Pesticide Safety: Improvements Needed in EPA's Good Laboratory Practices Inspection Program
Released: 2014-06-16T00:00:00

Letter

Background

The primary federal laws that govern how EPA regulates pesticides in the United States are FIFRA and FFDCA. Under FIFRA, EPA registers pesticides distributed, used, or sold, in the United States and prescribes labeling and other regulatory requirements to prevent unreasonable adverse effects on health and the environment. If use of a pesticide would result in a residue of the substance in or on food, EPA may not register a pesticide under FIFRA unless, among other things, it can determine that the residue is “safe” as defined by section 408 of the FFDCA.permissible pesticide residue in or on food or animal feed that is sold— that meets the FFDCA safety standard set forth in section 408 or may EPA may establish a tolerance level—the maximum choose to grant an exemption for a tolerance. To obtain a pesticide registration, or petition to establish a tolerance level, a registrant (company or person) submits an application for EPA’s review containing health and environmental effects data and other information on a pesticide. In addition to testing conducted in a laboratory, these data can include studies based on the analysis of data collected from field applications of the pesticide and other information on the pesticide. The application is submitted with a pesticide registration fee, with the fee amount depending on certain factors, such as the type of registration action that is being requested. According to an OPP official, registrants are required to provide data relating to the pesticide’s hazard and exposure levels to accompany a proposed registration. All studies submitted in support of a product registration are subjected to an initial screening and regulatory and scientific review by OPP staff to determine potential human and environmental risks. OPP reviews the applications and registers those products determined to meet FIFRA’s standards for registration and other regulatory requirements so that they can be marketed domestically.

Under FIFRA, when a registrant submits an application for pesticide products to OPP, the accompanying data to support the registration are required to be prepared in accordance with the agency’s GLP regulations to ensure the quality and integrity of the data in the study. Each study submitted is reviewed by OPP to see if GLP criteria have been met. OPP staff prepare science reports and/or data evaluation records to address the quality of each study. If studies submitted in support of this process contain questionable data, this can result in adverse action by OPP. For example, according to OPP officials, if OPP finds that a registrant provided false or inaccurate information about the certified limits of the active ingredients of a pesticide, or if there is a discrepancy in the number of formulas used to check concentrations, a study would be rejected, and OPP might deny such an application or request that it be withdrawn.

OECA’s GLP Program is tasked with monitoring compliance with the GLP regulations through on-site inspections of laboratories, as well as audits of the laboratories’ studies. According to EPA officials, the purpose of the study audit is to ensure that the study was conducted in accordance with the agency’s GLP regulations and that the study is supported by data generated by the laboratory. A study’s sponsor or applicant must include one of the following statements in the submission: (1) that the study was conducted in accordance with GLP, (2) a detailed description of all the differences between the practices used in the study and those required by GLP, or (3) that they do not know if their study was conducted in accordance with GLP. Laboratories eligible for inspection are those that have conducted studies submitted to the agency. In some instances, a single laboratory may have conducted more than one submitted study. During an inspection, OECA’s GLP Program inspectors will verify the accuracy of a study’s GLP compliance statement. GLP inspections can take place while OPP is still reviewing a pesticide registration application or a petition for a tolerance-setting, or it can take place after a pesticide has been registered, or the tolerance has been established. Figure 1 summarizes the pesticide registration and tolerance-setting process, as well as its relationship to OECA’s inspection of GLP laboratories.

EPA and FDA have each developed their own GLP standards to address problems found with laboratory studies submitted for the agencies’ review. Investigations by these agencies in the mid-1970s revealed that some studies had not been conducted in accordance with commonly accepted laboratory practices. For example, according to an industry representative, one of the first laboratories to attract regulatory and media attention was Industrial Bio-Test Laboratories (IBT), a contract toxicological research laboratory that conducted much of the U.S. toxicological testing at the time. As a result of EPA’s and FDA’s investigations of IBT, several hundred studies were invalidated because of deliberate fraud, and hundreds of chemicals had to be retested. Specific findings included poor recordkeeping, testing conducted by untrained and unqualified personnel, and data fabrication. For example, data were submitted on rats that had previously been reported as deceased. As a result, in 1978, FDA formulated and published GLP regulations under FFDCA. In 1983, EPA published its GLP standards for pesticide toxicology studies, and in 1989, EPA extended the standards’ coverage to include nearly all research data supporting pesticide registrations under FIFRA. The Organisation for Economic Co- operation and Development (OECD), which includes more than 30 member countries including the United States, published OECD Principles of Good Laboratory Practices and OECD Guidelines for the Testing of Chemicals in 1981.

GLP standards cover the proper handling of laboratory test substances, equipment maintenance and calibration, testing operations, study plans, quality assurance, recordkeeping and reporting requirements, and facility management, among other things. For example, when EPA conducts a GLP inspection, it determines, among other things, whether the laboratory is of suitable size and construction to facilitate the proper conduct of the studies. Specifically, an EPA inspection would determine, among other things, whether the laboratory has a sufficient number of rooms or other areas for proper separation of species and testing, as well as for the collection and disposal of contaminants and waste.

In 1981, OECD established the Mutual Acceptance of Data program designed to obtain international recognition of testing data in support of pesticide registrations. As of August 2012, there were 31 member countries, including the United States, and 5 nonmember countries, each participating on a rotating basis in evaluating each other’s testing programs compared with OECD test guidelines. EPA has signed memorandums of understanding with seven countries under the Mutual Acceptance of Data Program and has a bilateral agreement with China.According to EPA documents, U.S. companies seeking to sell pesticides in foreign countries and multinational companies seeking registration of pesticides to sell in the United States must meet two Mutual Acceptance of Data program criteria: (1) the country where a study was conducted has a valid and active GLP Compliance Monitoring Program and (2) the testing facility (or laboratory) was inspected by the country’s GLP compliance monitoring authority. Some other countries fund their GLP inspections through fee-based systems, under which the registrant or laboratory pays a portion or all of the inspection costs. For example, according to a European Commission official, there are currently 17 European Union member countries that charge some type of fee for conducting GLP inspections. According to FDA officials, FDA charges user fees for medical and animal product application reviews; these fees, together with appropriated funds, provide resources that FDA uses for conducting GLP inspections related to such products. According to EPA officials, although the agency charges fees for review of pesticide applications by OPP, it does not charge a fee for OECA’s GLP laboratory inspections.

EPA’s GLP inspection process includes three stages: (1) the preinspection targeting stage, (2) the inspection stage or on-site inspection of the laboratory, and (3) the postinspection stage.

Preinspection Targeting Stage

The preinspection targeting stage includes a series of activities performed by inspectors before the actual on-site inspection is conducted. OECA’s GLP Compliance Monitoring Program usually initiates its own inspections by using a targeting module—referred to as the “Neutral Scheme Targeting Module”—that automatically searches the GLP Program’s Laboratory Information and Study Audit (LISA) database to target potential studies and pesticide test laboratories. The GLP Compliance Monitoring Program selects laboratories for inspection from among the population of laboratories that have conducted studies submitted to OPP. Using the Neutral Scheme Targeting Module, the inspector identifies laboratories and applies numerical weights to them based on a set of criteria (e.g., the length of time since the last inspection, the severity of the last and prior inspection findings, and the number of submitted studies conducted by the laboratory) to establish a list of potential laboratories to inspect. Most laboratories are selected for inspection through the Neutral Scheme Targeting Module. When laboratories are identified for inspection through use of the Neutral Scheme Targeting Module, the GLP Program Manager assesses these laboratories to determine their eligibility for inspection along with the studies selected for audit. The assessment includes performing a preliminary review of studies to determine, among other things, whether the laboratory is still in business and whether any studies conducted by the laboratory have been rejected by OPP in a review of a pesticide application. The GLP Program Manager will then prioritize and select the laboratories for inspection. Criteria for selection can include whether the eligible laboratories are in the same geographic area. The inspector determines when the laboratory will be inspected and, 10 days prior to the inspection, notifies the laboratory of the impending inspection.

Inspections can also be initiated at OPP’s request or that of another EPA office. For example, as OPP reviews studies, it may have questions or problems with the supporting data. In those cases, OPP can request that OECA’s GLP Program conduct an audit of particular studies and inspect the laboratories used for these studies. In addition, according to EPA officials, foreign governments can request an EPA inspection if a U.S. registrant is applying to use its pesticide in a foreign country and that country requires a GLP inspection of the U.S. laboratories whose studies are to be used in support of the registration. Finally, according to EPA officials, OECA can conduct a “for cause” GLP inspection based on a tip or complaint received through anonymous phone calls, e-mails or letters about potential GLP violations at a laboratory.

Inspection Stage

The inspection stage begins with the OECA inspectors, prior to visiting a laboratory, conducting study audits and evaluating the laboratory studies submitted to OPP to determine whether they adhere to GLP standards. GLP Compliance Monitoring Program inspectors previously performed this data audit during the inspection of the laboratory. In April 2012, EPA changed its process to have inspectors audit studies before inspecting the laboratory to save time spent at the laboratory and therefore reduce travel expenses. However, OECA officials told us that its inspectors follow the old process if appropriate to the situation. The inspectors are also to verify that data generated by the laboratory support the conclusions made in the study.

Next, an inspector travels to the laboratory to perform the on-site inspection of the laboratory. As part of this inspection, the inspector performs a walk-through of the laboratory to gain an understanding of its capabilities. The inspector will ask to see and review inspection documentation associated with the laboratory, including qualifications and responsibilities of laboratory personnel, the receipt and storage of test substances, the laboratory’s standard operating procedures, and animal rooms. The inspector then conducts a compliance inspection to gauge the laboratory’s current practices and procedures by selecting one or two ongoing or recently completed studies from the laboratory’s master schedule to see whether they adhered to GLP standards. The inspector also observes a procedure in an ongoing study to determine adherence to standard operating procedures, the study plan, and GLP, as well as whether the person performing the procedure has the appropriate education and experience.

Postinspection Stage

The postinspection stage involves activities such as preparing an inspection report that contains a description of the general nature of the inspection and the laboratory being inspected. Report appendixes cover the findings from the study audits and the on-site inspection. Inspection reports are next reviewed by another GLP inspector to ensure the reports are complete and consistent. According to an EPA official, the GLP Program Manager then reviews the inspection report and assigns one of the following categories to the laboratory as specified in the Enforcement Response Policy for FIFRA GLP Regulations: (1) no GLP deficiencies noted, (2) minor GLP deviations, or (3) major/significant GLP violations. For laboratories given ratings in the first two categories, the inspector closes out the inspection and enters all the inspection information and the review category into the LISA database. The inspector also enters some of this information, such as laboratory information, inspection dates, number of study audits, and potential deficiencies, into OECA’s Integrated Compliance Information System (ICIS), which is used for OECA-wide compliance reporting results.

The GLP Program Manager sends a letter to the laboratory and the registrant notifying them of the results of the inspection and, in the case of any deficiencies, requesting assurances that appropriate action will be taken to remedy the deficiencies. In the case of a significant violation of the GLP standards that, in the opinion of the inspector, may have affected the validity and integrity of studies performed at the laboratory, the GLP Program Manager will refer this information to OPP for consideration in their decision-making process and, if appropriate, to OECA’s Office of Civil Enforcement (OCE), which develops and prosecutes administrative civil and judicial cases and provides legal support for cases and investigations initiated in EPA regions. If the violation is criminal in nature, it will be referred to OECA’s Office of Criminal Enforcement, Forensics and Training (OCEFT). The inspection will not be closed until OPP or OECA has made a final determination. Figure 2 summarizes the GLP inspection process.

EPA Has Inspected Few Laboratories for GLP Compliance and Faced Challenges in Selecting Laboratories for Inspections

EPA’s OECA has inspected few laboratories on an annual basis that test pesticides for GLP compliance for fiscal year 2009 through fiscal year 2013 and faced challenges in doing so. Because of resource limitations in the GLP Compliance Monitoring Program, OECA prioritizes laboratories for GLP inspections based on a set of criteria. However, our analysis showed that some laboratory information in the databases used to prioritize laboratories for inspection was either inaccurate or incomplete, and these data challenges may negatively affect prioritization. OECA officials said that budget cuts, among other things, have reduced the number of inspectors and the number of GLP inspections that can be performed. Given the concerns of some stakeholders about the infrequent GLP inspections, OECA is considering other approaches, such as charging fees or using third parties to review studies, in order to increase the number of inspections.

OECA Inspects Few Laboratories Annually, but Most Laboratories Are Not Regularly Inspected for GLP Compliance

OECA inspected from 51 to 80 laboratories each year for GLP compliance in fiscal year 2009 to fiscal year 2013, but most laboratories were not regularly inspected for GLP compliance. During this period, OECA inspected about 4 to 6 percent of 1,400 eligible laboratories each year, according to EPA data and officials. In contrast, FDA’s GLP compliance program guidance manual states that the program’s objective is to inspect all eligible nonclinical laboratories conducting safety studies that are intended to support applications for research or marketing of regulated products approximately every 2 years.member countries under OECD’s Mutual Acceptance of Data (MAD) agreement conduct inspections of their laboratories for GLP compliance every 2 years, according to an OECD official we interviewed.

Some laboratory representatives we surveyed stated that their laboratories were not inspected for GLP compliance by EPA from 2008 to 2013. EPA officials told us they inspect as many laboratories as they can, given financial constraints. OECA officials explained that a limited number of inspectors and tight budgets have hindered their ability to perform more inspections. In fiscal year 2013, according to EPA officials, OECA had four GLP inspectors to inspect 1,400 eligible laboratories in the United States. OECA officials acknowledged that their four inspectors cannot inspect all 1,400 eligible laboratories for GLP compliance every 2 years. From fiscal year 2009 to fiscal year 2013, EPA reduced its GLP Compliance Monitoring Program budget and the number of full-time equivalent staff by approximately 50 percent from eight to four inspectors. EPA officials said that the reduction in the number of full-time equivalent staff was due to retirements, an inability to hire new inspectors because of budgetary constraints, and most importantly, according to these officials, the inability to find inspector candidates with the requisite skills. During this same time period, the number of studies conducted by laboratories that were submitted to OPP has remained relatively constant, except for an increase in the number of studies submitted in fiscal year 2010. Estimates of the numbers of studies submitted, inspections conducted, inspection staff and GLP budget data are shown in table 1.

To increase efficiency and to respond to a reduced budget and workforce, as well as to address concerns from industry and the OECD, OECA implemented changes to its GLP inspection procedures in fiscal year 2012 to try to increase the number of GLP inspections from the low of 51 conducted in fiscal year 2011. Under its revised inspection procedures, agency officials consider laboratories’ geographic proximity to each other, as well as other criteria, when selecting laboratories to inspect. For example, in February 2013, the agency inspected five laboratories located in Oregon and, in March 2013, the agency inspected two laboratories in Texas. OECA officials explained that grouping laboratory visits geographically saves travel money and staff time. In addition, they stated that a change in OECA’s inspection procedures to allow inspectors to audit studies in EPA offices rather than on-site reduced the amount of time that inspectors spent at a laboratory.

Nevertheless, some stakeholders and international officials we interviewed expressed concern about the infrequent GLP inspections by EPA. Pesticide manufacturers and industry associations told us that if laboratories cannot prove GLP compliance to potential clients or to countries where their products may be used, their business can be negatively affected. According to a senior staff person at one U.S. laboratory, in 2011, the Netherlands rejected a study from a U.S.-based laboratory because the contractor laboratory that conducted the study had not been inspected by EPA. This same study had been previously submitted to EPA. Following the Netherlands’ rejection of this study, the laboratory had to repeat the study and subsequently contracted with a European-based laboratory to do so. In addition, two stakeholders we interviewed said that such rejections by other countries could likely increase if U.S laboratories could not show that they had a recent GLP inspection. One laboratory representative said his laboratory may stop doing GLP testing since many registrants require proof of GLP inspections, and his laboratory had not been inspected by EPA. In addition, this laboratory representative said that if U.S. laboratories cannot show that they have had a GLP inspection, registrants may not hire them to conduct studies because of the possibility that those studies may be rejected. In our survey of laboratories, 5 of 14 respondents reported that EPA could improve its implementation of its GLP Compliance Monitoring Program by increasing the number and frequency of inspections to prevent these business consequences. Twelve of 15 respondents from laboratories with study data submitted to OPP since fiscal year 2008 reported that EPA’s GLP inspections had a positive effect on their business. Nine of the 12 respondents who reported positive effects of a GLP inspection indicated that the inspections enabled them to prove GLP compliance to their customers, such as U.S. and international pesticide manufacturing companies, as well as to other countries’ governments.

OECA Prioritizes Laboratories for GLP Inspections, but Data Challenges May Negatively Affect Its Targeting Process

OECA prioritizes laboratories for GLP inspections, but challenges with some of the data used to determine those priorities may negatively affect its targeting process. GLP Compliance Monitoring Program inspectors use the OPPIN and LISA databases to develop a list of the highest priority laboratories to inspect for GLP compliance in a given year. Once a list is generated using the Neutral Scheme Targeting Module located in the LISA database, OECA officials said they try to select laboratories that are geographically near to one another to inspect. The information used to develop this priority list is based on data transferred from OPPIN to LISA. However, our analysis showed that the laboratories’ information in these databases was sometimes incomplete or inaccurate.

We found that the OPPIN system currently has three categories to classify an entity’s role in a study: sponsor, performing laboratory, or both. These categories do not allow EPA staff to differentiate between GLP laboratories and other entities involved in a study. As a result, we found some entities were identified in the OPPIN database as “performing laboratories,” which EPA defines as facilities where a study or part of a study is conducted, when in fact they were not. For example, of the respondents to our survey of performing laboratories found in the OPPIN database, six reported that they were not a laboratory and did not conduct GLP testing. Of these six, three said they were consultants, two said they contract with an outside source for laboratory testing, and one was a pesticide manufacturer. We were not able to determine how or why these entities were identified as performing laboratories in OPPIN. EPA officials told us that if the entity that submits the study puts inaccurate information on a study’s title page concerning who performed the study and where the study was performed, the information entered by EPA’s contractors into OPPIN will also be inaccurate. EPA’s documentation describing the Neutral Scheme Targeting of laboratories states that the entity’s role in a pesticide study determines whether it is a candidate for inspection. If entities are inaccurately identified in OPPIN as performing laboratories, the Neutral Scheme Targeting Module will not consider the correct universe of laboratories to inspect and, as a result, inspectors need to do additional manual research to verify that the laboratory selected for an inspection is indeed an entity eligible for a GLP inspection.

We also found that address information for some laboratories was missing or inaccurate in OPPIN. For example, we found missing address information for 23 percent of laboratories listed in OPPIN. In 2008, EPA updated its 1991 guidance to the contractors responsible for entering data into OPPIN. The updated guidance states that the agency wants to capture the physical address for each laboratory because OECA uses this information to select laboratories for inspection. The guidance acknowledges that determining the performing laboratory in published studies is challenging, but the goal is to identify where the actual location of the research was done. Without accurate address information, there could be problems determining where the testing was actually conducted.

In addition, we found that some laboratory identification numbers were not reliable. In its November 1991 guidance, OPP states that laboratories should be assigned a unique laboratory identification number. For example, we found that one laboratory that was given a ranking in fiscal year 2013 as second highest priority for a GLP inspection had an identification number that was the same as four other laboratories in four different states, making it unclear which of those five laboratories was actually the one selected for inspection.

The agency maintains two different databases to track GLP inspections, ICIS and LISA. The LISA database is used by the GLP Compliance Monitoring Program, while the ICIS database is used EPA-wide, according to officials. Because of technical problems EPA has been experiencing with the LISA database, inspection data have been entered only into ICIS since July 2011, according to officials. We reviewed inspection data contained in both databases for fiscal year 2008 to fiscal year 2013 in an effort to determine the total number of GLP inspections OECA conducted, but we were not able to match the inspection information contained in the two databases. While LISA uses laboratory identification numbers, ICIS does not. As a result, OECA may not be able to track if, or when, a specific laboratory had been inspected because the systems do not both use identification numbers. In addition, the laboratory names are not always the same in the two databases. We were also unable to match up the inspections in the two databases. Without accurate data on which laboratories have been inspected, OECA’s Neutral Scheme Targeting Module scoring of laboratories most in need of inspection may be inaccurate and, therefore, manual research is required to ensure that OECA is targeting the laboratories most in need of inspection.

Based on the incomplete or inaccurate data in ICIS, LISA, and OPPIN, it is not always possible for GLP Compliance Monitoring inspectors to identify where the testing was conducted without making telephone calls to individual laboratories. The data issues also impede the agency’s ability to efficiently track which laboratories need inspecting. The officials said GLP inspectors must spend time manually verifying laboratory data before deciding which laboratories to inspect. In the absence of reliable data, EPA may not have the data it needs to prioritize laboratories to inspect efficiently or effectively.

OECA Is Considering Other Implementation Approaches to Increase Inspections

OECA is considering other approaches to address laboratory representatives’ and others’ concerns about infrequent GLP inspections, such as using third parties or charging fees to increase the number of inspections. In August 2012, OECA developed a Budget Adjustment Plan, which provided general information on potential future approaches to the GLP Compliance Monitoring Program, including ways the program could be run more efficiently given its recent budget cuts and inability to hire GLP inspectors. In its Budget Adjustment Plan, EPA states that OECA will evaluate other implementation approaches, such as the use of a third party to conduct GLP inspections. EPA officials told us that they have also conducted internal and informal discussions regarding the possibility of using user fees for the GLP program, but the agency has not conducted a formal evaluation of user fees. Without formally assessing the need for such fees, EPA cannot determine whether charging and retaining the fees would be possible and whether such fees could help make the inspection program self-sustaining.

In 2012, we concluded that federal user fees and charges are generally related to some voluntary transaction or request for government goods or services beyond what is normally available to the public, such as fees for patent applications and customs inspections. In 2012, the federal government collected nearly $300 billion in user fees from the public. In 2008, we found that well-designed user fees can reduce the burden on taxpayers to finance those portions of activities that provide benefits to identifiable users. As we mentioned earlier, FDA charges user fees for medical and animal product application reviews, and these fees, together with appropriated funds, provide resources that FDA uses for conducting GLP inspections related to such products. In addition, some other countries, such as some that are members of the OECD, fund their GLP inspections through fee-based systems, whereby the registrant or laboratory pays a portion or all of the inspection costs.

According to Office of Management and Budget (OMB) Circular A-25, every 2 years, agencies should review programs that are not currently funded by user fees (such as the GLP program) to determine whether fees should in fact be assessed for government services. Once user fees are implemented, revenue from the fees will be credited to the general fund of the U.S. Treasury as miscellaneous receipts unless otherwise specified by law. Circular A-25 also states that it may be appropriate for an agency to request authority to retain the fee revenue if the user fees offset the expenses of a service that is intended to be self- sustaining. The OMB guidance states that agencies are to discuss the results of the biennial fee reviews and any resulting proposals in their Chief Financial Officers (CFO) Annual Report required by the Chief Financial Officers Act of 1990. In its most recent CFO Annual Report (EPA Agency Financial Report) EPA discussed its biennial review of its existing user fee programs. However, it did not discuss reviewing the GLP program—or any of its other programs that are not currently funded by fees—to determine whether fees should be assessed. Moreover, in March 2014, the EPA Office of Inspector General (OIG) reported that EPA did not conduct thorough biennial user fee reviews for fiscal year 2008 to fiscal year 2009 and for fiscal years 2010 to 2011, and it did not review all agency programs to determine whether they should assess fees for government services they provided. Among the OIG’s recommendations were that the EPA CFO discuss biennial user fee results in the EPA Agency Financial Report, coordinate with programs that claimed an exception to charging fees and costs and help determine whether fees should be assessed. Without assessing the need for user fees, EPA cannot determine whether fees could help make the laboratory inspection program self-sustaining.

When asked about user fees, representatives of 8 of 12 laboratories and pesticide manufacturers told us they would support EPA user fees for GLP inspections, and they cited more frequent GLP inspections as a possible benefit of such user fees. Representatives from the remaining 4 laboratories did not support user fees, and some of these expressed concern that a user fee system might be burdensome to smaller laboratories. However, as we previously reported, the amount of a user fee reflects the cost of providing the service, which may differ among users.

EPA Rarely Used GLP Inspection Results in Initial Pesticide Registration Decisions but Sometimes Used Them for Later Reexamination

EPA rarely used GLP inspection results in making its initial pesticide registration decisions. An OPP official told us that this is because most inspections occur after those decisions have been made. According to an OPP official, pesticide registration decisions are required by statute to be made within 3 to 24 months of receipt of the pesticide application. For example, new pesticide products that are identical in their uses and formulation to one or more products already registered usually require a registration decision within 3 months. the GLP Monitoring Program staff cannot set up and conduct inspections of many of the laboratories involved within those time frames.

The Pesticide Registration Improvement Act of 2003 (PRIA) provides a schedule of covered applications and registration service fees, including the category or type of application, the amount of the pesticide registration service fee, and the corresponding decision review timeframe in which the agency is to make a decision. There are 189 fee categories or types of applications, each with a fee and decision review time frame. Pub. L. No. 108-199, div. G, tit. V, § 501(f)(2), 118 Stat. 419, 422 (2004) (codified as amended at 7 U.S.C. § 136w-8). last 6 to 12 months when performing inspections under the Neutral Scheme Targeting Module in fiscal year 2013; and (3) OECA audit specific categories of studies that OPP officials considered critical to their pesticide approval decisions. An OECA official told us that as of March 2014, OECA inspectors had completed all of the eight OPP-requested inspections. An OPP official told us that OPP would like to continue to provide input to OECA prior to the beginning of each fiscal year to increase the opportunity for OPP to react to findings before a product is registered. The two offices appear to be communicating and prioritizing laboratories for GLP inspections informally, but according to an EPA official, there are no documented procedures that define the responsibilities of each office in coordinating and prioritizing GLP inspections. EPA has stated that formal procedures are not needed and that the current method of communication and coordination is satisfactory. However, by relying on informal coordination mechanisms, OECA and OPP are depending on relationships with individual officials to ensure effective coordination, and these informal relationships could end once personnel turnover occurs. Without documented procedures for effective coordination between the two offices, there is no assurance that the two offices will consistently coordinate on GLP inspections in the future. Under federal standards for internal control, agencies are to clearly document internal controls, and the documentation is to appear in management directives, administrative policies, or operating manuals.

When OECA’s GLP inspectors find deficiencies at a laboratory, they share the inspection reports with major or significant violations with OPP. According to OPP officials, once OPP receives the OECA inspection report, it sends it to the OPP registration division responsible for the registration (or pending registration) of products being supported by the studies audited. The OPP registration division then reviews the report and conducts a scientific reexamination of the studies that the laboratory in question conducted and that were submitted in support of the pesticide registration. Once OPP finishes its reexamination, if it finds that deficiencies affect a study’s findings, OPP is to reject the study and may request that the registrant repeat the study, submit other materials that support that aspect of the registration, or perform other corrective action deemed satisfactory to OPP. After the reexamination is complete, OPP informs both OECA’s GLP Compliance Monitoring Program and the registrant of the outcome.

We found that, from fiscal year 2008 to fiscal year 2012, OECA GLP inspectors referred for reexamination the inspection results from 26 laboratories and 73 studies to OPP. Table 2 lists the action taken by OPP as a result of its reexamination of studies, as of March 2014.

Our analysis of EPA data shows that this review process, from the initial OECA GLP inspection to completion of OPP’s reexamination, takes on average about 2 years (see table 3).

According to OPP officials, OPP has not denied a pesticide registration or revoked any registrations based on OECA laboratory inspection information during the past 5 years, but OPP has taken other actions because of that information, such as requiring a registrant to repeat a study or requesting that a registrant voluntarily cancel its registration. For example, according to data provided by an OPP official, in fiscal year 2012, 15 studies associated with an already registered pesticide product were found to be “unacceptable” based on OECA inspection information. For 10 of these studies, EPA informed the registrants that they needed to repeat the study. For the 5 others, the registrant voluntarily canceled or suspended its registration associated with the study, or the study was not a deciding factor in the products registration and therefore EPA took no further action. In addition, OPP has required that an efficacy claim be removed from the label of a registered product based on a study submitted by a laboratory not meeting GLP standards.

OPP officials explained that a single study is not likely to affect the denial or approval of a pesticide registration because OPP usually bases its registration decisions on more than one study (although OPP officials noted their decision depends on, among other things, the type of study). For example, according to OPP officials, some pesticides are the subject of more than 30 different studies before a decision is made on registration. However, these same officials stated that OPP believes that the GLP inspections are valuable not only to alert OPP to issues with study data and laboratories but to act as a deterrent to guard against the improper conduct of studies and submission of fraudulent or incorrect study data. According to OECA officials, GLP inspections often lead to positive action being taken by laboratories and pesticide registrants. They said that registrants have voluntarily withdrawn studies from OPP as a direct result of inspection notifications and inspection findings.

EPA and FDA Do Not Regularly Collaborate on Laboratory Inspections and May Be Duplicating Each Other’s Work

EPA and FDA do not regularly collaborate on GLP inspections and may be duplicating each other’s work by inspecting the same laboratories. In 1984, EPA and FDA entered into an interagency agreement to collaborate on GLP inspections that was last renewed in 2004. Under the agreement, the two agencies agreed to collaborate in monitoring testing laboratories’ adherence to GLP regulations, as well as in auditing of health-related toxicological test reports and related laboratory records. The agencies also agreed to exchange information and coordinate actions concerning active investigations, regulation correspondence, and legal or administrative action being considered against any laboratory covered under the agreement. Among FDA’s responsibilities under the agreement was to conduct a certain number of on-site inspections of laboratories identified by EPA. From 2000 to 2007, FDA conducted a total of nine inspections identified by EPA (three in 2000; three in 2001; and one each in 2002, 2005, and 2007). EPA officials said they also formally met with FDA officials on a quarterly and annual basis to discuss upcoming inspections, but that communication ended by 2007 when, according to EPA officials, FDA began selecting laboratories for inspection on an annual basis instead of on a quarterly basis as EPA does. FDA also shifted from having its Office of Regulatory Affairs select laboratories for inspection to a more decentralized system, whereby its centers select laboratories for inspection, which made it more difficult for EPA to learn which laboratories FDA plans to inspect because it has to coordinate with multiple centers instead of the Office of Regulatory Affairs, according to EPA officials. EPA officials also said the last year FDA sent EPA a list of laboratories it planned to inspect was in 2007. They explained that, in the past, when EPA knew which laboratories FDA was going to inspect, it would ask FDA to audit a study for them and would avoid going to the same laboratory in the same year as FDA. However, since these meetings ended, EPA officials said that they do not always know if a laboratory was already inspected by FDA until they arrive on-site. If EPA knew in advance that a laboratory was inspected by FDA recently, EPA inspectors could use FDA’s inspection results to inform their decision regarding whether conducting their own inspection was necessary. If FDA’s inspection results were sufficient for EPA’s purposes, EPA inspectors could potentially select a different laboratory to inspect in place of the one recently inspected by FDA, thereby extending limited resources. It is important to note, however, that, in some circumstances, it may be necessary for both agencies to inspect the same laboratory.

EPA officials stated that they occasionally coordinate with one of FDA’s centers on GLP inspections and stated that the two agencies performed a joint GLP inspection in 2013. In addition, EPA and FDA officials also said that both agencies participate in an FDA-led work group focusing on the modernization of laboratories. Officials from both agencies said that it would be useful to know which laboratories the other agency was planning to inspect and to have the results from those inspections. Since each agency only inspects a certain number of laboratories each year, sharing such information could help both agencies leverage resources. This coordination also could increase the number of laboratories that are inspected for GLP compliance, which in turn would help ensure that the study data submitted for pesticide registrations were generated in accordance with GLP regulations. However, the agencies do not regularly collaborate on or communicate about future inspections or share results from completed inspections.

FDA conducts two types of laboratory inspections, surveillance inspections, which are periodic, routine determinations of a laboratory’s compliance with GLP regulations and include a facility inspection and study audit, and directed inspections, which are inspections assigned to achieve a specific purpose, such as verifying the reliability, integrity, and compliance of critical safety studies. Because the two agencies do not regularly share GLP inspection-related information, we found that EPA and FDA may be duplicating each other’s work in some of their GLP inspections. For fiscal year 2005 to fiscal year 2012, EPA and FDA conducted a total of 170 GLP inspections of the same 37 laboratories.In 38 of the 170 inspections, the agencies inspected the same laboratory during the same fiscal year (see app. III.). For example, EPA inspected a Colorado laboratory in November 2011, and FDA conducted a surveillance inspection of this same laboratory 7 months later in June 2012. Similarly, although EPA inspected a Utah laboratory in January 2012, FDA conducted a surveillance inspection of this same laboratory 5 months later, in June 2012. According to EPA and FDA officials, the GLP standards of the two agencies upon which these inspections are based are largely similar. Moreover, a senior official in OECA’s GLP Compliance Monitoring Program and representatives from three laboratories that were inspected by both EPA and FDA told us that the inspections were comparable.

We have defined overlap as two or more agencies or programs engaging in similar activities or providing similar services to similar beneficiaries. communication between the two agencies on which laboratories they plan to inspect and what they may have found at inspections that were conducted, although they have communicated this information in the past. FDA officials said they would welcome a list of inspections planned and conducted by EPA.

EPA and FDA officials said that, at present, they do not share the results of completed inspections at facilities that do both EPA and FDA-related studies, and they do not have a process in place to collaborate on future GLP inspections. As a result, EPA is not learning about laboratories that FDA has inspected and at which it may have found deficiencies. Similarly, FDA is not learning about the results of EPA laboratory inspections. In addition to potentially duplicating each others’ work, by not collaborating, the two agencies are missing opportunities to leverage each other’s resources and expand their inspection coverage. FDA officials told us it would be helpful to know if EPA had inspected a laboratory and that it would be particularly useful if EPA shared information if the agency had found problems during its inspection. EPA officials also said collaborating and communicating on inspections would be helpful.

In April 2013, we concluded that when executive branch agencies carry out activities in a fragmented and uncoordinated way, the resulting patchwork of programs can waste scarce funds, confuse and frustrate program customers, and limit the overall effectiveness of the federal effort. The federal government uses a range of mechanisms to implement interagency collaboration, such as interagency groups, and interagency agreements and memorandums of understanding. Key practices state that agencies that articulate their agreements in formal documents can strengthen their commitment to working collaboratively. Written agreements are most effective when they are regularly updated and monitored. As we concluded in April 2013, where federal programs or activities are fragmented, overlapping, or duplicative, there are opportunities for agencies to improve the efficiency and effectiveness of government programs and activities. Moreover, without leveraging its inspection resources with FDA, EPA may continue to have difficulty increasing annual GLP inspections of laboratories.

Conclusions

OECA has taken some steps to increase the number of GLP compliance inspections of laboratories conducting studies submitted to EPA for pesticide registration. However, OECA officials acknowledge that their four inspectors cannot inspect all 1,400 eligible laboratories for GLP compliance every 2 years, a time frame used by many of the countries that are members of OECD’s MAD agreement. Because some laboratories have never had a GLP inspection, laboratory and industry representatives expressed concern that if OECA continues to inspect so few laboratories for GLP compliance, U.S. laboratories and manufacturers will be less competitive with foreign laboratories and manufacturers. In addition, with so many laboratories going uninspected, EPA may not have full assurance of the quality and integrity of data used to make pesticide registration decisions.

OECA officials told us that they have informally discussed the possibility of instituting user fees for the GLP program, but EPA has not conducted a formal evaluation of GLP user fees as directed by OMB guidance for programs not currently funded by such fees and, as recommended by EPA’s OIG. OECA might be able to increase the number of inspections it conducts if it were to charge a fee, which may be used to fund GLP inspections, as FDA does, and as do 17 European countries. Without assessing its authority and need for user fees, EPA cannot determine whether fees could make the laboratory inspection program self- sustaining. In addition, we found that the information in EPA databases used by OECA to set priorities for laboratory inspection is sometimes incomplete or inaccurate. In the absence of reliable data, EPA may not have the data it needs to prioritize laboratories to inspect efficiently or effectively.

We commend OECA and OPP staff for communicating with each other on GLP inspection matters, including OECA consideration of OPP’s recent steps to identify laboratories that OPP considers to be priorities for GLP inspections. Considering OPP’s request is important because most OECA inspections currently take place after OPP has made its registration decisions. However, EPA does not have documented procedures that define the responsibilities of each office in coordinating and prioritizing laboratories for GLP inspections consistent with federal standards of internal control. Without such procedures, there is no assurance that the two offices will consistently coordinate on GLP inspections in the future.

Furthermore, because EPA and FDA do not regularly share inspection- related information, as they did when they had an agreement to collaborate on GLP inspections, the agencies have inspected some of the same laboratories since 2007, while other laboratories may have gone without needed inspections. Without collaboration and information- sharing on planned and completed GLP inspections, EPA and FDA may duplicate GLP inspections, and EPA will have difficulty efficiently using its limited resources to increase the number of inspections it conducts. Officials from both agencies said that collaborating and communicating on inspections would be helpful. However, absent a formal written agreement, it is not clear that the agencies would regularly collaborate on future planned inspections and share results from completed inspections.

Recommendations for Executive Action

We are making four recommendations in this report.

To improve the OECA GLP inspection process, we recommend that the EPA Administrator take the following three steps: 1. Assess the authority and need for a fee-based inspection system, and if such a system is warranted, establish a user fee system, seeking additional legislative authority, if necessary, to make the laboratory inspection program self-sustaining. 2. Direct OECA and OPP to ascertain the exact causes of inaccurate and incomplete data in its databases and take action to ensure that the data, such as identification of performing laboratories and inspection history, are accurately recorded. 3. Direct OECA and OPP to develop documented procedures to coordinate and prioritize laboratories for inspections.

In addition, we recommend that the EPA Administrator and the FDA Commissioner develop a formal written agreement, such as a memorandum of understanding, that outlines how the two agencies plan to regularly collaborate and share information on GLP inspections and avoid duplication of inspections so that EPA can more efficiently use its limited resources.

Agency Comments and Our Evaluation

We provided EPA and HHS with a draft of this report for their review and comment; EPA provided written comments, which are reproduced in appendix IV, and HHS provided written comments, which are reproduced in appendix V.

In its written comments, EPA stated that it agreed with our findings, conclusions, and all four of our recommendations. In response to our first three recommendations, EPA agreed to assess the authority and need for a fee-based GLP inspection system; to ascertain the exact causes of inaccurate and incomplete data and ensure that the data are accurately recorded; and, that OECA and OPP should develop written procedures to coordinate and prioritize GLP inspections.

In response to our fourth recommendation, EPA agreed to develop written procedures that outline how EPA and FDA will collaborate and share information on GLP inspections. EPA stated that it did not agree that a formal memorandum of understanding between the two agencies was necessary. Our recommendation did not prescribe the type of agreement the agencies should undertake and offered a memorandum of understanding as one example. We agree that written procedures developed and agreed to by both EPA and FDA will address the recommendation.

In its technical comments, EPA noted that, while EPA and FDA have similar GLP regulations, and in a small number of cases both agencies may inspect the same laboratory, EPA does not believe the work is duplicative. However, we define duplication in this report as occurring when two or more agencies or programs engaged in the same activities or provided the same services to the same beneficiaries. We continue to believe that there is a possibility of duplication when both EPA and FDA are inspecting the same laboratories within a short period of time because both agencies provide a similar service to the same beneficiaries (ensuring laboratory compliance with GLP through facility inspections and study audits). Also in its technical comments, EPA acknowledged the problems we found with the databases used for targeting GLP inspections but stated that it does not believe these problems negatively affect targeting for inspection because OECA is able to gather the necessary information manually. While we agree that, ultimately, EPA may target the appropriate laboratories for inspection through its manual research when the databases are inaccurate or incomplete, we believe that the agency’s reliance on manual research is not as efficient or effective as using databases containing accurate information.

In its written comments, HHS also agreed with our fourth recommendation. HHS also reiterated the point that there are legitimate reasons why GLP inspections may be conducted by both EPA and FDA at a single laboratory within a relatively short period of time. For example, when FDA observes significant violations during for cause or surveillance inspections, follow-up inspections may be required to verify corrective actions. HHS also provided technical comments on our report, which we incorporated as appropriate.

As agreed with your office, unless you publicly announce the contents of this report earlier, we plan no further distribution until 30 days from the report date. At that time we will send copies to the EPA Administrator and the FDA Commissioner, the appropriate congressional committees, and other interested parties. In addition, the report will be available at no charge on the GAO website at http://www.gao.gov.

If you or your staff members have any questions about this report, please contact me at (202) 512-3841 or neumannj@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix VI.

Appendix I: Objectives, Scope and Methodology

Our objectives were to examine the extent to which (1) the Environmental Protection Agency (EPA) inspects for GLP compliance laboratories that test pesticides and the challenges, if any, EPA faces in doing so, (2) EPA uses the information obtained through Good Laboratory Practices (GLP) laboratory inspections in its pesticide decision-making process, and (3) EPA and the U.S Food and Drug Administration (FDA) collaborate on GLP inspections. To address these objectives, we reviewed relevant federal statutes and regulations, EPA program and guidance documents, federal internal control standards, Office of Management and Budget circulars, and previous GAO and EPA Inspector General reports. We also reviewed EPA’s fiscal year 2011-2015 strategic plan; EPA’s fiscal year 2011, 2012, and 2013 annual agency financial reports; and EPA Office of Enforcement and Compliance Assurance (OECA) fiscal year 2012 Budget Adjustment Plan. In addition, we interviewed EPA’s Office of Pesticide Programs (OPP) and OECA officials and reviewed documentation they provided to obtain further information and clarification on EPA’s pesticide registration process and how it relates to the GLP process, and we interviewed FDA officials and reviewed documentation they provided on FDA’s GLP process. Furthermore, we reviewed recent literature related to GLP, including information and documents found on the websites of a variety of industry, international, environment, and academia organizations, and foreign government GLP inspection programs. We interviewed about 25 representatives from these organizations. We selected these individuals based on referrals from EPA, and industry and environmental stakeholders.

To examine to what extent EPA inspects for GLP compliance laboratories that test pesticides; and the challenges, if any, EPA faces in doing so, we collected and analyzed documentation from OECA officials on its GLP inspection process and analyzed EPA laboratory and inspection data, the agency’s use of this data , and the accuracy and completeness of the data. Specifically, we obtained information on how OECA determines which laboratories to inspect and how EPA’s Office of Pesticide Programs Information Network (OPPIN), Laboratory Information and Study Audit (LISA), and Integrated Compliance Information System (ICIS) databases are used to assist inspectors in making these decisions, as well as the type of inspection data that are entered into these databases. Regarding inspection data, we requested OECA to provide us with several data elements contained in its LISA database for the years 2000 to 2013, including name and location of laboratory inspected, reason for inspection, number and type of inspections conducted, and number and name of studies associated with the laboratory inspected. We determined that inspection data were sufficiently reliable to present results on the number of inspections from fiscal year 2009 to fiscal year 2013 as a range. Since data, such as laboratories names and addresses, as well as information on studies contained in OECA’s LISA database are transferred from OPP’s OPPIN, we also requested OPP provide information from OPPIN on the number of studies associated with performing GLP laboratories from fiscal year 2008 to fiscal year 2012. We analyzed this study data for accuracy and completeness. However, we determined that data for “performing laboratories,” identification numbers, and addresses were not sufficiently reliable to assess the number and location of laboratories that had submitted studies to EPA. As a result, we were not able to define the universe of laboratories subject to a GLP inspection. However, EPA did provide estimates of the number and percentage of eligible laboratories that were inspected each year, and we used that information in this report.

To determine the views on EPA’s GLP Compliance Monitoring Program, we interviewed individuals representing 25 entities, including laboratories, pesticide manufacturers, international organizations, environmental and health organizations, national and trade associations and foreign government GLP programs, which we selected based on referrals from various stakeholders and EPA officials. Specifically, we spoke with representatives of nine laboratories and conducted site visits to four of these laboratories located in Maryland and Illinois. We also conducted a Web-based survey of performing laboratories. For our survey, we drew a randomly selected sample of 80 performing laboratories included in the OPPIN database that sent study data to OPP from fiscal year 2010 to fiscal year 2012. Because OPPIN does not contain e-mail addresses, we searched for laboratories’ e-mail addresses and found them for 53 of the 80 laboratories that we sampled. We sent the Web-based survey to these 53 laboratories. We obtained responses from 26 laboratories and other entities. However, 6 of these 26 respondents stated that they were not a laboratory and did not conduct GLP testing. Therefore, we received usable survey responses from 20 laboratories. Not all respondents to our survey, however, answered every question. Our survey asked if the laboratory had conducted GLP testing for EPA or FDA, experienced a GLP inspection by EPA, what was the effect of having an inspection, and what improvements they thought could be made to EPA’s GLP Inspection Monitoring Program. The survey results are not generalizeable to all laboratories that are covered by the GLP program, but they were randomly selected, and the results can provide examples of such laboratories’ experiences and challenges with GLP inspections. We were not able to select a representative sample because some data in the OPPIN database was not sufficiently reliable.

To assess the extent to which OPP uses the information obtained through GLP laboratory inspections in its pesticide decision-making process, we analyzed relevant documents and databases to determine the number of OECA’s GLP inspections that produced results that were referred to OPP for reexamination, the time it took to conduct these reexaminations, and any impact the inspections had on OPP’s pesticide registration decisions.

To determine the extent to which EPA and FDA collaborate on inspections, we analyzed EPA and FDA GLP laboratory inspection data and determined that the inspection data were sufficiently reliable for our purposes. We also analyzed the 20 laboratory survey responses to determine if they had conducted GLP tests or studies for submission to both EPA and FDA since 2008. We reviewed agency documents, such as a 1984 agreement entered into by EPA and FDA to cooperate on GLP inspections and FDA’s Compliance Program Guidance Manual. We interviewed EPA and FDA officials, laboratory representatives and other stakeholders about the potential for the two agencies to collaborate.

We conducted this performance audit from November 2012 to May 2014 in accordance with generally accepted government auditing standards. Those standards require that we plan and perform the audit to obtain sufficient, appropriate evidence to provide a reasonable basis for our findings and conclusions based on our audit objectives. We believe that the evidence obtained provides a reasonable basis for our findings and conclusions based on our audit objectives.

Appendix II: Web-Based Survey to Laboratories

Appendix III: Laboratories Inspected for GLP Compliance by EPA and FDA, FY 2005-2012

Our analysis of Environmental Protection Agency (EPA) and U.S. Food and Drug Administration (FDA) Good Laboratory Practices (GLP) inspections data identified the following instances where laboratories were inspected by both agencies (see figure 3). We do not know the reason for every inspection. In some instances, EPA and FDA may have needed to conduct their own inspection.

Appendix IV: Comments from the Environmental Protection Agency

Appendix V: Comments from the Department of Health and Human Services

Appendix VI: GAO Contact and Staff Acknowledgments

GAO Contact

Staff Acknowledgments

In addition to the individual named above, Anne K. Johnson, Assistant Director; Cheryl Arvidson; Mark Braza; Greg Carroll; Cynthia Grant; Angela Miles; and Patricia Moye made key contributions to this report. Richard Johnson, Stuart Kaufmann, Anna Maria Ortiz, and Dan Royer also made important contributions.