Capturing and Reporting Electronic Data - American Chemical Society

Chapter 25

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Electronic Data Submission in the Environmental Protection Agency Office of Pesticide Programs: Supplemental Files Susan V. Hummel Office of Pesticide Programs, U.S. Environmental Protection Agency, Mail Stop 7509C, 1200 Pennsylvania Avenue, N. W., Washington, DC 20460

The EPA Office of Pesticide Programs (OPP) recognizes that there are significant potential benefits to be gained by the implementation of electronic submission of studies to support pesticide registration or re-registration. Supplementalfilesof additional study datacanbe submitted electronically to the EPA to facilitate study reviews and data analysis. This paper reports on OPP experiences with electronic submissions of supplemen-talfilesincluded as part of a full electronic submission package for a chemical, or provided separately in response to a specific need. Efforts are being made to define the nature and content of supplementalfiles,to define the attributes offilestructure and content, and to develop guidance for their use. Issues and concerns regarding the use of supplementalfilesare identified and addressed and future developments outlined.

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U.S. government work. Published 2002 American Chemical Society

Garner et al.; Capturing and Reporting Electronic Data ACS Symposium Series; American Chemical Society: Washington, DC, 2002.

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Background In the United States, pesticide products are registered for use under the provisions of the Federal Insecticide Fungicide and Rodenticide Act (FIFRA), 7 U.S.C. 136 et seq. If the pesticide is used on foods, tolerances, or legal limits for the pesticide chemical residue in or on a food, may be required to be established under the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 301 et seq. The Food Quality Protection Act of 1996 (FQPA) (Pub. L. 104-170) was signed into law August 3, 1996, and amended both the FIFRA and the FFDCA. The Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP) is charged with administering these laws. Under the provisions ofFIFRA and FFDCA, the pesticide manufacturers (i.e., registrants), are required to submit a full and comprehensive battery of product chemistry, toxicity, residue chemistry, occupational and residential exposure, and environmental fete and effects data. All the submitted data are reviewed by Agency scientists for conformity with standard practices within the discipline and conformity with Agency Testing Guidelines. The data requirements for registration of a pesticide have been published in the Code ofFederal Regulations, Title 40, Part 158 (40 CFR §158). The Agency Testing Guidelines have been published on the World Wide Web at http://www.epa.gov/OPPTS Harmonized/. A summary listing is given below in Table I: Table I. OPPTS Harmonized Test Guidelines Series 810

Description Product Performance

830 835 840 850 860 870 875 880 885

Product Properties (Product Chemistry) Fate, Transport and Transformation Spray Drift Ecological Effects Residue Chemistry Health Effects (Toxicity) Occupational and Residential Exposure Biochemicals Microbial Pesticide



200 The data required for pesticide registration and tolerance setting are submitted by the pesticide registrant (often the pesticide manufacturer) and the submitted data are reviewed by Agency scientists. The reviewers prepare a summary of the information and data contained in the submission, verify the data submitter's calculations, and perform statistical analyses of the data. They identify information missing in the study report and determine study conclusions. They then assess the appropriateness and adequacy of the submitted data, determine if additional information is needed from other Agency scientists, and conclude whether the submitted data support the requested action (i.e., registration, tolerance). The technology available for both conducting the scientific studies and preparing the study report at the laboratory level, and for analyzing the data and preparing the scientific reviews at EPA has changed over the years, as shown in Table II. Initially in OPP, science reviews were written by hand, and then typed by a secretary. Calculations using the data were performed using a desk calculate or by hand. Today, almost all EPA science reviewers prepare their own reviews using a word processor, and many use other software tools for analyzing the data, such as spreadsheets, database programs, and statistical software packages. Additionally some types of data such as tumor incidence data undergo rigorous specialized statistical analyses by Agency experts. Table EL Technology in Use at EPA Technology Available

Typewriter

Time Frame

Review Preparation

pre-1975

Handwritten by reviewer, typed by secretary

Typewriter with memory

1975


Dedicated word processor

1979


1981

Some reviewers typed

1984

Some reviewers typed

1993

Almost all reviewers typed

Computer


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Definition of Supplemental Files A workshop to discuss electronic data submission in support of pesticide registration was conducted by the American Crop Protection Association (ACPA) and EPA in March 2000. The participants were divided into four groups - two groups discussed the overall data submissions, the remaining two groups discussed supplemental files. In the groups discussing supplementalfiles,representatives from EPA andfromthe pesticide industry defined the term, "Supplemental Files." The storting assumption was that the report for the electronic data submission would be made using PDF files. PDF is an acronym for "Portable Document Format." PDF is afileformat created by Adobe that is platform independent and enables a user to view and print a file exactly as the author designed it without needing the application or fonts used to create the file. Each study submitted to the Agency in support of pesticide registration generally consists of a textual summary report with tables of summary data, illustrativefiguresif appropriate and a number of appendices. The appendices may include a copy ofthe protocol, analyses of the test substance, detailed data on individual animals or test sites, analytical methods, and analytical data such as chromatograms. The assumption was that the summary portion of the report (including text and summary tables) would be saved as a PDF file, directlyfromthe word processor used to create the report, and not scannedfroma paper copy, with a PDF file createdfromthe image. However, due to the variety of systems that may be used to create tables and appendices of data in the laboratory, it was recognized that some of these might require that PDFfilesbe createdfromthe scanned paper copy. The overall format of the study report is being discussed in a separate chapter entitled Electronic Data Submission: Pilot Efforts in the Office of Pesticide Programs, U.S. EPA, along with results of EPA review of thefirstpilot electronic data submission. At the workshop, the two groups came up with two slightly different definitions. Neither group liked the term "supplementalfiles,"and one came up with an alternate term, "Review Aids." At this point, the Agency continues to use the term, "Supplemental Files." We have combined the definitionsfromthe two groups. "Supplemental Files (Review Aids) are: Any data set needed by the reviewer for additional analysis purposes that cannot be readily extracted from the PDF report, or, additional information in electronic format that would enhance thereviewer'sunderstanding or facilitate presentation ofthe data."



202 Therefore, supplemental files are not equivalent to appendices of individual data, although they may sometimes contain the same informa tion. Additionally, supplementalfileswould not include new data which were not included elsewhere in the study report. They would not include summaries ofdatafromacross multiple studies. Supplementalfilesare not required by the Agency in order to complete a study review because the information or data must be in the paper or PDF copy of the report. Supplementalfilesare not needed for every type of study, nor for every type of data included in a particular study. The types offilesthe groups at the March 2000 workshop agreed would be useful for reviewing studies depended on the type of data being submitted. Some examples of these types offilesare listed in Table III. Table ΠΙ. Examples of Supplemental Files •

•

• • • •

• • • •

Data tablesfrommammalian toxicity studies • body weights • ante or post mortem observations ο clinical chemistry • tumor incidence Data tablesfromresidue chemistry and environmental fate studies • analytical method validation • residues reported by sample • cropfieldtrials • dislodgeable foliar residues ο residue dissipation • water monitoring Chemical structures in ISIS compatible format Metabolic pathways (metabolism studies) in ISIS compatible format Photographs (e.g., slides, crop production or processing, crop injury) Video (e.g., crop production, or food processing procedures) Full text (including graphics) of analytical methods or study reports Models (Spray Drift, Efficacy, ARTF) Dietary exposure inputfiles(including residue distributions) PRZM input files


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Issues and Concerns The Agency science reviewers feel that the advantages of having supplementalfilesare many, that they would primarily increase efficiency and quality of science reviews. The reviewers would have less data entry to do to check the reported results and to perform statistical calculations cm the data. They could more easily add text and tables and graphics to their reviews. Chemical structures and metabolic pathways would not need to be redrawn to be inserted into reviews or Agency databases. The reviewers could have on-line access to the actual study data at internal EPA meetings. Not needing to retype data would result in increased accuracy in data analyses and in reviews, more efficient use of review time, and more comprehensive use of the study data. OPP heard some concerns at the Electronic Data Submission Workshop in March 2000, which is discussal in more detail below.

Formatting The data submitters do not want EPA to implement strict mandatory formatting of supplemental files, and mandatory software requirements. Also, there was concern that OPP may change guidance on supplemental files and require early submitters of supplementalfilesto resubmit their files in a different format. Strict formatting may force the data submitters to purchase specific brands of software to produce thefilesdesired by EPA. However, OPP is committed to open standards forfilesubmission formats, and has no plans to make the submission of supplementalfilesa mandatory requirement. OPP plans on beingflexibleon the formatting of supplemental files.

Over-Analysis Concern was expressed that, presented with the data electronically, the reviewers may more easily over-analyze the study data. While access to the data electronically will make data analysis easier, the timeframesfor review of pesticide data are relatively short, not leaving time for overanalysis of the data.


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Archiving Some data submitters were concerned about whether the supplemental files would be archived along with the data, and whether the supplemental files would be subject to Freedom oflnformation Act (FOIA) requests. OPP expects to maintain the compact disc (CD) provided as the electronic data submission, and archive the supplementalfileson CD along with the rest of the electronic data submission. However, the official archive format at the present time is paper, and the supplementalfilesduplicate material in the paper submission. It is expected that supplementalfilescan be released upon FOIA requests after the first registration for the pesticide active ingredient, subject to the requirements of FIFRA 10(g), which include an affirmation statement from requestor, and notice to the data owner, excluding any FIFRA CBI.

Certification of Authenticity Concern was expressed about certification of authenticity, or whether the data submitter would guarantee that the data in the supplemental files was identical to the data in the paper submission. If the supplemental files are created at the same time as the PDFfilesofthe ofthe study report, there shouldn't be any difficulty in guaranteeing that the data in the supplemental files match the data in the study report. OPP will require that the data submitter sign a Certification with Respect to Data Integrity.

Security

There was also concern about the security of the electronic data submission, including supplementalfiles,particularly improper access to Confidential Business Information (CBI). The electronic data submission has the same security requirements as a paper submission. The difference is the smaller physical size, resulting in increased portability and ease of copying. OPP science reviewers must be cleared to handle CBI, and the requirements for handling CBI properly are no different for an electronic submission than for a paper submission. At this time, OPP plans to make the electronic data submission available to science reviewers on the Local


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Area Network (LAN), but at the present time cannot place CBI on its LAN. OPP expects approval of a security plan that will permit FIFRA CBI on the LAN. An alternative in the meantime would be to provide reviewers with copies of the data on a CD if there was a CBI claim.


Current Activities OPP has been involved with informal electronic data submissions for several years, predating the recent pilot electronic data submissions. Activities have rangedfrominformal requests for electronic datafromthe science reviewer to the formal pilot efforts now ongoing. At the present time, OPP scientists are evaluating PDF submissions and supplemental files. For a pilot electronic data submission, OPP has discussed the content of supplementalfileswith the registrant interested in providing an electronic data submission, and has worked on the data fields of interest for several toxicology studies. OPP is evaluating SAS-XPORT (SAS Transport) files as a neutral file format for data tables. Two programs being evaluated by OPP are DBMS Copy and Stat Transfer to transfer the datafromthe SAS-XPORT format into a format usable by the reviewer. OPP scientists are identifying the data elements (orfields)of interest for each study type where the reviewers felt that supplementalfileswould be useful, identifying other information for each study type which would be useful to have as electronicfiles,and developing guidance for submission of supplemental files. This guidance is not ready to be published, but the scientists will work with the data submitters to ensure that the supplemental files for the particular study will be useful to the science reviewers. Even when guidance becomes available, OPP intends to beflexibleabout the format of the supplementalfiles,and will modify the guidance as needed. Sofer,the majority of the experience ofthe OPP science reviewers has been with informal requests for electronic data submissions. These informal submissions laid the groundwork for the more formal pilots. For the informal submissions, the reports generally have been submitted in word processing formats and the data tables in Excel or word processor format. The science reviewers have been enthusiastic, and have felt that reviews were completed much more quickly.


206 Examples of Experiences with Pilot and Informal Submissions


Residue Chemistry

One electronic data submission has been received for the pilot. The submission included studies for plant metabolism, crop field trials, analytical method, and storage stability. The reports were submitted in PDF, with the appendices to the report submitted as paper copies only. The science reviewer used only the PDF copy ofthe summary report, which was well formatted with bookmarks, and well documented. A paper copy ofthe appendices was used in the review. Some text was copied directlyfromthe PDF summary report and attributed to the company. Some data tables were copied from the PDF summary report and reformatted slightly. The reviewer had some difficulty getting one table copied into Excel, and felt that the data tables would have been more useful as supplemental files. This review resulted in a significant time savings, but supplemental files would have saved the reviewer even more time. A second informal submission is undergoing review in OPP. This is a Task Force submission of monitoring data. The summary report is in Word with appendices on paper only. The data tables are in Excel. The reviewers like the ease of viewing and manipulating the data in the spreadsheet, and expect significant time savings in the review process, although the time savings may be difficult to quantify. A number of other electronic data submissions have been made informally. These generally consisted of a summary report and data tables in a word processing format. The reviewers felt the time savings was substantial, but noted a difficulty transferring data tables from Word to Word Perfect.

Occupational-Residential

The science reviewers have worked informally with Task Forces on the format for electronic data submissions of large data sets. A data set is under review now. The electronic format facilitated rapid summary of the data in the submissions.

Toxicology

The science reviewers have been working with a pesticide



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registrant to identify the datafieldsneeded for several toxicology studies - a chronic feeding/oncogenicity study in rodents, a chronic dog study, a developmental neurotoxicity study, and a multi-generation reproduction study. The studies have not been submitted yet to the Agency for review. Supplementalfilesusing SAS Transport will be included. In several instances, informal requests to data submitters resulted in submission of supplemental files of tumor date from carcinogenicity studies. This enabled the statistical analyses of these data and resulted in substantial savings in data entry and analysis time. Other informal experiences included individual science reviewers requesting electronic copies of the submission and data tables. Generally the report and data tables were provided in word processingformat.These resulted in significant time savings during the review process. One electronic data submission was made in the CADDY format with no supplemental files. The science reviewers found no time savings with this format.

Environmental Fate and Effects

The experience of the science reviewers has been with informal requests for electronic data submission made directly to the pesticide registrants and disks containing raw data being received along with the paper submissions. Pesticide registrants have been including with their paper submission a diskette with raw datafromavian reproduction and terrestrial plant studies for about 5 years. Data for terrestrial field dissipation and water monitoring are often received in spreadsheets. The result was significant time savings and accuracy in analyses of the data.

Future Developments OPP will continue with pilot electronic data submissions with supplementalfiles.We will continue to refine the data elements needed for each type of study. We need pilot electronic data submissions with supplementalfilesto help with this refinement. OPP is willing to receive supplementalfilesof other types as well, especially chemical structures and metabolic pathways in ISIS compatible format, and photographs and video files. Watch the EPA Web Site for guidance on submission of supplemental files with Electronic Data Submission, or contact the author for more


208 information. The following web sites may be helpfiil to the reader for additional information: • *

http://www.epa. gov/pesticides http://www.epa.gov/oppfeadl/edsgoals.htm


Conclusions In summary, supplementalfilesreceived to date have been very useful in the analysis of data, resulting in saving review time. Supplemental files have been most useful for large data sets. EPA has been flexible in the acceptance of supplemental files. Supplementalfileshave been received in a number offileformats, and all have been useful. Receipt of the study reports electronically is useful as well, saving time in the summarizing of the study. Most of OPP's experience to date has been with supplemental files of data tables, model input parameters, and full text of study reports.


Capturing and Reporting Electronic Data - American Chemical Society

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