An MD&DI September 1997 Column
WASHINGTON WRAP-UPThere is plenty of work left to do on the U.S.European Union mutual recognition agreement.
On June 21 the U.S.European Union mutual recognition agreement (MRA) on medical device inspections and product reviews for marketing approval was signed without fanfare in Denver while world leaders attended the latest of their Group of Seven economic summits. The signing occurred almost a full month after its hoped-for consummation during President Clinton's European tour in May, and another week of joint bureaucratic formalities passed before the 52-page document was released.
If all goes well, the MRA will provide its intended benefits to U.S. and EU manufacturers of those products regulated by both parties as medical devices (almost everything but in vitro diagnostics) on or before June 1, 2001.
Mechanism. Under this MRA, manufacturers will work with conformance assessment bodies (CABs)--firms or agencies called "notified bodies" in the EU and recently accredited as third-party reviewers in the United States. The CABs will be selected by their nation's regulatory authority (FDA in the United States), but each must be, and must remain, satisfactory to the regulating authority in the nation that will import the products it assesses.
Premarket Product Reviews. U.S. device manufacturers will be able to obtain the basis for EU approval--a European Commissiontype examination and verification report--from a CAB applying EC standards and following EC forms but located in the United States and initially accredited by FDA. Conversely, EU manufacturers will be able to obtain a 510(k) evaluation report from a CAB that is following an FDA guidance document, FDA-approved standards, and an FDA-dictated format, but located in its own part of the globe and designated by an EU authority. However, the products eligible for these reviews will be limited to the lowest-risk categories, even after the three-year transition period. Specifically, CABs in both the United States and the EU will only be authorized to look at 510(k) submissions for devices in Class I and on a list of 50 categories in Class II (initially, 30 categories). Device categories requiring review of clinical data are excluded from the MRA's marketing approval mechanisms.
Inspections. The MRA will also cover all inspections of facilities that manufacture products regulated by both the United States and the EU as medical devices. This means that, for example, a pacemaker firm in Minneapolis should be able to find an American CAB in the Midwest that is accredited to inspect its plant and send an EC quality system evaluation report to Europe. The firm's competitor in, say, Manchester, England, should not need to go far before locating a British CAB authorized to conduct an FDA good manufacturing practices inspection and issue either a premarket approval report (PMA) or a routine surveillance report for FDA's endorsement. For both the United States and the EU, premarket (initial) inspections will be "full," whereas surveillance inspections or audits will be "abbreviated."
Vigilance. Both parties to the MRA hope to devise an alert system to tell each other "when there is an immediate danger to public health." The agreement speaks no more specifically than that about notification "of any confirmed problem reports, corrective actions, or recalls." Apparently the Europeans don't want to have to cope with FDA's medical device report (MDR) paperwork.
The MRA provides a three-year transition period for working out the details and for building the parties' confidence in each other's ability to conduct inspections and reviews to foreign standards. Much must be done, however, before that period can begin, and a footnote to the MRA notes that "it is understood" the period won't begin until June 1, 1998.
Further Approval. Although all parts of the MRA were carefully drafted to avoid impinging on national law and sovereignty, it is unclear whether further ratification may be needed from the governments of the United States and the 15 European Union member states beyond the formal initialing of the documents that took place in Denver as an adjunct to the Group of Seven meeting. FDA has said that it intends to promulgate its portions of the MRA through a formal notice-andcomment period. This is unlikely to change any of the document's substance, however. As Commerce Department acting assistant secretary for Europe Charles Ludolph put it on June 18, the United States has no desire for revision, "and there's no heart among the 15 member states to make any change."
Translations. What would seem the simplest and most mechanical task, translating the MRA, is expected to take four to six months. Translation into the 11 official languages must precede mutual transition activities, particularly those involving customs agents.
Guidances. The coverage of the MRA's review provisions is based on the scope of FDA's third-party review pilot project--30 Class II device categories to start with, 20 to be added during the transition period. For all of these, FDA has insisted, guidance documents must be written for the reviewers' use. Only 14 guidances have been written so far, and FDA is behind schedule on the 16 due by next year.
Designating CABs. Not necessarily by June 1, 1998--but soon thereafter if the MRA's device program is to have any credibility--designated authorities on both sides of the Atlantic must recruit third parties with technical expertise, then train them in foreign procedures to become CABs. The EU starts with a sizable group of known quantities, the notified bodies of its present device system. FDA has no third-party inspectors and only six accredited third-party reviewers, although two (TÜV Product Services and British Standards Institution) are also notified bodies native to Europe, and a third (Underwriters Laboratories) has some EU experience. It can be done. FDA's pilot program was first announced on April 15 last year and was up and running less than three months later.
Confidence Building. The MRA sets out a series of rather obvious steps by which the CABs can be trained, led through the inspection and review processes, and then fully accredited and turned loose by the 2001 deadline. Industry is talking about jumping to the same end more quickly with joint inspections--although no one is talking about who will pay the plane fare of a Helsinki engineer coming to Palo Alto to join an FDA San Francisco district office investigator on a walk-through of a latex glove factory.
Leftovers from Negotiations. Over the past six or eight months, the MRA negotiators followed the expedient strategy of pushing into the transition period thorny issues they couldn't resolve as hypotheticals. Designing the alert system is the simplest example. The MRA also provides that sometime before the 2001 deadline the parties will "jointly determine the necessary information which must be present" in review and inspection reports--even though during the talks FDA had proposed templates for the requisite data. The general MRA agreement provides that no one shall disclose to the public, such as through the Freedom of Information Act, "trade secrets, [or] confidential commercial or financial information." Is the simple fact of a follow-up inspection "confidential commercial," as it may be now in some European countries? Only the transition period will tell.
Many of the conformance assessments covered by the MRA may soon become moot due to such factors as the Center for Devices and Radiological Health's steady exemption of Class I devices from review, the likely congressional mandate of certification to international standards for Class II devices, the eventual demise of "substantial equivalence" to 1976 products as any sort of standard, and FDA's plan to use risk as the determinant for routine GMP inspections. No doubt mindful of this, the MRA drafters expressly noted that their document was "intended to evolve as programs and policies of the parties evolve" and called for periodic assessments to "identify potential enhancements." Additional products and procedures may be added by agreement, and the parties are directed to take into account the documents developed by the Global Harmonization Task Force. As Health Industry Manufacturers Association associate vice president Matt Gallivan noted, the MRA is "a good starting point . . . a framework."
Editor's note: The full text of the MRA is available on-line. Provision dealing specifically with medical devices can be found in the Sectoral Annex on Medical Devices.
Review times at CDRH have dropped markedly and steadily since 1993, according to a General Accounting Office report made public on June 3. The report confirms FDA's claims of improvement and concludes, despite industry skepticism, that "the decrease in review times that began in 1994 continued in 1995 and 1996."
The study looked at all submissions, 1989 and since, for 510(k) equivalence findings, premarket approvals, and PMA supplements. The most striking figures are the average times for successful 510(k)s (109 days in 1996, down from 247 in 1993) and PMAs (271, down from 777). GAO also calculated the median times, but in general "the results are the same regardless of the measure that is used."
CDRH's Office of Device Evaluation director Susan Alpert commented that she's "pleased that our numbers are confirmed" and that she expects continued improvement from the center's current reengineering effort; how much "is hard to predict until that's up and running." The shorter review times shown in the GAO report reflect, she said, a long stretch of specific thought and effort at the center--instituting management and model changes, for example, "focusing reviewers' attention on a 90-day cycle," and attaching goals to each submission. In addition, she said, "the staff has been wonderful."
One subset of the GAO's numbers indicates that collaboration with increasingly savvy sponsors also helped knock down the review times. Non-FDA time has declined, the report shows. For 510(k)s, the average dropped to 19 days in 1996 from 40 in 1993; for PMAs, to 36 from 243. The statistics are admittedly skewed by the fact that not all decisions have been made on the 1996 cohort, but the trend is clear.
GAO's report met with cynical disbelief from some in the device industry. One company called me to see if FDA had possibly pulled the wool over GAO's eyes by feeding them "filed" dates instead of "received" dates (indicating that FDA sat on an application for months after initial receipt before formally filing it), but GAO insisted they were aware of that possibility and had used only the "received" dates while making their analyses.