By Diagnostics World Staff
May 26, 2016 | Qiagen received a warning letter from the US Food and Drug Administration (FDA) last week detailing repeated complaints for high false positive rates for Qiagen’s QuantiFERON-TB Gold (QFT) test device—its blood test used for diagnosing tuberculosis. As the diagnostics community continues to watch Theranos implode, warning letters to other groups are becoming increasingly scrutinized.
The FDA’s May 16 letter is the Agency’s second in this correspondence with Qiagen, based in Germantown, Maryland. The Agency first contacted the company on February 5 after visits to Qiagen’s Maryland manufacturing facility. Qiagen responded to the Agency twice in the spring, but in today’s letter the Agency details violations still outstanding.
Although the letter includes many redactions protecting against disclosure of trade secrets or commercial or financial information, FDA highlighted quality system violations, medical device reporting violations, and corrections and removals violations.
Under quality system violations, the Agency contends that the TB test is “adulterated” and portions of the manufacturing process, “are not in conformity with the current good manufacturing practice requirements of the Quality System regulation.”
The Agency cited CAPAs— corrective and preventive actions—dating back to 2013 for which, “corrective action was not effective.”
For instance, several CAPAs were related to high false positive rates, which Qiagen attributed to elevated endotoxin levels in the TB blood collection tubes. False positive rates for the QuantiFERON-TB Gold In-Tube Assay have been reported in the literature since at least 2012 (J. Clin. Microbiol. September 2012 vol. 50 no. 9 3105-3107).
The author of that paper, Niaz Banaei, Medical Director, Stanford Health Care Clinical Microbiology Laboratory, spoke to Diagnostics World by email yesterday. "We and others have known for some time that certain lot [numbers] give rise to unusually high false positivity rate. These observations have been published and reported to Qiagen. It has been frustrating to not know exactly what caused these false positives and what Qiagen is doing to prevent them from recurring," Banaei wrote. "Having said this, we haven't had problems with false positives in the recent years."
Qiagen has responded to FDA, saying that it was reviewing the tube manufacturing process, and had changed the specifications for endotoxin, but the Agency pointed out that the review process didn’t include updated quality controls for the manufacturer to ensure the new specifications are actually met in the future.
“We should note that the validation documents included in your response do not directly address endotoxin levels and do not provide evidence that your current process has been appropriately validated,” the Agency said. “In your response to this letter, include an updated agreement with your contract manufacturer that includes endotoxin levels.”
Among the medical device reporting violations, FDA warned Qiagen for failing to submit reports to FDA after a device malfunctioned in such a way that another malfunction could cause or contribute to death or serious injury. In addition, FDA said that Qiagen had failed to adequately develop, maintain, and implement written medical device reporting procedures.
Malfunctions that led to a recall of Qiagen devices in Japan should have been reported to FDA within 30 days, but weren’t. Qiagen’s reporting procedure, “does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements,” the Agency said.
Twice in recent years, Qiagen tests in Japan were recalled or returned to the company, once for high false positive rates. In one case, the returned devices were “reworked” and distributed in the U.S. In neither case did Qiagen submit a Report of Correction or Removal to FDA, the Agency said.
Reached via email, Qiagen sent Diagnostics World a prepared response:
We have received the letter from the FDA. There are no performance issues with the QuantiFERON-TB Gold (QFT) test and there is no request to discontinue selling the product. The FDA warning letter describes deficiencies in our procedures relating to manufacturing process and CAPA / complaint handling processes.
We take these matters seriously and have already taken appropriate actions to correct the procedures and ensure FDA compliance. This includes making improvements during the ongoing transfer of QFT manufacturing and the transition to the fourth-generation version to the QIAGEN site in Germantown. QIAGEN is following the guidance provided by FDA; we will respond to FDA within the time period requested, and we expect to be fully compliant with FDA regulations.
The FDA gave Qiagen 15 days to respond to the letter and address the violations.