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U.S. Department of Health and Human Services

MedSun: Newsletter #15, June 2007

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Newsletter #15, June 2007


FDA Nurse Consultants Publish Article on Luer Connector and Tubing Misconnections

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When the Joint Commission issued a Sentinel Event Alert in April 2006 about the widespread occurrence of luer connector and tubing misconnections and potentially deadly consequences, there was new awareness among health care organizations nationwide about this alarming problem.

Three FDA nurse consultants, Beverly Gallauresi, Melissa Eakle, and Audrey Morrison, who have been monitoring such events over the past few years, have published an article in Safe Practices in Patient Care, an online serial publication for nurses. In their article, “Misconnections Between Medical Devices With Luer Connectors: Underrecognized but Potentially Fatal Events in Clinical Practice,” the authors conclude that luer connector misconnections are a well-known issue in patient safety and that misconnections "continue to occur because luer connectors are widely available, easy to use, and inexpensive." Even though the health care industry has not yet reached a consensus on preventing misconnections, the authors advise that the number of luer connector misconnections can be reduced by following Joint Commission recommendations contained in the alert.

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FDA Releases Human Tissue Task Force Report

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June 12, 2007

The U.S. Food and Drug Administration (FDA) today released a report that concludes there are no significant industrywide problems in the recovery of human tissues used for transplantation.

The report was issued by FDA's Human Tissue Task Force (HTTF), an intra-agency group assembled in August 2006 to evaluate the effectiveness of FDA's tissue regulations.

The HTTF recommended targeted inspections or a “blitz” of U.S. companies that recover human tissues—including tendons, ligaments, bone, and other musculoskeletal tissues. One goal of the blitz was to look for more widespread problems in tissue recovery after FDA ordered two companies to cease manufacturing in 2006. FDA had found that these companies were not following procedures intended to prevent infectious disease transmission.

Investigators from FDA's Office of Regulatory Affairs (ORA) inspected 153 major human tissue recovery firms from October 2006 through March 2007. While some deviations from the regulations were identified, no major inaccuracies or deficiencies were found that could put tissue recipients at risk.

Based on data from the blitz, HTTF reported that nearly all recovery firms were in substantial compliance with FDA's comprehensive risk-based tissue regulations that went into effect in May 2005.

The task force report also made several recommendations on how to enhance FDA's tissue safety activities. FDA will use the information to better understand and oversee industry practices and to develop or revise guidance documents, regulations, and future inspection strategies. “The results, particularly of the blitz, show that FDA's new tissue regulations help keep human tissue safe,” said Jesse L. Goodman, M.D., M.P.H., director of FDA's Center for Biologics Evaluation and Research (CBER). “The work of the HTTF and FDA has provided valuable information about tissue recovery firms, our status on tissue safety, and important additional steps that should be taken to enhance the safeguards already in place.”

The overall risk of disease transmission through tissue transplantation is believed to be very low, according to Goodman. While 1.5 million musculoskeletal tissue transplants are performed annually, reports of disease transmission are rare. However, any instance of disease transmission can be serious, and up to 100 recipients may receive tissue from a single donor. In addition, the industry is growing in size, scope, and complexity, further underscoring the need for strong process control by manufacturers and effective Federal oversight.

“The recommendations of the task force will help us provide greater assurance of tissue safety,” said ORA Associate Commissioner Margaret O'K. Glavin. “The collaboration between CBER and the Office of Regulatory Affairs through the HTTF is a model that served us particularly well and will be continued.”

There are more than 2,000 active cell and tissue establishments registered with FDA. In fiscal year 2007, FDA intends to conduct 484 inspections. The task force recommends that all tissue establishments performing manufacturing steps considered to represent the highest potential risk for disease transmission be inspected every 2 years. It recommends that all others be inspected every 3 years.

Other task force recommendations include:
Increased Education and Outreach: FDA will sponsor a workshop on tissue processing and microbiology for industry, implanting surgeons, and academia to explore public and private partnerships and to develop and share best practices for reducing the risk of disease transmission.

Enhanced Adverse Reaction Reporting and Analysis: FDA received expert advice that is being used to refine the activities of FDA's multidisciplinary Tissue Safety Team, formed in 2004 to investigate adverse reaction reports and other tissue safety issues. CBER has further strengthened its communications and collaboration with the Centers for Disease Control and Prevention, FDA's principal Federal partner in tissue safety surveillance and adverse reaction investigations. FDA also intends to expand its use of voluntary adverse reaction reporting.

Regulations and Guidance: FDA issued a guidance document in September 2006 to emphasize responsibilities for ensuring tissue safety between establishments and their contractors. FDA will issue guidance on Current Good Tissue Practices that will encourage tissue manufacturers to achieve best practices that can further reduce the risk of infection transmission.

To enhance investigative and compliance activities, FDA is considering options to improve the speed and reliability of tissue tracking from donor to recipient.

Science of Tissue Safety: Much still needs to be learned about microorganisms that could affect tissue safety. FDA will initiate a tissue microbiology program in collaboration with other partners, to work on opportunities for reducing risk through detection, prevention, and best practices in manufacturing.

Additional Information:

Human Tissue Task Force Report

CBER's Human Tissue Web Page

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National Heart, Lung, and Blood Institute Report of the Working Group on Drug Eluting Stents and Bare Metal Stents: Summary of a January 30, 2007, Telephone Meeting

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The Working Group on Drug Eluting Stents met in a 2-hour conference call on January 30 to discuss the most effective role for the National Heart, Lung, and Blood Institute (NHLBI) in advancing the science related to stents, both Drug Eluting Stents (DES) and Bare Metal Stents (BMS): Where we are, where we should be going, and a possible leadership role for the NHLBI.

The panel included representatives from academia, industry, and the Food and Drug Administration (FDA).

The general sense of the group was that there was no need for a large, NHLBI-sponsored randomized clinical trial at the present time, but that a number of more basic questions should be addressed. A summary of the issues addressed and the conclusions follows.

Question: Is there a role for the NHLBI in better understanding the safety signal associated with DES?
Yes, the NHLBI does have a role because the Institute:
•Lends credibility to results since the Institute is free of vested interests;
•Can garner cooperation from various industrial and university stakeholders in sharing data;
•Conducts mechanistic studies that would not attract funding from other sponsors.

Question: Are there important problem areas to which the NHLBI might make a unique contribution?
Yes, there are a number of areas to which the NHLBI could make a significant contribution.
These include:
•Examples of clinical research issues or goals:
–Determine the rate of adverse events when DES (and BMS) patients are followed for much longer periods than has heretofore been the case;
–Develop an approach to standard data collection across studies; describe stent patients clinically [including demographics, disease state (i.e., extent of coronary disease and its clinical stability)]; describe associated comorbidities, procedure history, procedure received, procedural results, and followup results;
–Use of clinical modeling for risk stratification;
–Determine the optimal duration of dual antiplatelet therapy;
–Potential effects of new antiplatelet drugs on DES outcome;
–Determine how patients who must stop dual antiplatelet therapy (e.g., for noncardiac surgery) can be most effectively bridged to a period when they can resume dual antiplatelet therapy;
–Examine the role of stent malaposition in later stent thrombosis;
–Determine the role of optical coherence tomography and coronary angioscopy in identifying patients at risk of subacute stent thrombosis.

•Examples of mechanistic questions and goals:
–Study the processes involved in healing following BMS placement;
–Examine how each component of the DES interacts with the healing process;
–Determine the drug elution kinetics affecting the healing process;
–Use atherosclerotic animal models to study both BMS and DES;
–Genotypes of P 2Y 12 platelet receptors in identifying hyporesponders to clopidogrel and subsequent stent thrombosis;
–Determine the optimal type, dose, and duration of antiplatelet therapy;
–Investigate effective management of patients requiring premature termination of antiplatelet therapy for nonelective surgery.

Question: What organizational constructs are likely to be the most cost-effective for the NHLBI to employ?
•Registries: The clinical research issues above (with the exception of the duration of dual
antiplatelet therapy) could be addressed with carefully designed registries. A key role for the NHLBI would be to broker data-sharing among registries and use of common data collection approaches.
•Mechanistic and some clinical studies could be added to already-existing trials at a cost lower than setting up de novo infrastructure.

•A large trial that would assess DES versus BMS for freedom from death or MI (myocardial infarction) is not recommended. No other RCT (randomized controlled trial) was suggested.
•NHLBI should explore serving as a clearinghouse for sharing of data among registries and as the nidus for developing common data collection formats.
•An attempt should be made to imbed mechanistic and other ancillary questions inside ongoing trials to reduce cost.
•Establish collaboration between the NHLBI, FDA, academic centers, and industry.

Additional Information:

National Heart, Lung, and Blood Institute Report of the Working Group on Drug Eluting Stents and Bare Metal Stents: Summary of a January 30, 2007, Telephone Meeting

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DS-X Device Safety Exchange, a MedSun Program

DS-X Lessons Learned

Question of the Month with Comment

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How are you handling dated equipment when the expiration date is extended by the manufacturer? A catheterization laboratory manager requested “fresh” carotid stents rather than those on hand, which had expiration dates that had been extended by 1 year, according to a letter from the manufacturer. The risk manager supported the reorder although the materials manager of the institution felt there was no risk in using the extended expiration date stents. What’s your opinion?

From FDA: A review of the manufacturer’s letter extending the expiration date of the “stents” revealed that it was not the shelf life of the stents themselves that was being extended but rather that of the embolic protection system (EPS). [Embolic protection system devices are catheter-based nonimplant devices that are used during stenting and balloon angioplasty procedures. They are used to capture and remove embolic material generated during the procedure, which might otherwise migrate downstream in the blood and cause a stroke or heart attack.] No change to the shelf life of the stent itself was mentioned in the letter.

Because the EPS was cleared for marketing by the Food and Drug Administration (FDA) 510(k) process (see below), it was the manufacturer’s responsibility to determine if extending the shelf life (expiration date) had a detrimental impact on safety or effectiveness. Once that determination was made, the manufacturer was able to change its labeling and notify its customers of the change. No new 510(k) submission was required. Stents and the EPS devices are regulated differently by FDA; as a result, the regulatory process requirements to be followed when extending shelf life for each are different.

FDA Regulation of Stents: Premarket Approval Application
Stents are currently regulated under the Premarket Approval Application (PMA) regulations [21 CFR Part 814.20]. Here, a manufacturer must submit a comprehensive application that demonstrates that the device is safe and effective for its intended use(s). The evidence for this assertion typically includes the results of the sponsor’s laboratory and clinical testing and other detailed supporting documentation. Devices that require PMAs are typically life-supporting, implantable, high-risk devices that often use novel technology, such as silicone breast implants and artificial hearts. With devices that are approved for marketing through the PMA process, an expiration date (shelf life) is included in the device labeling. This shelf life is based on testing results obtained by the manufacturer using a defined testing protocol. Manufacturers can perform additional testing with this protocol to show that the shelf life of the device is longer than that in the approved labeling. If the manufacturer has an approved protocol for shelf-life testing, shelf-life extensions can simply be submitted to FDA in an annual report for the PMA. If the manufacturer does not have an approved protocol, such a change in shelf life would be considered a change in the safety and/or effectiveness for the device and must be reported in a supplement. Such a supplement would then have to be approved by FDA before the manufacturer could market the device with the extended shelf life claim.

FDA Regulation of EPSs: Premarket Notification Procedures [510(k)s]

Unlike stents, EPSs are regulated under the Premarket Notification Procedures 510(k) regulations [21 CFR Part 807.81]. For these devices, the manufacturer must submit a notice that it intends to market a given device and in it show that the device is substantially equivalent to another device (called a predicate) that is already legally on the market in the United States. This notice or application is not as involved as a PMA, and about 90 percent of the medical devices that go to market each year use this process. Devices such as magnetic resonance imaging scanners and digital blood pressure monitors are cleared for marketing by the 510(k) process.

There are no provisions for supplements (that is, changes, updates, or modifications) to a 510(k) submission once it has been cleared. As a result, when changes are made to a 510(k)-regulated device that will affect its safety or effectiveness, a new 510(k) submission is required.

Manufacturers are required to submit prescribed annual reports to FDA for all approved PMA devices that are being marketed (per 21 CFR Part 814.84).

A supplement is defined in 21 CFR Part 814.39(a)(7). It is an additional submission that provides a full explanation of the basis for the change and evidence that the device’s safety and effectiveness are maintained after the change is implemented.

Guidance is available in “Deciding When To Submit a 510(k) for a Change to an Existing Device." Part B9 of this guidance addresses changes to expiration dating and states in part, “Generally…changes in the expiration date for use of a device do not result in the need for a new 510(k).” There are some exceptions to this, so it is best to consult the guidance whenever a change of any kind is made to a 510(k) device.

Additional Information:

Deciding When To Submit a 510(k) for a Change to an Existing Device

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Updated June 1, 2007

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