Specifications for Electronic Data from Toxicology Studies for Translation to SEND

Transcription

1 Specifications for Electronic Data from Toxicology Studies for Translation to SEND SEND Express - Timely and accurate preparation of FDA-Submission ready, validated SEND datasets February 2016 PDS AMERICAS 100 Valley Road, Suite 204 Mt. Arlington, NJ USA PHONE PDS ASIA Aoihigashi Naka-ku, Hamamatsu Japan PHONE PDS EUROPE Duerrenhuebelstrasse 9 CH-4133 Pratteln, Basel Switzerland PHONE PDS Life Sciences

2 Specifications for Electronic Data from Toxicology Studies for Translation to SEND Table of Contents 1. Purpose of this Document Some General Specifications for all Electronic Source Data Intended for SEND Translation TranSEND Functionalities SEND Conversion for Data Warehouses PDF Files Required Documents for SEND Translation by SEND Express Domain by Domain Specifications for Electronic Data for SEND Conversion Contact information for SEND Express, SEND, and our Software Solutions

3 1. Purpose of this Document Based on our experience producing submission-ready SEND datasets approved for review by FDA, the SEND as a service (SEND Express ) division of PDS Life Sciences developed a set of specifications and requirements for electronic source data that will facilitate automated electronic translation into SEND. These specifications are necessary because not all Contract Research Organizations (CRO)s are familiar with data requirements for SEND compliance. Moreover, there are different types of raw data extracts available from any given Laboratory Information Management System (LIMS), and the client or CRO will need to knowledgeably select what is appropriate for SEND translation and adaptor development. This document includes general specifications applicable to all electronic data across all SEND domains 1 as well as specific requirements for individual SEND domains. Adherence to these specifications will result in the automated production of submission-ready SEND Datasets. These specifications do not pertain to SEND-formatted XPT, XML, XLS, TXT, or CSV files. PDS TranSEND engine is able to process and integrate all of these file formats to produce submission-ready, validated SEND datasets, complete with define files (PDF and XPT) and Study Data Reviewer s Guide with no additional development. 2. Some General Specifications for all Electronic Source Data Intended for SEND Translation The rules and observations following pertain to all electronic source data. Conversion to SEND can be considered a giant computer mapping exercise: data from one format are mapped or translated by computer to a different format. To accomplish this without manual manipulation, electronic data must be formatted consistently across individual animals for a given domain. For example, microscopic pathology findings involve a number of different components for each animal: organ; primary finding; modifiers including severity, chronicity, distribution; histologic stain and, occasionally, comments. All of these components need to be in a consistent order across animals for successful adaptor development. One cause of data format inconsistencies across animals is inconsistent data entry into LIMS. Proper LIMS use is essential for accurate SEND mapping. 1 A SEND domain is a SAS transport flat file (XPT) that contains a set of related data and associated metadata. For example, body weight (BW) and microscopic results (MI) are two SEND domains. 3

4 The purpose of SEND is to translate data in the final toxicology report to a standard electronic format. However, some data extracts may include data that are not part of the final report, such as: o Quarantine body weights o Quarantine clinical signs o Body weights of toxicokinetic animals Generally, clients prefer data not in the final toxicology report not be included in SEND. Accordingly, it is important that electronic data output selected for SEND conversion only include data in the final report. We have also seen electronic data extracts that do not include all data that are in the report. This may occur for calculated values, because not all LIMS store calculated values as raw data, making them unavailable for export. Some examples of calculated values that may be in the report but not in the electronic dataset include: o A/G ratio o Feed efficiency o MCH, MCHC, MCV o Body weight gain o Relative organ weights SEND requires the inclusion of metadata that are not part of final reports, such as time and date stamps. Accordingly, electronic files that contain report tables do not contain all of the data needed for SEND-compliant submissions. If data for a particular animal or animals were not collected or if the animal was not examined as specified in the protocol, a reason needs to be provided and included in the SEND datasets for SEND compliance. 3. TranSEND Functionalities It is important to have a general understanding of TranSEND functionalities to appreciate what TranSEND is programmed to do automatically. The automatic functionalities of TranSEND are designed to simplify the requirements and specifications for electronic data. Controlled Terminology mapping: TranSEND has a robust controlled terminology functionality, and it is a straightforward matter for TranSEND to update controlled terminology mapping of SEND datasets to the latest CDISC SEND version. This is important because CDISC releases four controlled terminology updates each year. It is therefore not necessary for clients to do any controlled terminology mapping in their own LIMS. TranSEND and PDS will do this using the latest CDISC controlled terminology release (or any other controlled terminology release specified by the client), and PDS will submit the mapping file to the client for review. 4

5 Define file: There is no need for a sponsor to provide a define file. TranSEND is programmed to automatically generate a validated define file (XML and PDF formats) each time a SEND dataset is created. USUBJID (SEND variable name for Unique Subject Identifier): This variable is defined in SENDIG 3.0 as Identifier used to uniquely identify a subject across all studies for all applications or submissions involving the product. TranSEND follows the example established in SENDIG 3.0 for establishing a USUBJID for each subject: a combination of STUDYID (Study Identifier) and SUBJID (Animal Number). For a study with a number of and an animal number of 1001, TranSEND will automatically create a USUBJID of Therefore, there is no need for clients to create USUBJIDs. Validation against SEND 3.0: The Pinnacle 21 SEND validator is integrated into TranSEND. TranSEND is programmed to automatically validate every SEND dataset using the Pinnacle 21 validator and produce a validation report that identifies any issues. The Pinnacle 21 validator includes all of the SEND validation rules developed and used by FDA. The Pinnacle 21 validator report is one of the SEND Express deliverables. Validation of submission-ready SEND datasets (including define) does not need to be done by the client. 4. SEND Conversion for Data Warehouses Many clients are beginning to create data warehouses that include SEND datasets. Data warehouses and associated analytical tools enable sponsors to rapidly respond to FDA questions concerning their submissions. They also allow data to be analyzed and queried efficiently in ways that are not currently feasible: across species, programs, and clinical and nonclinical programs. Conversion of legacy data to SEND for data warehousing does not need to comply with all of the SEND rules for FDA submission. The SEND Express business unit of PDS Life Sciences has experience creating SEND datasets for data warehousing and can guide clients towards a cost effective and practical way to meet data warehousing needs. For example, although information in reports may not be sufficient for an FDA SEND submission, they can meet data warehousing needs. See also the following section on PDF files. 5. PDF Files As stated in the previous section, data in final reports will likely meet data warehousing needs even though certain information necessary for FDA SEND submissions may not be present. SEND Express can convert data in PDF report files using two general methods. Our preference is to work with machine readable PDF whenever possible. 5

6 Table 1 Methods for Converting PDF Data Machine-Readable PDF We can convert machine-readable PDF files to Excel and develop adaptors for TranSEND to automatically read and process the file(s) into an integrated SEND dataset. These datasets will be subject to the same rigorous QC (Quality Control) procedures used for FDA SEND submissions. Non Machine Readable PDF If machine-readable PDF files are not available, SEND Express can manually create input files in Excel that TranSEND can process and integrate. SEND Express will perform extensive QC checks on the data. 6. Required Documents for SEND Translation by SEND Express In addition to requirements for electronic source data, it is also necessary that we have copies of the documents listed below. We have found information necessary for SEND in report narratives that was not been included in tables, such as the type of histologic stain used. Moreover, the report is necessary for preparation of a Study Data Reviewer s Guide, which needs to include a discussion of any differences between the report and SEND datasets. Study Documentation Needed for Preparation of SEND Datasets and Study Data Reviewer s Guide by SEND Express Protocol and amendments Final (or mature draft) study report Any FDA correspondence that documents agreements regarding SEND 7. Domain by Domain Specifications for Electronic Data for SEND Conversion In this section, specifications for electronic data for SEND conversion will be presented as specifications that apply to all SEND Findings domains (Section 7.1), followed by additional domain-specific specifications for Findings domains (Section 7.2). Finally, specifications for electronic data for Special Purpose, Interventions, Events, and Trial Design SEND Domains are presented in Section 7.3. It is important to bear in mind that these sections represent minimal requirements for electronic data intended for SEND translation. For a complete inventory of information that can be included in SEND, please refer to the SEND Implementation Guide (SENDIG) 3.0, which can be found at: If a client provides data electronically to PDS as described in Sections , the PDS SEND Express group can create a complete and compliant SEND Dataset with minimal development. 6

7 7.1 Specifications for All SEND Findings Domains Information that must be Included in Electronic Data for SEND-compliant Findings Domains Study Number Individual animal numbers Name of measurement (Examples: body weight, microscopic observations) Result or findings as collected Unit of original result (if applicable) Planned study day of collection Date and time of actual observation (or specimen collection for macroscopic and microscopic domains or tissue weighing for the organ measurements domain) Reason for any missing data Comments This pertains to Body Weight (BW), Body Weight Gain (BG), Clinical Observations (CL), Food and Water Consumption (FW), Laboratory Test Results (LB), Macroscopic Findings (MA), Microscopic Findings (MI), Organ Measurements (OM), Palpable Masses (PM), Pharmacokinetic Concentrations (PC), Pharmacokinetic Parameters (PP), Subject Characteristics (SC), Tumor Findings (TF), Vital Signs (VS). 7.2 Additional Specifications for Specific SEND Findings Domains SEND Domain Abbreviation Body Weight BW Body Weight Gain BG Death Diagnosis - DD ECG Test Results - EG Food and Water Consumption FW Information that must be Included in Electronic Data for Specific SEND-compliant Findings Domains 2 Test name (examples: body weight, final body weight) Baseline flag: this is the value used to calculate differences or changes from baseline or predosing values End date/time animal was weighed (end of weight interval) Animal Number for each animal that died, whether due to moribund sacrifice, found dead, accidental death, including mortalities that were not treatment related Date (and time, if available) for each animal that died Result of the diagnosis of the cause of death, as originally collected Test name (examples: Qtc, heart rate) Position of subject during examination ECG lead(s) used ECG method (example: 12 lead standard) Consciousness state Baseline flag: this is the value used to calculate differences or changes from baseline or predosing values End date/time for the end of the observation period 2 The requirements in Section 7.2, which are for specific SEND Findings domains, are in addition to requirements for all SEND findings domains listed in Section

8 SEND Domain Abbreviation Laboratory Test Results LB Information that must be Included in Electronic Data for Specific SEND-compliant Findings Domains 2 Category for laboratory test (examples: clinical chemistry, hematology, urinalysis) Specimen type (examples: blood, serum, urine, liver) Method (examples): electrophoresis, dipstick Baseline flag: this is the value used to calculate differences or changes from baseline or predosing values Macroscopic Observations MA Specimen type (examples: kidney, liver) Anatomical region of specimen (examples: cortex, medulla, serosa) Study day of specimen collection Microscopic Observations MI Specimen type (examples: kidney, liver) Anatomical region of specimen (examples: cortex, medulla, serosa) if applicable Specimen condition (example: autolyzed) if applicable Severity Relationship to death, if applicable Any neoplastic lesions must be identified as neoplastic Study day of specimen collection Organ Measurements OM Organ measurement test (examples: weight, organ to body weight ratio, organ to brain weight ratio) Specimen (examples: kidney, liver) Study day of organ weighing Palpable Masses PM Mass identifier (examples: mass 1, mass 2) Test name (examples: length, width, ulceration) Location of mass (examples: left hind limb, abdomen) Study day of observation Pharmacokinetics Concentrations PC Pharmacokinetics Parameters PP Tumor Findings - TF Vital Signs - VS Test name (examples: metabolite, parent drug) Lower limit of quantitation Time point reference (examples: day 1 dose) and date and time of reference point Test name (examples: half-life, Cmax) Category or analyte (examples: metabolite, parent drug) Specimen material type or matrix (examples: serum, plasma, urine) Date and time for time point reference (same as for PC domain, above) Mass number Tumor malignancy status Specimen type (examples: pancreas, bone) Relationship to death Time in days to detection of tumor Test Name (examples: diastolic blood pressure, temperature) Baseline flag: this is the value used to calculate differences or changes from baseline or predosing values Consciousness state 8

9 7.3 Specifications for Special Purpose, Interventions, Events, and Trial Design SEND Domains SEND Domain - Abbreviation Demographics DD Disposition DS Exposure EX Information that must be included in Electronic Data for Special Purpose, Interventions, Events, Trial Design, and Relationships SEND Domains Study Number Individual animal numbers Start and end date and time for each animal: start refers to the first day of dosing for each animal and end refers to when the animal left the study (this may be sacrifice) Age for each animal can be a range. Be sure to include the unit (days, weeks, etc) Gender of each animal Study Number Individual animal numbers Disposition (fate) of each animal (examples: sacrificed, returned to colony, found dead, moribund sacrifice) Planned study day of the disposition event for scheduled events Date and time of the disposition event There are 2 SEND-compliant ways to populate EX: One entry for each time each animal was dosed o Study Number o Individual animal numbers o Name of treatment o Amount of treatment & units o Dose form (examples: tablet, solution, suspension) o Dose frequency (examples: once daily, once weekly) o Route o Lot number(s) of text article o Vehicle description (example: saline) o Start date / time of treatment One entry for each animal o Study Number o Individual animal numbers o Name of treatment o Amount of treatment & units o Dose form (examples: tablet, solution, suspension) o Dose frequency (examples: once daily, once weekly) Comments The first method (one entry for each time each animal was dosed) is appropriate for interrupted or irregular dosing. It is also appropriate if electronic data exports are readily available that supply all of the needed data. If there were 60 animals in a study, and each animal was dosed once daily for 28 days, there would be a total of 1,680 records in the SEND dataset. The second method (one entry for each animal) is appropriate for uninterrupted dosing, such as daily (or weekly) dosing. Example: if animals were dosed once daily for 28 days, the start date (without time), the study day for the start of treatment (day 1), and the study day for the end of treatment (Day 28) for each animal would be 9

10 SEND Domain - Abbreviation Subject Elements - SE Trial Sets TX Trial Summary Information that must be included in Electronic Data for Special Purpose, Interventions, Events, Trial Design, and Relationships SEND Domains o o o o o Route Lot number(s) of text article Vehicle description (example: saline) Start date of treatment (time not needed) Starting and ending study day of dosing for each animal Study number Individual animal numbers The start and end dates and times for each animal for each study phase that it experienced. Example of study phases: prestudy, dosing, recovery. The type of control needs to be identified (examples: vehicle control, positive control) Experimental end date: the last date on which data were collected, excluding microscopic evaluation. Experimental start date: the date on which the first study specific data were collected. Test animal supplier Name of study director Animal strain Test facility name and address CAD registry number, if available Identification of vehicle (examples: saline, water) Comments sufficient. If there were 60 animals on study, there would be 60 records in the SEND dataset. This domain needs to include dosing information for all animals, including satellite Toxicokinetic animals. 8. Contact information for SEND Express, SEND, and our Software Solutions Ken DePinto: ; kendepinto@pdslifesciences.com (Mt Arlington, NJ) Reto Aerni: ; reto.aerni@pdslifesciences.com (Basel, Switzerland) Takayuki Anzai, PhD, MBA: ; anzai.takayuki@pdslifesciences.com (Hamamatsu, Japan) 10