FDA said it had received State Department approval to establish eight full-time permanent positions at U.S. diplomatic posts in China, pending authorization from the Chinese government. The announcement did not use the words “investigators” or “inspectors,” which may mean that FDA is unsure what authority Beijing will allow its personnel to assert.
Commissioner Andrew von Eschenbach studies test results with laboratory technicians in Shanghai.
Now that it has permission from the U.S. side, FDA said it plans to hire and place the new FDA staff in China over the next 18 months. It will also hire five Chinese nationals to work with them at the U.S. embassy in Beijing and at the U.S. Consulates General in Shanghai and Guangzhou.
FDA's Murray Lumpkin and Andrew von Eschenbach met with Chinese counterparts during a visit to China last fall.
“In an age when a border is not a barrier, the globalized economy demands heightened regulatory inter-operability, information exchange, and cooperation, especially on product quality and enforcement matters,” said Murray Lumpkin. He is FDA's deputy commissioner for international and special programs.
“Along with the important Memoranda of Agreement signed with two FDA counterpart Chinese agencies,” Lumpkin said, “our efforts to fill permanent FDA positions in China are a significant step toward ensuring access to safe food, drugs, and medical devices in the global market.”
FDA Issues Alert on Incorrect Glucose Monitor Readings
CDRH said in March that it has received reports of incorrect blood glucose readings due to the wrong test strips being used with blood glucose meters. For example, LifeScan's OneTouch Ultra test strips are not intended for use with Abbott's Precision Xtra meters, an FDA notice said, “and doing so may lead to lower-than-expected blood glucose results. Similar problems can also occur if other brands and models of meters and strips are not used in proper combination.” Users are advised to read each meter's owner's manual to determine which test strips are appropriate. To access the FDA notice, visit www.fda.gov/cdrh/oivd/test-strips.html.
FDA Counters NEJM Article on Device Safety
NEJM article criticized
industry and agency safeguards for
implantable devices, ICDs in particular.
The article, which criticized industry and agency safeguards for implantable devices—especially ICDs—was written by William Maisel, a consultant to FDA. Maisel is also director of the Beth Israel Deaconess Medical Center Medical Device Safety Institute (Boston). He urged congressional action to ensure that the welfare of medical device recipients becomes a higher priority for FDA and manufacturers. Long said the agency is giving the article a thorough review.
A number of essential consumer protections are currently lacking, he wrote. “Patients with a recalled medical device are not even assured of a single visit with their healthcare provider at no cost to themselves (paid for by either insurance or the device manufacturer) to discuss the health implications of the recall.” Maisel also wrote that although FDA regulations protect human subjects participating in research studies, no such protections are available for the millions of patients who receive devices outside of clinical trials.
In addition, he claimed that the vast majority of FDA approvals of medical devices occur without any representation of consumers' interests, and that decisions concerning postmarket safety rarely include input from patient advocacy groups. “Meanwhile, manufacturers have an inherent conflict of interest when addressing device safety issues and have stronger legal obligations to their shareholders than to the patients who use their products. This imbalance must be corrected.”
Maisel's article described the controversy over Medtronic's Sprint Fidelis lead that was approved in 2004 on the basis of bench testing but no human clinical data. In 2007, after 38 months on the U.S. market and 268,000 implantations worldwide, Medtronic recalled the lead because of an unacceptable fracture rate. Maisel recognized the high demands placed on ICD leads and acknowledged that no complex device can be 100% free of design, manufacturing, or performance flaws.
But after concerns arose about the device's performance, Maisel wrote, Medtronic notified a “limited number” of doctors who saw a higher-than-expected lead fracture rate. The firm said performance of the Sprint Fidelis lead was “in line with other Medtronic leads” and cited a small prospective postmarketing study that found a 1.1% lead failure rate within two years of implantation. Maisel said the company didn't report that the study was “grossly underpowered to detect even a moderate increase in fracture rate in the Fidelis as compared with its predecessors. In short, despite implantation of the device in hundreds of thousands of patients during several years on the market, the available postmarketing data were insufficient to provide a definitive conclusion about whether there was a performance problem.”
Maisel said that even as the company maintained that the lead functioned within acceptable parameters, it submitted a May 2007 FDA application for design and manufacturing changes and received approval two months later. But already manufactured leads remained available and continued to be used. By last October, Medtronic had confirmed 665 fractures in returned leads, five deaths, and a 2.3% fracture rate within 30 months of implantation, and recalled the product.
Maisel's article said that flawed products often continue to be marketed while the manufacturer submits a revised marketing application to FDA and then waits for approval of the amended product design and manufacturing plan.
And, the article said, failure to notify the public about important flaws is not unique to the arrhythmia device industry. It cited a U.S. House of Representatives investigation into whether FDA took proper action after determining that Cordis Corp. (Miami Lakes, FL) violated laws in manufacturing its drug-eluting stent. Maisel said FDA did not issue a public warning letter until several months after inspections revealed manufacturing errors and Cordis was permitted to continue marketing the device. “The failure of manufacturers and FDA to provide the public with timely, critical information about device performance, malfunctions, and fixes enables potentially defective devices to reach unwary consumers,” he asserted.
Maisel challenged the notion that disclosure of reliability information produces too much anxiety for patients and may lead some to reject having a device implanted. “Isn't that exactly the point?” his article asked. “When given information about reliability, some patients will choose not to have a device implanted. The solution is to educate patients, inform them about benefits and risks, and allow them to make their decision in consultation with their physician and family—a process called informed consent. The failure to publicly disclose adverse information about device safety subverts this process.”
He faulted FDA for failing to fulfill its mission to protect the public health and help the public get the accurate, science-based information it needs. In response, Long said, “As an agency rooted in science, we take a scientific approach to examining any product issue, and we recognize that there can be differences of opinion, especially on such complex and intricate issues. We will address the public comments and opinions thoroughly after a complete and detailed review of the issue.”
Although no medical device can be 100% free of problems, she said, “implantable defibrillators and their leads have been remarkably reliable and have helped many people.”
Guidance Released on Expedited Premarket Submissions
FDA has issued a guidance for industry and FDA staff titled Expedited Review of Premarket Submissions for Devices. Its purposes are to develop a common understanding of when it is best to grant expedited reviews and to outline standard procedures to be followed to achieve an efficient expedited review process. The guidance has been updated from its 2003 version to reflect changes from last year's FDA Amendments Act and corresponding changes in FDA's expedited review policy for premarket approval (PMA) applications, premarket reports, product development protocols, and 510(k)s.
Under this revision, FDA will no longer require additional conditions so that an expedited PMA can be measured against Medical Device User Fee and Modernization Act expedited performance goals. As a result, the guidance no longer includes information specific to those additional conditions. Also, if a PMA or 510(k) is granted expedited status, such status would not be revoked during its review should a device of the same type be approved or cleared.
The document addresses topics such as devices appropriate for expedited review, the meaning and effect of expedited review, and how to request expedited reviews. To view the guidance, visit www.fda.gov/cdrh/mdufma/guidance/108.html.
Grassley Seeks FDA Report on Synthes Spinal Disk
Prodisc was developed by Spinal Solutions, a start-up company funded by a New York investment firm. It later was sold to Synthes. In his February letters to von Eschenbach and Orsinger, Grassley cited a New York Times article stating that the investment firm stood to earn $175 million if FDA approved the Prodisc. The newspaper also reported that clinical investigators at half of the 17 research centers testing the device had substantial investment interests in the New York firm and thus would also profit from FDA approval. “This suggests a dangerous conflict of interest,” he wrote.
Grassley asked von Eschenbach to
- Determine whether Synthes disclosed the investigators' investment interests and, if it did so, to provide documentation of the disclosure.
- List the actions FDA can and will take if such a disclosure was not made.
- Reveal FDA's findings on the disclosure if it was made, providing any relevant internal documents and communications.
- Describe in detail any actions taken if the agency determined the disclosure compromised the device's integrity.
In addition, Grassley asked Orsinger to do the following:
- Reveal what information the company submitted to FDA regarding the financial interests of the clinical investigators and to provide relevant documentation.
- Discuss and document any internal policies, guidelines, or standards Synthes has on potential conflicts of interest with clinical investigators.
- Provide copies of any documents or communications on the Prodisc clinical investigators and their interests in the investment firm.
Grassley said federal regulations require clinical investigators to provide a list of all financial interests relevant to the drug or device company developing or manufacturing a product being considered for FDA approval. A company is required to submit that information to FDA, and the agency must then evaluate the information and determine its effect on the study. If the interests raise serious questions about a study's reliability, he said, FDA is authorized to take any action it deems necessary.
FDA Revises Guidance on Interactive FDA Reviews
FDA has revised a guidance it issued in December 2007 titled Interactive Review for Medical Device Submissions: 510(k)s, Original PMAs, PMA Supplements, Original BLAs, and BLA Supplements. It provides clarification of the agency's interactive review policy. Such reviews are intended to help facilitate an efficient and timely evaluation by FDA of premarket submissions “through increased informal interaction between FDA and applicants, including the exchange of scientific and regulatory information,” the agency says. According to the guidance, interactive reviews are designed to help accomplish the following:
- Improve the interaction between FDA review staff and applicants during a review.
- Prevent unnecessary delays in completing reviews, thus reducing overall time to market.
- Ensure that FDA's concerns are clearly communicated to applicants during the review, as appropriate.
- Minimize the number of review cycles.
- Minimize the number of review questions conveyed through formal requests to applicants for additional information.
The guidance says FDA's preferred communication tools are e-mail and fax because both are efficient and create a documented, permanent record of the interaction. “One-on-one telephone calls should be used primarily for requests for clarification that the FDA reviewer can easily document (e.g., the location of specific information within the [premarket approval application], interpretation of a graph, etc.). The applicant should send a follow-up e-mail to FDA that summarizes the telephone discussion and any commitment(s).” To view the guidance, visit www.fda.gov/cdrh/ode/guidance/1655.html.
Baxa Corp. Warned over QSR Findings
According to a warning letter released in March, FDA investigators found quality system violations during an inspection last July at Baxa Corp.'s Englewood, CO, facility.
The inspection also found that the firm failed or refused to furnish material or information required under the medical device reporting rule. The violations cited pertained to the company's electromechanical infusion pumps and related sterile tubing sets and pharmacy-related equipment.
FDA acknowledged receipt of a company response and status updates and said they appear to be adequate. A follow-up inspection is required to ensure corrections are effective.
The company was asked to submit certification by its outside expert consultant that he or she has audited the manufacturing and quality assurance systems relative to quality system requirements. The company is to certify that it has reviewed the consultant's report and initiated or completed all corrections requested.
Quality System Violations AT Baxa Corp.
FDA's letter says the violations included the following:
- Failure to follow design control procedures to ensure that design changes are identified, documented, reviewed, and approved before implementation.
- Failure to adequately validate design changes in acceptance criteria that were not established before performing validation activities.
- Failure to establish and maintain corrective and preventive action procedures that identify the actions needed to correct recurrence of nonconforming product and other quality problems.
- Failure to ensure that all complaints involving the possible failure of a device to meet its specifications are investigated.
- Failure to establish and maintain procedures to ensure that complaints are evaluated to determine whether the complaint represents an event that is required to be reported to FDA.
- Failure to establish and maintain procedures that ensure that management with executive responsibility shall review quality system suitability and effectiveness at defined intervals.
SyntheMed Cited Over Clinical Study Conditions
An FDA inspection last October at SyntheMed (Iselin, NJ) found “objectionable conditions” in the firm's activities as a medical device clinical study sponsor, according to a February 19 warning letter. It says the inspection was conducted under a program ensuring that data and information contained in requests for investigational device exemptions (IDEs), premarket approval applications, and 510(k)s are scientifically valid and accurate. Another inspection objective, the letter says, is to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.
The warning letter says a review of the inspection by the New Jersey district office showed serious violations of IDE regulations. Deviations noted on the FDA-483 included the following:
- Failure to secure the investigator's compliance with the signed investigator agreement, the investigational plan, applicable FDA regulations, and any other conditions of approval imposed by the reviewing institutional review board (IRB) or FDA.
- Failure to ensure adequate monitoring of the investigation and to include written procedures for monitoring the investigational plan.
- Failure to accurately document device shipment records.
- Failure to prepare and submit progress reports at least once a year to FDA and reviewing IRBs.
- Failure to obtain adequate signed investigator agreements for each participating investigator.
FDA says the firm's written response to the deviations was inadequate because it did not include written action plans and documentation of corrections carried out. SyntheMed was given 15 working days to provide written documentation of the actions that have been taken or will be taken to correct the violations. Such actions are also meant to prevent recurrence of similar violations in current or future studies for which it is the study sponsor.
FDA Cites Duke's Andrew Lodge
Duke University Health System's Andrew Lodge failed to follow regulations on a clinical study conducted under an investigational device exemption, according to a recent warning letter that followed a May 2007 inspection at the clinical site. Observations on the FDA-483 left at the end of the inspection included:
- Failure to ensure that an investigation is conducted in accordance with the investigational plan, any conditions of approval imposed by an institutional review board (IRB), and the applicable FDA regulations.
- Failure to submit progress reports to the sponsor or the reviewing IRB during the investigation.
The warning letter says the health system's responses were inadequate because they did not include measures that have been or will be taken to prevent future occurrences of the two observations.
FDA said Lodge should submit written documentation within 30 days of actions taken or to be taken to ensure that the noted violations will not be repeated in any future studies for which he is the clinical investigator.