Originally Published MDDI July 2003

WASHINGTON WRAP-UP

A small radiation-oncology manufacturer has been ordered to halt production and distribution of its controversial therapy devices.

James G. Dickinson

More FDA Work Needed on Part 11 | Ex-FDAer Join AdvaMed | Imported Test Strips in Touble Again | Guidance on Third-Party Inspections

After the rare federal court seizure orders and petitions for injunction, the consent decree is FDA's toughest enforcement tool—and one that is increasingly used. Typically, consent decrees are sought when a company manufactures "necessary" products and has persistent GMP problems it is unable to resolve, despite its cooperative attitude.

The latest FDA consent decree was handed out in May and involved St. Louis–based Multidata Systems International, a small manufacturer of radiation oncology devices.

FDA said it issued a decree because the company's radiotherapy treatment planning unit had caused excessive radiation to be administered to 28 patients, several of whom died, at a medical facility in Panama City, Panama. On top of that, the company's manufacturing problems stretch back over many years. The decree, which stops Multidata from manufacturing and distributing radiation therapy medical devices, was filed in the U.S. District Court for the Eastern District of Missouri, and will be enforced until the firm convinces FDA it has corrected its problems.

According to FDA, Multidata failed to conform to current GMP and design standards, and also failed to file prompt reports with the agency after becoming aware that its products may have caused or contributed to death or serious injury. The company initiated a recall of its radiation-treatment planning software in September 2001 but, according to FDA, did not complete the recall until early this year.

FDA said it inspected Multidata several times between April 1993 and September 2001 and found extensive and persistent deficiencies in the firm's manufacturing practices every time. The firm did not respond to warnings and, according to FDA, the same violations were observed from one inspection to the next.

During the most recent inspection, FDA said it found that Multidata failed to establish, maintain, or follow procedures to control the design of the radiation-treatment planning software to ensure the specifications were met. It also failed to establish and follow procedures for taking preventive and corrective action, according to the agency, and failed to establish and follow procedures for investigating all complaints. What's more, Multidata failed to adhere to other standard GMPs. Finally, FDA said, the firm failed to identify the root cause of software code problems.

FDA issued a warning letter in July 1998 after an inspection revealed that the firm's Decision Support System for Radiation Support device had been adulterated within the parameters of Section 501(h) of the Federal Food, Drug and Cosmetic (FD&C) Act. In the letter, FDA stated that the company was not conforming with GMPs.

An additional warning letter was issued in December 2001, following the company's noncompliance with electronic product radiation control requirements. According to FDA, the company provided no evidence that the Multidata Model 8532 Block Cutter was certified in accordance with the federal laser performance standard. Specifically, the device was missing aperture labels and a warning for a Class II laser product.

FDA's consent decree with Multidata contains standard provisions that the agency has sought in previous enforcement cases. For example, it says, the firm must establish, operate, and administer its design and manufacturing methods, facilities, and controls in conformity with the current GMPs set forth in the quality system regulation for medical devices.

The decree says Multidata must also establish, operate, and administer its design and manufacturing methods, facilities, and controls in a manner designed to ensure that it maintains all records, which are then to be submitted to the agency. Retention of a qualified expert is also required by the agreement. This person will be responsible for inspecting Multidata's facility and its operations, evaluating the code quality of all software products, and certifying in writing to FDA that requirements set forth in the consent decree have been met and violations have been corrected.

To the company's benefit, FDA decided not to require an all-encompassing product-quality certification before software manufacture and distribution can continue. "Once the code of quality of a software product has been certified by the expert and all other cGMP requirements and requirements of this decree pertaining to that product have been met," the decree states, "defendants may design, manufacture, process, pack, label, hold for sale, and distribute each such certified product, even if other software products have not yet been so certified, provided that defendants have also first received written notification from FDA that they appear to be in compliance."

Within 45 days of receiving certification from Multidata and its expert, the decree says FDA may initiate an inspection of the firm's facility, as well as perform additional reviews as it deems appropriate to determine if the facility is in compliance with the FD&C Act, FDA regulations, and this decree. FDA said it plans to notify the firm, within 60 days of completing an inspection, if it is, in fact, in compliance. If no inspection is conducted, the agency will provide notification within 45 days of receiving the expert's and firm's certification.

FDA also took exception to unapproved Multidata devices that were cited in a December 2001 warning letter. Premarket notification clearance for these devices is required by the agreement, which specifies the following products: Model 8532 Multicut Block Cutter System, Model 8533 Compensator Milling System, Model 9310 Multidose Electrometer, Model 9390 Therapy Beam Monitor, Model 9723 In-Air Scanning Frame, Model 9763-XL Extra-Large, Model 9750 Universal, and Model 9740 Portable Water Phantoms.

The decree stipulates that if at any time Multidata fails to comply with the decree, FDA may order the firm to: (1) immediately cease designing, manufacturing, processing, packing, labeling, storing, installing, holding for sale, and distributing any article of medical device; (2) recall any article of medical device as and when FDA deems it necessary, in accordance with procedures identified by the agency; and/or (3) take any other corrective action(s) as FDA deems necessary to bring the firm into compliance with statutory and regulatory requirements.

More FDA Work Needed on Part 11

FDA's decision to apply "enforcement discretion" to areas of Part 11 (electronic records and signatures) needs more-explicit clarification, according to AdvaMed (Washington, DC). The organization referred specifically to the Part 11, Electronic Records, Electronic Signatures—Scope and Application draft guidance.

"Part 11 affects a broader constituency within the regulated industries than most FDA rules," AdvaMed wrote. "Consequently, many parties unfamiliar with regulatory language and interpretation will be reading and implementing this guidance document. These parties will find the existing language vague, resulting in excessive or deficient implementation actions." Unnecessary expense and confusion could result without some additional effort on the part of FDA to explain its discretionary concept, the group added.

AdvaMed said it was concerned that the guidance does not explicitly state that a risk-based approach should be applied to all Part 11 activities. The guidance could be interpreted as applying risk-based approaches only in the areas that are specifically addressed in the document, such as validation and audit trail. "We believe that the agency's intent is for manufacturers to apply a risk-based approach to their entire compliance effort for Part 11," the group said.

AdvaMed also believes FDA's interpretation of legacy systems is creating confusion. In the guidance, FDA describes a legacy system as an electronic system in place prior to the effective date of Part 11. This definition is not practical, AdvaMed argued, because most systems have been modified in some way since the regulation's inception. "If one maintains that any modification to a system removes the legacy status, then there is no value to the guidance's exclusion of legacy systems. There is a clear need for a broader definition of legacy system that takes into account the normal maintenance and changes to systems that are necessary to keep them running properly and satisfying the needs of the enterprise," said AdvaMed.

Additionally, it asked FDA to re-evaluate previous guidances as part of its review of Part 11, such as its guidance on computerized systems used in clinical trials (1999), which references the regulation and in some cases could exceed the requirements of Part 11.

Ex-FDAer Joins AdvaMed

Former CDRH deputy director Elizabeth D. Jacobson joined an old adversary, AdvaMed, in June, as its new technology and regulatory affairs executive vice president. In this capacity, Jacobson will represent the group on all scientific, technical, regulatory, and environmental issues. She joined FDA in 1975 as a research geneticist and held a number of senior science and management positions in CDRH and FDA. Before turning to consulting work in 2001, Jacobson was acting FDA senior advisor for science (2000–2001).

Previously, as CDRH deputy director (1990–2001), she developed programs to assure the safety and effectiveness of medical devices and participated in the reengineering of the medical device review process. She is also a former chair of the Global Harmonization Task Force, and currently serves as a member of Health Canada's Science Advisory Board. Jacobson has a doctorate in biology from Georgetown University.

Imported Test Strips in Trouble Again

Roche Diagnostics Corp. (Basel, Switzerland) has issued an alert to healthcare professionals regarding its Advantage II diagnostic test strips. Certain lots that were intended only for foreign distribution have been repackaged and reimported as Accu-Chek Comfort Curve strips. In some cases, according to FDA, the expiration date on these strips has been altered and extended, which may affect result accuracy.

This situation echoes the Troy Biologicals case involving a harsh FDA crackdown on imported but unapproved Canadian diagnostic test strips. Because the Roche strips were manufactured for non-U.S. markets, they are calibrated differently, FDA noted. As MD&DI reported in June 2003, this was the agency's main objection to the Troy Biologicals products. Yet FDA's current attitude seems to be that Roche does not require the intervention of armed agents it used with Troy Biologicals six years ago.

In the latest case, FDA added that product performance could be affected if the persons who altered the expiration dates did not store or handle the strips properly.

The affected product lot numbers are 445662 (expired 2/28/03), 225620 (expired 2/28/03), 445718 (expired 4/30/03), and 445705 (expired 7/3/03). If consumers have Accu-Chek Comfort Curve test strips from any of these lot numbers, FDA says they should stop using them and contact Roche Diagnostics for further instructions.

Guidance on Third-Party Inspections

FDA has released a guidance intended to implement Section 704(g) of the FD&C Act. The subject of the document is accrediting third parties to conduct inspections of eligible Class II and Class III medical device manufacturers.

The guidance is titled Implementation of the Inspection by Accredited Persons Program Under The Medical Device User Fee and Modernization Act of 2002; Accreditation Criteria: Guidance for Industry, FDA Staff, and Third Parties. It provides information for those interested in the new program. These include persons who seek to be accredited to perform quality system/GMP inspections under the FD&C Act, medical device establishments subject to inspection under Sec. 704 of the Act, and FDA staff responsible for implementing the program.

FDA says it will use the Third Party Recognition Board (TPRB) to accredit persons to conduct inspections of medical device establishments under MDUFMA. Applications to become an accredited person under MDUFMA's Inspection by Accredited Persons Program should be submitted to the TPRB.

Only applicants who can show the qualifications and competence needed to perform inspections can be accredited. Applicants must also prove they have instituted controls to prevent any conflict of interest (or appearances to that effect) that could affect the inspection outcome. In addition, before accredited persons can conduct independent inspections, FDA says the individuals will need to successfully complete classroom training and qualifying inspections performed under agency supervision.

The qualifications necessary to become an accredited person, as well as information on required training, monitoring, inspection records submissions/maintenance, and accreditation withdrawal are detailed in the guidance.

In order to be eligible to employ an accredited person in lieu of an FDA inspector, device establishments must meet the following basic criteria under Sec. 704(g)(6)(A) of the FD&C Act: (1) The establishment's most recent inspection was classified by FDA as "No Action Indicated" or "Voluntary Action Indicated"; (2) the establishment submits a notice to FDA requesting clearance to use an accredited party and identifying the person it intends to use, and FDA agrees to use that person; (3) the establishment markets a device in the United States and markets or intends to market a device in one or more foreign countries; (4) the accredited person is certified, accredited, or otherwise recognized by one of the foreign countries in which the device is to be marketed; and (5) the establishment submits a statement that the laws of one of the countries in which the device is to be marketed recognize an inspection of the establishment by FDA.

The intent of these provisions, the agency says, is to focus the use of third-party inspections on manufacturers that operate in a global market and are likely to be subject to multiple inspection requirements.

FDA says it plans to issue additional guidance with details about requesting a third-party inspection. In general, however, an establishment will need to send a notice to the applicable Office of Compliance in CDRH or the Center for Biologics Evaluation and Research requesting clearance to employ a specific third party to do a QSR inspection.

Under section 704(g)(6)(B)(i), FDA must respond within 30 days of receiving an establishment's notice. If FDA fails to respond to a notice within 30 days, the establishment is deemed to have clearance to use the accredited person it selected. For establishments whose request for clearance is denied or whose accredited inspector is rejected, recommended actions are provided in the just-issued guidance. To view it, visit http://www.fda.gov/cdrh/mdufma/guidance/1200.pdf.

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