pds send primer for cros sept 2015 -...

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Are You SEND Ready?

A SEND Primer of Frequently Asked Questions and Definitions for CROs

September 2015

©PDS Life Sciences 2

Are You SEND Ready? A SEND Primer of Frequently Asked Questions and Definitions

for CROs

Table of Contents

1 Introduction – What Is SEND? .............................................................................................................. 3 2 Why Is SEND Important? ...................................................................................................................... 3 3 Is SEND Primarily an IT Responsibility? ............................................................................................... 3 4 When Will SEND and SDTM Be Required? ......................................................................................... 3 5 What Types of Studies Are Within Scope for SEND 3.0? ..................................................................... 4 6 What Are the Critical Features of a SEND-Compliant Dataset? ........................................................... 4 7 Study Data Reviewer’s Guide ............................................................................................................... 9 8 Study Data Standardization Plan .......................................................................................................... 9 9 What Is the Best Way to Prepare for SEND? ....................................................................................... 9 10 How Are SEND Datasets Submitted to the FDA? .............................................................................. 11 11 The Next SEND Release: Version 3.1 ............................................................................................... 11 12 Coming After SENDIG 3.1 ................................................................................................................. 11 13 Links ................................................................................................................................................... 11 14 SEND Support Offered by PDS ......................................................................................................... 12 15 About PDS Life Sciences ................................................................................................................... 12


1 Introduction – What Is SEND? SEND or the Standard for Exchange of Nonclinical Data is the nonclinical implementation of SDTM (Standard Data Tabulation Model), the electronic data standard adopted by the FDA for clinical regulatory submissions. Both SEND, SDTM, and associated electronic standards1 are developed by CDISC (Clinical Data Interchange Standards Consortium), an international standards development organization with representatives from pharma, biotech, CROs, consultants, vendors, and the FDA. SEND is the reformatting of nonclinical data into a standardized electronic format or flat file that consists of domains, variables, records, terms, metadata, and data.

Starting in December 2016, SEND and SDTM will become mandatory for nonclinical and clinical FDA submissions.2 While this may appear a long way off, in reality it is not. It can take companies 1.5 years to build a SEND team, validate systems, and tackle changes to internal processes, timelines, and budgets before they are able to submit trial SEND submissions to the FDA and evaluate the effectiveness of these processes. Moreover, the FDA recommends that each sponsor submit three trial SEND submissions in preparation for the mandate.

2 Why Is SEND Important? SEND and SDTM have major implications for drug development:

• Compliance to SEND and SDTM will be required, and noncompliance can result in a refusal to file from the FDA and submission delays.

• SEND and SDTM are being used by the FDA to analyze submissions. • SEND and SDTM result in faster FDA review and therefore faster time to market. • Along with analytical and visualization tools for SEND and SDTM, it will be possible to query data

rapidly across species, compounds, and clinical and preclinical disciplines in ways that are not currently feasible. These standards and tools will lead to new approaches for clinical and preclinical drug development.

3 Is SEND Primarily an IT Responsibility? Preparing for SEND is a process that involves the participation and coordination of multiple disciplines including Toxicology, Pathology, Bioanalytical, Pharmacokinetics, Regulatory, and Quality Assurance in addition to Information Technology. For example, mapping study terms to CDISC SEND controlled terminology is an important part of SEND and needs to be done by subject matter experts. SEND datasets must support data analysis in addition to data transport, and they need to be more than an aggregation of standardized XPT (SAS transport) data files. Metadata needs to be consistent across SEND domains. Correlations between records from different XPT files are required for appropriate data interpretation, and all data collected for a toxicology study needs to be included in a SEND submission, e.g., in-life, bioanalytical, pharmacokinetics, clinical pathology, postmortem, and planned and actual study design. The flexibility of the SEND model itself requires upfront and potentially iterative agreements between study contributors for trial domains and mapping decisions.

4 When Will SEND and SDTM Be Required? The final FDA guidance on standardized electronic formats, issued on December 17, 2014, will become binding (SEND and SDTM will be required) as follows:

• For applicable NDAs, ANDAs, and BLAs: studies starting after December 17, 2016 • For applicable INDs: studies starting after December 17, 2017

1 Other nonclinical standards include Controlled Terminology and Define.xml (data definition file). All data standards and versions accepted by FDA can be found in the FDA’s Data Standards Catalog at: http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm. 2 USDHHS, CDER, CBER: Providing Regulatory Submissions in Electronic Format – Standardized Study Data. December 2014.


5 What Types of Studies Are Within Scope for SEND 3.0? The current version of SEND (3.0) covers single- and repeat-dose toxicology studies, both non-GLP and GLP, and carcinogenicity studies.

6 What Are the Critical Features of a SEND-Compliant Dataset? A SEND-compliant dataset consists of multiple integrated XPT (SAS transport files) and a Define file. Each XPT file represents a SEND domain, which is a group of related observations. The exception is the Define.xml file or data definition file, which functions as an index to the SEND dataset and identifies which domains, variables, and controlled terminology were used. A diagram of the SEND model is shown in Figure 1, where it can be seen that the different domains are grouped into categories and subcategories.

6.1 SEND Domains to be Included in All SEND Datasets Regardless of whether a SEND dataset is for a single-dose, repeat-dose, or carcinogenicity study, there are certain domains that need to be included for compliance so the dataset can be used for meaningful data analysis. These domains are presented in Table 1.

Table 1 SEND Domains to be Included in all SEND Datasets

File Name (Domain)

Abbreviation Description

Demographics

DM Includes gender, age, group assignment, start date for treatment, date animal left study.

Disposition

DS Describes disposition for each animal on study including planned study day of disposition and date/time of actual disposition.

Exposure

EX Describes dosing details for each animal on study, including treatment or control, route, dose, dose volume, dosing frequency, lot number(s), dose form, date/time for start of each treatment.

Subject Elements

SE Includes the study elements each animal actually experienced. Study elements are basic building blocks in the study design, e.g., pretreatment, treatment dose or control, recovery.

Trial Elements TE Identifies the planned “building blocks” of a study, such as pretreatment, treatment, recovery.

Trial Arms TA Describes the sequence of planned elements for each control and treatment group.

Trial Sets

TX Any division of a trial arm. For example, if a high-dose trial arm includes some animals designated for toxicokinetics (TK) and others for toxicology, the TK animals will comprise one high-dose trial set, and the toxicology animals will comprise another high-dose trial set.

Trial Summary

TS An overall summary of study metadata, including type of study design, control and treatments, test facility, study director, and regulatory status.

Data Definition File

DEFINE.XML DEFINE.PDF

An index of the entire dataset. It includes a list of all domains, variables populated for each domain, and controlled terminology used in the dataset.


SEND 3.0 Model

Special Purpose Domains

General Observations Domains

Trial Domains

Relationships Domains

Inter-ventio

ns

Findings Events Demo-graphics

Trial Arms

Trial Elements

Pool Definition

Supple-mental

Qualifiers

Relation-ships

Comments

Subject Elements

Exposure

Trial Summary

Trial Sets

Disposition Body Weight

Clinical Obs

PK Concentra-

tions

Organ Measure-

ments

Macro Findings

Food / H20 Consump-

tion

Subject Character-

istics

BW Gain

Palpable Masses

Micro Findings

Lab Test Results

Death Diagnosis

PK Parameters

Tumor Findings

ECG Test Results Vital Signs

Figure 1: SEND 3.0 model. Red boxes represent categories or sub-categories. Blue boxes represent XPT files (domains).


6.2 Data-driven Requirements for Additional SEND Domains In addition to the required SEND domains that are necessary for all SEND datasets (Section 6.1),, additional domains need to be included that will describe the data collected for the study at hand. If correlations were made between macroscopic and microscopic findings, the RELREC domain is used to describe these relationships. If animals were group housed or if blood samples were pooled for analysis, a POOLDEF domain will be necessary to describe the groupings. The Supplemental Qualifier domain is used for any nonstandard variables. Supplemental Modifiers are used to describe certain macroscopic and microscopic modifiers, which have not yet been included in SENDIG 3.0. All comments, regardless of the “parent” domain to which they pertain, are gathered into one Comment domain.

All animal data collected for a toxicology study need to be represented in SEND. If there is any doubt whether specific data are covered by the SEND model, sponsors should contact their FDA reviewing division. If results were not collected for a particular SEND findings domain, that domain should not be included in the dataset (no “null domains).

Data-driven SEND domains are shown in Table 2.

Table 2 Additional Data-Driven SEND Domains File Name (Domain)

Abbreviation Description (if needed)

Comments CO Required if comments were recorded. All comments go in the comments domain, regardless of the domain to which they refer.

Pool Definition POOLDEF Required if blood samples are pooled for clinical pathology, pharmacokinetics, or other biological parameters, e.g., biomarkers, or for certain clinical signs from group-housed animals.

Related Records RELREC Required to relate data across domains, e.g., for macroscopic and microscopic data, clinical observations, and palpable masses

Supplemental Qualifiers

SUPP-- This domain is used to capture nonstandard variables and their association to parent records. For SEND 3.0, it is often used to capture macroscopic and microscopic qualifiers.

Findings

Body Weight BW Includes terminal body weights as well as body weights collected in-life.

Body Weight Gain

BG

Clinical Observations

CL Includes clinical signs in addition to ophthalmology, physical examinations, and dermal examinations.

Death Diagnosis DD Required if unscheduled mortalities occurred.

Laboratory Test Results

LB Includes clinical pathology test results.

Macroscopic Findings

MA

Microscopic Findings

MI

Organ Measurements

OM Includes absolute and relative organ weights.


File Name (Domain)

Abbreviation Description (if needed)

Palpable Masses PM

Pharmacokinetics Concentrations

PC Includes bioanalytical data for each animal at each time point.

Pharmacokinetics Parameters

PP

Subject Characteristics

SC Includes data not expected to change over the course of a study, such as physical markings, hair coat.

Vital Signs VS Includes blood pressure, heart rate, respiratory rate, body temperature.

ECG Test Results

EG

6.3 Domains Required for Carcinogenicity Studies Additional domains are required for carcinogenicity studies as shown in Table 3.

Table 3 Domains Required for Carcinogenicity Studies Domain Abbreviation Description

Microscopic Findings

MI Includes all microscopic findings for each animal and special stains if applicable. Tumor findings are also included in this domain.

Tumor Findings

TF Includes all tumor findings for reach animal. Records in this domain are a subset of those in the microscopic domain.

Tumor.xpt file Not applicable

This is the SEND equivalent of the FDA’s specifications for tumor data from rodent carcinogenicity studies (Study Data Specifications, July 12, 2012, FDA)3

6.4 What Does a SEND Domain Look Like? An example of a BW (body weight) domain is shown in Figure 2. SEND domains are flat SAS transport (XPT) files. The column headers are referred to as variables. Each row is a record, which is generally a single finding for an individual animal at a single time point. Note the variable “BWORRES” in Figure 2 following (red arrow), which is the body weight result as collected for an individual animal at a single time point without any controlled terminology mapping. The “ORRES” variable is included in each of the SEND findings domains, which means that all original findings, including those for pathology, are part of SEND in addition to their controlled terminology equivalents.

3 Study Data Specifications, v. 2.0, July 18, 2002: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM312964.pdf.


Figure 2: An example of a populated BW (body weight) domain from SENDIG 3.0 (page 64).The red arrow points to

the BWORRES variable, which is the body weight result for an individual animal as collected without controlled terminology mapping. Abbreviations: STUDYID = study identifier; DOMAIN = domain abbreviation; USUBJID = unique subject identifier; BWSEQ = body weight sequence number; BWTESTCD = body weight test code; BWTEST = body weight test; BWORRES = body weight result or findings as collected; BWORRESU = unit of the original result; BWSTRESC = standardized result in character format; BWSTRESN = standardized result in numeric format; BWSTRESU = unit of the standardized result; BWSTAT = examination status; BWREASND = reason not done; BWBLFL = baseline flag (used to calculate differences or changes from baseline); BWFAST = fasting status; BWEXCLFL = exclusion flag, for exclusion from calculations; BWREASEX = reason for exclusion from calculations; VISITDY = planned study day of collection; BWDTC = date/time animal was weighed.

6.5 Define Fi les Data definition or define files are XML files that function as an index to a SEND dataset. They are a required part of every SEND dataset and include a list of domains, identification of variables that have been populated for each domain, and a list of controlled terminology used in the dataset. The define standard is separate from the SEND and SDTM standards and is therefore on a different release cycle.

6.6 Controlled Terminology Mapping As part of the SEND file creation process, some of the study terminology needs to be mapped or converted to controlled terminology established by CDISC. CDISC SEND controlled terminology is updated four times/year. Importantly, all findings as originally collected by the sponsor are also included in every SEND findings domain (in the ORRES variable) in addition to being mapped to controlled terms.

6.7 Validation Validation of a SEND dataset against the SEND model is a critical part of preparing SEND datasets for FDA submission. Version 2.0 and later of the OpenCDISC validator includes the FDA’s published SEND validation rules, version 2.0. The OpenCDISC validator can be downloaded at: http://www.opencdisc.org/projects.


7 Study Data Reviewer’s Guide A Study Data Reviewer’s Guide (SDRG) is considered by the FDA to be “an integral part of every standards-compliant submission”.4 An SDRG should describe, for each study, any special considerations that may facilitate an FDA reviewer’s and data manager’s use of the datasets. These can include clarification of the differences between the study report and SEND datasets; mapping decisions that require explanation; and terminology, standards, and validation rules versions. Preparation of an SDRG needs to have sufficient leeway to focus on what is important on a study-by-study basis. The SDRG should include a description of how the datasets came together, from data collection to translation to SEND and to integration of the datasets, and a quality statement indicating that the SEND datasets are an accurate representation of data in the study report.

8 Study Data Standardization Plan According to the Study Data Technical Conformance Guide,4 sponsors should include a plan (Study Data Standardization Plan) for clinical and nonclinical studies describing the submission of standardized study data. This plan can be part of the General Investigational Plan at IND stage, discussed with the FDA at a pre-IND meeting, and updated in subsequent communications with the FDA as the program progresses. The Study Data Standardization Plan assists the FDA in identifying potential data standardization issues early in development. It should include a list of planned studies and study types, study designs, planned data standards, formats, terminologies, and versions as well as a justification for studies that may not conform to currently supported standards.

9 What Is the Best Way to Prepare for SEND? 9.1 SEND-Related Processes

Although SEND is new and SEND-related processes can appear as unknowns, the general workflow is more familiar than people may think initially. Like other flat files, SEND files require versioning, storage, review, and QC. Similarly, data coming from multiple sources, eg, bioanalytical, in-life, pathology, needs to be integrated in SEND datasets, just as must be done for conventional toxicology reports and their associated files.

However, there are some SEND-specific processes that need to be established for a successful transition to SEND. These include:

• Formation of interdisciplinary SEND team • Decision of whether to develop SEND data conversion expertise in-house or to outsource • Review of SEND datasets • Terminology lists and CDISC controlled terminology equivalents • Workflow, timelines, resources, budget, training, and personnel for SEND, whether SEND is done

in-house or outsourced. • Integration of data from different LIMS for SEND datasets • Development of Study Data Standardization Plan • Strategic decision of what to do with SEND datasets besides FDA submission, e.g., data

warehouse, data repository

9.2 Trial SEND Submissions to FDA To aid sponsors in preparation for SEND, the FDA will evaluate trial SEND submissions for SEND compliance using the same electronic validation tools used with actual SEND submissions. Trial SEND submissions do not undergo scientific review. The FDA recommends that sponsors submit three trial

4 USDHHS, FDA, CDER, CBER: Study Data Technical Conformance Guide, March 2015.


SEND submissions in preparation for the mandate. A flow chart showing processes involved in preparation for and submission of a SEND pilot submission is shown in Figure 3.

SEND Team meeting: select study for SEND trial submission, discuss

Trial & other needed domains, Controlled Terminology mapping,

adaptor development needs

Development & validation of any needed adaptors, Controlled

Terminology mapping.

Processing through TranSEND to produced integrated SEND dataset, define, Study Data Reviewers Guide

QC and completion check

Submit SEND dataset to FDA

No validation errors

Trial Submission is Complete.

Validation errors

Formation of SEND Team: representatives from Toxicology,

Pathology, Bioanalytical, PK, Regulatory Affairs, Quality

Assurance, Information Technology

Figure 3 Flow chart outlining processes involved in preparation for and submission of a pilot SEND dataset. Blue boxes represent tasks that need to be done before submission, and red boxes represent FDA submission and related tasks. Note that SEND files with errors identified during the FDA’s validation processes are sent back to the sponsor for correction. Resubmission of a corrected dataset is recommended.


10 How Are SEND Datasets Submitted to the FDA? SEND datasets are submitted to the FDA as part of Module 4 of the eCTD (electronic Common Technical Document), which is a separate electronic standard that will also become mandatory for pharmaceutical regulatory submissions.5 The eCTD and SEND datasets are submitted to the FDA through the FDA’s Electronic Submission Gateway (ESG).

For submission of trial SEND datasets, sponsors are advised to follow the instructions at the following FDA webpage:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm174459.htm

11 The Next SEND Release: Version 3.1 CDISC expects to release Version 3.1 of SENDIG before the end of 2015. It will include the following additions:

• Cardiovascular and respiratory safety pharmacology domains • New variables for the microscopic domain: chronicity and distribution • New variables to indicate the grouping of parameters that should be analyzed together when

evaluations or sample collection falls over multiple days • CDISC has released a set of controlled terminology for use with SENDIG 3.1 that includes a code

list of non-neoplastic microscopic lesions using INHAND terminology

12 Coming After SENDIG 3.1 CDISC is currently at work on the following SEND domains:

• CNS safety pharmacology • DART (developmental and reproductive toxicology) • Dermal, genetic, and ocular toxicology

13 Links Links to websites containing additional information on SEND are shown following.

• FDA Study Data Standards Resources: FDA guidances on electronic data standards, data standards catalog, SEND (and SDTM) validation rules

http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm

• SEND Implementation Guide and Controlled Terminology www.cdisc.org/SEND

• PhUSE SEND Implementation Wiki http://www.phusewiki.org/wiki/index.php?title=SEND_Implementation_Wiki

• FDA validated, sanitized TranSEND dataset from PDS www.senddataset.org

• OpenCDISC OpenSource SEND Validator http://www.opencdisc.org/

• Try SEND Explorer™ with a TranSEND™ dataset! https://sendexplorer.azurewebsites.net/

5 Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. USDHHS, FDA, CDER, CBER, May 2015.


14 SEND Support Offered by PDS Our SEND Express™ group consists of experienced toxicologists and software engineers with a proven track record of preparation of successful FDA SEND submissions using TranSEND™, our platform-agnostic SEND solution. We offer a complete turnkey SEND service, assistance with any specific aspect of SEND such as controlled terminology mapping or creation of Study Data Reviewer’s Guides to get you up and running quickly with TranSEND™. Please contact your PDS representative to work out the best solution for you. You can also contact us at: [email protected]

15 About PDS Life Sciences PDS Life Sciences is a privately owned, Swiss-born provider of software and solutions for life sciences research and development. For more than 30 years, we’ve developed software by scientists, for scientists — a hallmark that is unrivaled in our field. For that reason, eight of the world’s top 10 pharma companies rely on PDS software, as do industry-leading CROs, chemical companies, universities and regulatory agencies. With offices on three continents and clients spanning North and South America, Europe and Japan, we are a truly global company.

Developed by a team that understands the workflow of laboratories and submissions, the PDS software lineup is centered on Ascentos™, our toxicology, clinical pathology, reproductive toxicology and pathology modules, which interface seamlessly to streamline data using cutting-edge technologies, and TranSEND™, our platform-agnostic SEND solution designed to produce submission-ready SEND datasets from any data source.

pds send primer for cros sept 2015 -...

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