agency should take action to reduce needlestick injuries. FDA said it shares the Ralph Nader organization's concerns about such injuries but does not believe a product ban is needed.

FDA told Public Citizen it does not yet have sufficient information to justify such a ban on the devices. The agency also declined to develop a performance standard incorporating the design criteria requested by the petition. Instead, it will invite interested persons to submit any data to FDA that will help develop a standard. In addition, it will invite organizations to develop their own standards.

The most effective risk-reduction efforts, FDA said, will result from user education and training, increased use of products that have risk reduction features, and compliance with OSHA's existing blood-borne pathogens standard. Additionally, it intends to hold a public meeting following the comment period to gather information on the topic and revise and reissue its August 1996 guidance, "MDR Guidance Document No. 3—Needlestick & Blood Exposure." FDA also said it will review a previous safety alert to healthcare workers on the risk of injuries to determine if it should be rewritten, among other measures.

In its November 2000 petition, Public Citizen said needlestick injuries should be minimized to prevent the spread of infectious diseases such as HIV and hepatitis. It said that healthcare workers sustained over 500,000 injuries from needlesticks a year. "An estimated 100 to 200 healthcare workers die annually from hepatitis B," the petition said, a number that does not include deaths from HIV and other blood-borne pathogens.

Public Citizen requested that FDA ban unsafe blood collection materials and require additional labeling that recommends not using the equipment for standard blood draws. It also asked FDA to issue five criteria as performance standards, among them fixed safety features providing a barrier between the hands and the needle after use and a feature allowing the worker's hands to remain behind the needle at all times.

Needle Destructor Needs 510(k)

FDA has recommended that PDC Innovative Industries (Coral Springs, FL) submit a 510(k) for its Hypo-Pro 2000 device-decontaminating product. The company met with FDA in September because the device's construction raised issues relating to the type of premarketing application it should file with the agency.

The Hypo-Pro 2000 is a container for use in a medical setting that holds contaminated, disposable syringes and other smaller devices after use on a patient. When filled, the container is subjected to very high temperatures followed by a compacting process that reduces the materials to the size of a U.S. quarter.

Ortho Development Cited for MDR Failures

A four-day FDA inspection of Draper, UT–based Ortho Development Corp. in June found significant quality system and GMP deviations at the device maker's facility, according to an August 22, 2001, warning letter. In the letter, FDA also said the orthopedic hip, knee, and spinal implant maker failed to submit reports under the medical device reporting (MDR) regulation.

For example, Ortho Development did not report two injuries caused by its B2 bipolar cup hip system. FDA said the firm should have reported these because both events required "medical intervention to preclude permanent impairment of a body function." The agency also charged that the company did not report a recall of the product initiated in February 2000.

FDA's warning letter said the company did not have adequate corrective and preventative action procedures. "For example, your firm does not conduct failure investigations or determine the root cause of complaints of defective and returned devices," the letter charged.

FDA's letter also said that Ortho Development had failed to validate processes that could not be fully verified by the firm's inspection or test methods. In addition, FDA said the company did not conduct periodic management reviews of the firm's quality system, and did not perform adequate design control reviews.

Cooper Companies Also Cited

Cooper Companies (Lake Forest, CA) failed to report at least 19 complaints of device failure to FDA, according to a recent warning letter issued to the company. The letter said the agency considered the device to be misbranded because the firm had failed to furnish information required by law.

According to the letter, an inspection of the company's Shelton, CT, facility found that the firm, which manufactures the HUMI Harris-Kronner Uterine Manipulator Injector, had records of at least 20 incidents of breakage where the distal tip of the HUMI device broke off in use (inside the patient). Only one of these was ever reported to the agency, the letter said. The letter also told the company it must report any still-unreported instances of tip breakage and report any such event in the future as required.

James G. Dickinson is a veteran reporter on regulatory affairs in the medical device industry.

Copyright © 2001 Medical Device & Diagnostic Industry