Medical Devices: Challenges for FDA in Conducting Manufacturer Inspections
Released: 2008-01-29T00:00:00

Letter

Background

FDA is responsible for overseeing the safety and effectiveness of medical devices that are marketed in the United States, whether manufactured in domestic or foreign establishments. All establishments that manufacture medical devices for marketing in the United States must register with FDA. As part of its efforts to ensure the safety, effectiveness, and quality of medical devices, FDA is responsible for inspecting certain domestic and foreign establishments to ensure that they meet manufacturing standards established in FDA’s quality system regulation. FDA does not have authority to require foreign establishments to allow the agency to inspect their facilities. However, FDA has the authority to prevent the importation of products manufactured at establishments that refuse to allow an FDA inspection. Unlike food, for which FDA primarily relies on inspections at the border, physical inspection of manufacturing establishments is a critical mechanism in FDA’s process to ensure that medical devices and drugs are safe and effective and that manufacturers adhere to good manufacturing practices.

Within FDA, CDRH assures the safety and effectiveness of medical devices. Among other things, CDRH works with ORA, which conducts inspections of both domestic and foreign establishments to ensure that devices are produced in conformance with federal statutes and regulations, including the quality system regulation. FDA may conduct inspections before and after medical devices are approved or otherwise cleared to be marketed in the United States.

Premarket inspections are conducted before FDA will approve U.S. marketing of a new medical device that is not substantially equivalent to one that is already on the market. Premarket inspections primarily assess manufacturing facilities, methods, and controls and may verify pertinent records.

Postmarket inspections are conducted after a medical device has been approved or otherwise cleared to be marketed in the United States and include several types of inspections: (1) Quality system inspections are conducted to assess compliance with applicable FDA regulations, including the quality system regulation to ensure good manufacturing practices and the regulation requiring reporting of adverse events. These inspections may be comprehensive or abbreviated, which differ in the scope of inspectional activity. Comprehensive postmarket inspections assess multiple aspects of the manufacturer’s quality system, including management controls, design controls, corrective and preventative actions, and production and process controls. Abbreviated postmarket inspections assess only some of these aspects, but always assess corrective and preventative actions. (2) For-cause and compliance follow- up inspections are initiated in response to specific information that raises questions or problems associated with a particular establishment. (3) Postmarket audit inspections are conducted within 8 to 12 months of a premarket application’s approval to examine any changes in the design, manufacturing process, or quality assurance systems.

FDA determines which establishments to inspect using a risk-based strategy. High priority inspections include premarket approval inspections for class III devices, for-cause inspections, inspections of establishments that have had a high frequency of device recalls, and other devices and manufacturers FDA considers high risk. The establishment’s inspection history may also be considered. A provision in FDAAA may assist FDA in making decisions about which establishments to inspect because it authorizes the agency to accept voluntary submissions of audit reports addressing manufacturers’ conformance with internationally established standards for the purpose of setting risk-based inspectional priorities.

FDA’s programs for domestic and foreign inspections by accredited third parties provide an alternative to the traditional FDA-conducted comprehensive postmarket quality system inspection for eligible manufacturers of class II and III medical devices. MDUFMA required FDA to accredit third persons—which are organizations—to conduct inspections of certain establishments. In describing this requirement, the House of Representatives Committee on Energy and Commerce noted that some manufacturers have faced an increase in the number of inspections required by foreign countries, and that the number of inspections could be reduced if the manufacturers could contract with a third-party organization to conduct a single inspection that would satisfy the requirements of both FDA and foreign countries. Manufacturers that meet eligibility requirements may request a postmarket inspection by an FDA-accredited organization. The eligibility criteria for requesting an inspection of an establishment by an accredited organization include that the manufacturer markets (or intends to market) a medical device in a foreign country and the establishment to be inspected must not have received warnings for significant deviations from compliance requirements on its last inspection.

MDUFMA also established minimum requirements for organizations to be accredited to conduct third-party inspections, including protecting against financial conflicts of interest and ensuring the competence of the organization to conduct inspections. FDA developed a training program for inspectors from accredited organizations that involves both formal classroom training and completion of three joint training inspections with FDA. Each individual inspector from an accredited organization must complete all training requirements successfully before being cleared to conduct independent inspections. FDA relies on manufacturers to volunteer to host these joint inspections, which count as FDA postmarket quality system inspections.

A manufacturer that is cleared to have an inspection by an accredited third party enters an agreement with the approved accredited organization and schedules an inspection. Once the accredited organization completes its inspection, it prepares a report and submits it to FDA, which makes the final assessment of compliance with applicable requirements. FDAAA added a requirement that accredited organizations notify FDA of any withdrawal, suspension, restriction, or expiration of certificate of conformance with quality systems standards (such as those established by the International Organization for Standardization) for establishments they inspected for FDA.

In addition to the Accredited Persons Inspection Program, FDA has a second program for accredited third-party inspections of medical device establishments. On September 7, 2006, FDA and Health Canada announced the establishment of PMAP. This pilot program was designed to allow qualified third-party organizations to perform a single inspection that would meet the regulatory requirements of both the United States and Canada. The third-party organizations eligible to conduct inspections through PMAP are those that FDA accredited for its Accredited Persons Inspection Program (and that completed all required training for that program) and that are also authorized to conduct inspections of medical device establishments for Health Canada. To be eligible to have a third- party inspection through PMAP, manufacturers must meet all criteria established for the Accredited Persons Inspection Program. As with the Accredited Persons Inspection Program, manufacturers must apply to participate and be willing to pay an accredited organization to conduct the inspection.

FDA relies on multiple databases to manage its program for inspecting medical device manufacturing establishments.

DRLS contains information on domestic and foreign medical device establishments that have registered with FDA. Establishments that are involved in the manufacture of medical devices intended for commercial distribution in the United States are required to register annually with FDA. These establishments provide information to FDA, such as establishment name and address and the medical devices they manufacture. As of October 1, 2007, establishments are required to register electronically through FDA’s Unified Registration and Listing System and certain medical device establishments pay an annual establishment registration fee, which in fiscal year 2008 is $1,706.

OASIS contains information on medical devices and other FDA-regulated products imported into the United States, including information on the establishment that manufactured the medical device. The information in OASIS is automatically generated from data managed by U.S. Customs and Border Protection, which are originally entered by customs brokers based on the information available from the importer.

FACTS contains information on FDA’s inspections, including those of domestic and foreign medical device establishments. FDA investigators enter information into FACTS following completion of an inspection.

According to FDA data, more than 23,600 establishments that manufacture medical devices were registered as of September 2007, of which 10,600 reported that they manufacture class II or III medical devices. More than half—about 5,600—of these establishments were located in the United States. As of September 2007, there were more registered establishments in China and Germany reporting that they manufacture class II or III medical devices than in any other foreign countries. Canada, Taiwan, and the United Kingdom also had a large number of registered establishments. (See fig. 1.) Registered foreign establishments reported that they manufacture a variety of class II and III medical devices for the U.S. market. For example, common class III medical devices included coronary stents, pacemakers, and contact lenses.

FDA Is Not Inspecting Domestic Establishments Biennially as Required and Faces Challenges in Inspecting Foreign Establishments

FDA has not met the statutory requirement to inspect domestic establishments manufacturing class II or III medical devices every 2 years. The agency conducted relatively few inspections of foreign establishments. The databases that provide FDA with data about the number of foreign establishments manufacturing medical devices for the U.S. market contain inaccuracies. In addition, inspections of foreign medical device manufacturing establishments pose unique challenges to FDA—both in human resources and logistics.

FDA Is Not Inspecting Domestic Establishments Biennially and Inspects Relatively Few Foreign Establishments

From fiscal year 2002 through fiscal year 2007, FDA primarily inspected establishments located in the United States, where more than half of the 10,600 registered establishments that reported manufacturing class II or III medical devices are located. In contrast, FDA inspected relatively few foreign medical device establishments. During this period, FDA conducted an average of 1,494 domestic and 247 foreign establishment inspections each year. This suggests that each year FDA inspects about 27 percent of registered domestic establishments that reported manufacturing class II or class III medical devices and about 5 percent of such foreign establishments. The inspected establishments were in the United States and 44 foreign countries. Of the foreign inspections, more than two-thirds were in 10 countries. Most of the countries with the highest number of inspections were also among those with the largest number of registered establishments that reported manufacturing class II or III medical devices. The lowest rate of inspections in these 10 countries was in China, where 64 inspections were conducted in this 6-year period and almost 700 establishments were registered. (See table 1.)

Despite its focus on domestic inspections, FDA has not met the statutory requirement to inspect domestic establishments manufacturing class II or III medical devices every 2 years. For domestic establishments, FDA officials estimated that, on average, the agency inspects class II manufacturers every 5 years and class III manufacturers every 3 years. For foreign establishments—for which there is no comparable inspection requirement—FDA officials estimated that the agency inspects class II manufacturers every 27 years and class III manufacturers every 6 years.

FDA’s inspections of medical device establishments, both domestic and foreign, are primarily postmarket inspections. While premarket inspections are generally FDA’s highest priority, relatively few have to be performed in any given year. Therefore, FDA focuses its resources on postmarket inspections. From fiscal year 2002 through fiscal year 2007, 95 percent of the 8,962 domestic establishment inspections and 89 percent of the 1,481 foreign establishment inspections were for postmarket purposes. (See fig. 2.)

FDA’s Databases Provide Inconsistent Information Regarding the Number of Foreign Medical Device Manufacturing Establishments Subject to Inspection

FDA’s databases on registration and imported products provide divergent estimates regarding the number of foreign medical device manufacturing establishments. DRLS provides FDA with information about domestic and foreign medical device establishments and the products they manufacture for the U.S. market. According to DRLS, as of September 2007, 5,616 domestic and 4,983 foreign establishments that reported manufacturing a class II or III medical device for the U.S. market had registered with FDA. However, these data contain inaccuracies because establishments may register with FDA but not actually manufacture a medical device or may manufacture a medical device that is not marketed in the United States. FDA officials told us that their more frequent inspections of domestic establishments allow them to more easily update information about whether a domestic establishment is subject to inspection.

In addition to DRLS, FDA obtains information on foreign establishments from OASIS, which tracks the import of medical devices. While not intended to provide a count of establishments, OASIS does contain information about the medical devices actually being imported into the United States and the establishments manufacturing them. However, inaccuracies in OASIS prevent FDA from using it to develop a list of establishments subject to inspection. OASIS contains duplicate records for a single establishment because of inaccurate data entry by customs brokers at the border. According to OASIS, in fiscal year 2007, there were as many as 22,008 foreign establishments that manufactured class II medical devices for the U.S. market and 3,575 foreign establishments that manufactured class III medical devices for the U.S. market. Despite the divergent estimates of foreign establishments generated by DRLS and OASIS, FDA does not routinely verify the data within each database. Although comparing information from these two databases could help FDA determine the number of foreign establishments marketing medical devices in the United States, the databases cannot exchange information to be compared electronically and any comparisons are done manually.

Efforts are underway that could improve FDA’s databases. FDA officials suggested that, because manufacturers are now required to pay an annual establishment registration fee, manufacturers may be more concerned about the accuracy of the registration data they submit. They also told us that, because of the registration fee, manufacturers may be less likely to register if they do not actually manufacture a medical device for the U.S. market. In addition, FDA officials stated that the agency is pursuing various initiatives to try to address the inaccuracies in OASIS, such as providing a unique identifier for each foreign establishment to reduce duplicate entries for individual establishments.

Challenges Unique to Foreign Inspections Influence the Manner in Which FDA Conducts Such Inspections

Inspections of foreign establishments pose unique challenges to FDA— both in human resources and logistics. FDA does not have a dedicated cadre of investigators that only conduct foreign medical device establishment inspections; those staff who inspect foreign establishments also inspect domestic establishments. Among those qualified to inspect foreign establishments, FDA relies on staff to volunteer to conduct inspections. FDA officials told us that it is difficult to recruit investigators to voluntarily travel to certain countries. However, they added that if the agency could not find an individual to volunteer for a foreign inspection trip, it would mandate the travel. Logistically, foreign medical device establishment inspections are difficult to extend even if problems are identified because the trips are scheduled in advance. Foreign medical device establishment inspections are also logistically challenging because investigators do not receive independent translational support from FDA or the State Department and may rely on English-speaking employees of the inspected establishment or the establishment’s U.S. agent to translate during an inspection.

Few Third-Party Inspections Are Conducted, but Recent Changes Could Eliminate Some Obstacles to Manufacturers’ Participation

Few inspections of medical device manufacturing establishments have been conducted through FDA’s two accredited third-party inspection programs—the Accredited Persons Inspection Program and PMAP. FDAAA specified several changes to the requirements for inspections by accredited third parties that could result in increased participation by manufacturers.

Few inspections have been conducted through FDA’s Accredited Persons Inspection Program since March 11, 2004—the date when FDA first cleared an accredited organization to conduct independent inspections. Through January 11, 2008, five inspections had been conducted independently by accredited organizations (two inspections of domestic establishments and three inspections of foreign establishments), an increase of three since we reported on this program one year ago.

As of January 11, 2008, 16 third-party organizations were accredited, and individuals from 8 of these organizations had completed FDA’s training requirements and been cleared to conduct independent inspections. As of January 8, 2008, FDA and accredited organizations had conducted 44 joint training inspections. Fewer manufacturers volunteered to host training inspections than have been needed for all of the accredited organizations to complete their training. Moreover, scheduling these joint training inspections has been difficult. FDA officials told us that, when appropriate, staff are instructed to ask manufacturers to host a joint training inspection at the time they notify the manufacturers of a pending inspection. FDA schedules inspections a relatively short time prior to an actual inspection, and as we reported in January 2007, some accredited organizations have not been able to participate because they had prior commitments.

As we reported in January 2007, manufacturers’ decisions to request an inspection by an accredited organization might be influenced by both potential incentives and disincentives. According to FDA officials and representatives of affected entities, potential incentives to participation include the opportunity to reduce the number of inspections conducted to meet FDA and other countries’ requirements. For example, one inspection conducted by an accredited organization was a single inspection designed to meet the requirements of FDA, the European Union, and Canada. Another potential incentive mentioned by FDA officials and representatives of affected entities is the opportunity to control the scheduling of the inspection by an accredited organization by working with the accredited organization. FDA officials and representatives of affected entities also mentioned potential disincentives to having an inspection by an accredited organization. These potential disincentives include bearing the cost for the inspection, doubts about whether accredited organizations can cover multiple requirements in a single inspection, and uncertainty about the potential consequences of an inspection that otherwise may not occur in the near future—consequences that could involve regulatory action.

Changes specified by FDAAA have the potential to eliminate certain obstacles to manufacturers’ participation in FDA’s programs for inspections by accredited third parties that were associated with manufacturers’ eligibility. For example, an eligibility requirement that foreign establishments be periodically inspected by FDA was eliminated. Representatives of the two organizations that represent medical device manufacturers with whom we spoke about FDAAA told us that the changes in eligibility requirements could eliminate certain obstacles and therefore potentially increase their participation. These representatives also noted that key incentives and disincentives to manufacturers’ participation remain. FDA officials told us that they are currently revising their guidance to industry in light of FDAAA and expect to issue the revised guidance during fiscal year 2008. It is too soon to tell what impact these changes will have on manufacturers’ participation.

FDA officials acknowledged that manufacturers’ participation in the Accredited Persons Inspection Program has been limited. In December 2007, FDA established a working group to assess the successes and failures of this program and to identify ways to increase participation. Representatives of the two organizations that represent medical device manufacturers with whom we recently spoke stated that they believe manufacturers remain interested in the Accredited Persons Inspection Program. The representative of one large, global manufacturer of medical devices told us that it is in the process of arranging to have 20 of its domestic and foreign device manufacturing establishments inspected by accredited third parties.

As of January 11, 2008, two inspections, both of domestic establishments, had been conducted through PMAP, FDA’s second program for inspections by accredited third parties. Although it is too soon to tell what the benefits of PMAP will be, the program is more limited than the Accredited Persons Inspection Program and may pose additional disincentives to participation by both manufacturers and accredited organizations. Specifically, inspections through PMAP would be designed to meet the requirements of the United States and Canada, whereas inspections conducted through the Accredited Persons Inspection Program could be designed to meet the requirements of other countries. In addition, two of the five representatives of affected entities noted that in contrast to inspections conducted through the Accredited Persons Inspection Program, inspections conducted through PMAP could undergo additional review by Health Canada. Health Canada will review inspection reports submitted through this pilot program to ensure they meet its standards. This extra review poses a greater risk of unexpected outcomes for the manufacturer and the accredited organization, which could be a disincentive to participation in PMAP that is not present with the Accredited Persons Inspection Program.

Concluding Observations

Americans depend on FDA to ensure the safety and effectiveness of medical products, including medical devices, manufactured throughout the world. However, our findings regarding inspections of medical device manufacturers indicate weaknesses that mirror those presented in our November 2007 testimony regarding inspections of foreign drug manufacturers. In addition, they are consistent with the FDA Science Board’s findings that FDA’s ability to fulfill its regulatory responsibilities is jeopardized, in part, by information technology and human resources challenges. We recognize that FDA has expressed the intention to improve its data management, but it is too early to tell whether the intended changes will ultimately enhance the agency’s ability to manage its inspection programs. We and others have suggested that the use of accredited third parties could improve FDA’s ability to meet its inspection responsibilities. However, the implementation of its programs for inspecting medical device manufacturers has resulted in little progress. To date, its programs for inspections by accredited third parties have not assisted FDA in meeting its regulatory responsibilities nor have they provided a rapid or substantial increase in the number of inspections performed by these organizations, as originally intended. Although recent statutory changes to the requirements for inspections by accredited third parties may encourage greater participation in these programs, the lack of meaningful progress raises questions about the practicality and effectiveness of establishing similar programs that rely on third parties to quickly help FDA fulfill other responsibilities.

Mr. Chairman, this completes my prepared statement, I would be happy to respond to any questions you or the other Members of the subcommittee may have at this time.

Contacts and Acknowledgments

For further information about this testimony, please contact Marcia Crosse at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may found on the last page of this testimony. Geraldine Redican-Bigott, Assistant Director; Kristen Joan Anderson; Katherine Clark; Robert Copeland; William Hadley; Cathy Hamann; Mollie Hertel; Julian Klazkin; Lisa Motley; Daniel Ries; and Suzanne Worth made key contributions to this testimony.

Appendix I: Summary of GAO Testimony on FDA’s Program for Inspecting Foreign Drug Manufacturers

In congressional testimony in November 2007, we presented our preliminary findings on the Food and Drug Administration’s (FDA) program for inspecting foreign drug manufacturers. We found that (1) FDA’s effectiveness in managing the foreign drug inspection program continued to be hindered by weaknesses in its databases; (2) FDA inspected relatively few foreign establishments; and (3) the foreign inspection process involved unique circumstances that were not encountered domestically.

Our preliminary findings indicated that more than 9 years after we issued our last report on FDA’s foreign drug inspection program, FDA’s effectiveness in managing this program continued to be hindered by weaknesses in its databases. FDA did not know how many foreign establishments were subject to inspection. Instead of maintaining a list of such establishments, FDA relied on information from several databases that were not designed for this purpose. One of these databases contained information on foreign establishments that had registered to market drugs in the United States, while another contained information on drugs imported into the United States. One database indicated about 3,000 foreign establishments could have been subject to inspection in fiscal year 2007, while another indicated that about 6,800 foreign establishments could have been subject to inspection in that year. Despite the divergent estimates of foreign establishments subject to inspection generated by these two databases, FDA did not verify the data within each database. For example, the agency did not routinely confirm that a registered establishment actually manufactured a drug for the U.S. market. However, FDA used these data to generate a list of 3,249 foreign establishments from which it prioritized establishments for inspection.

Because FDA was not certain how many foreign drug establishments were actually subject to inspection, the percentage of such establishments that had been inspected could not be calculated with certainty. We found that FDA inspected relatively few foreign drug establishments, as shown in table 2. Using the list of 3,249 foreign drug establishments from which FDA prioritized establishments for inspection, we found that the agency may inspect about 7 percent of foreign drug establishments in a given year. At this rate, it would take FDA more than 13 years to inspect each foreign drug establishment on this list once, assuming that no additional establishments are subject to inspection.

FDA’s data indicated that some foreign drug manufacturers had not received an inspection, but FDA could not provide the exact number of foreign drug establishments that had never been inspected. Most of the foreign drug inspections were conducted as part of processing a new drug application or an abbreviated new drug application, rather than as current good manufacturing practices (GMP) surveillance inspections, which are used to monitor the quality of marketed drugs. FDA used a risk-based process, based in part on data from its registration and import databases, to develop a prioritized list of foreign drug establishments for GMP surveillance inspections in fiscal year 2007. According to FDA, about 30 such inspections were completed in fiscal year 2007, and at least 50 were targeted for inspection in fiscal year 2008. Further, inaccuracies in the data on which this risk-based process depended limited its effectiveness.

Finally, the very nature of the foreign drug inspection process involved unique circumstances that were not encountered domestically. For example, FDA did not have a dedicated staff to conduct foreign drug inspections and relied on those inspecting domestic establishments to volunteer for foreign inspections. While FDA may conduct unannounced GMP inspections of domestic establishments, it did not arrive unannounced at foreign establishments. It also lacked the flexibility to easily extend foreign inspections if problems were encountered due to the need to adhere to an itinerary that typically involved multiple inspections in the same country. Finally, language barriers can make foreign inspections more difficult to conduct than domestic ones. FDA did not generally provide translators to its inspection teams. Instead, they may have had to rely on an English-speaking representative of the foreign establishment being inspected, rather than an independent translator.

This is a work of the U.S. government and is not subject to copyright protection in the United States. It may be reproduced and distributed in its entirety without further permission from GAO. However, because this work may contain copyrighted images or other material, permission from the copyright holder may be necessary if you wish to reproduce this material separately.