Note |
---|
This page was recently migrated and is still under review for organization, formatting, and links. Text content is still present, and can be found with Ctrl+F. |
Table of Contents
Table of Contents |
---|
Basics |
---|
What is SEND? |
Timing/Regulatory |
---|
When Was SEND Released? SENDIG (SEND Implementation Guide) |
Document | Release Date | Note |
---|---|---|
SENDIG 3.1 | 2016-06-27 | First supported by CDER in Q3 2017 |
SENDIG 3.0 | 2011-07 | First supported by CDER in Q4 2011 |
SENDIG DART (SEND Implementation Guide for Developmental and Reproductive Toxicology) |
Document | Release Date | Note |
---|---|---|
SENDIG DART 1.1 | 2017-12-11 | Awaiting CDER notification of support |
NOTE: please see the When Is SEND Mandatory? question below for information regarding when any of the above are required, with the Data Standards Catalog being the official resource and guidance. |
When is SEND Mandatory |
---|
When Is SEND Mandatory? See the following sections below:
|
Submission Types and Study Start Timing |
---|
Each version of the SENDIG also has its own specific window of when it may first be used and when it may last be used (aka sunset). The definitive list of supported/mandated versions is maintained by the FDA in the FDA Data Standards Catalog (which provides links to relevant guidance, etc.): Since SEND has already been required since at least 2017-12-17 (INDs) and 2016-12-17 (NDAs), as to the question of "when do I first need to be SEND-ready", the answer is "now". Below are the dates applicable to the very first version, SENDIG 3.0, as these are the absolute minimum times industry needed to abide by in being SEND-ready. |
SENDIG 3.0 dates: |
Submission Type | Timing |
---|---|
NDA, ANDA, and certain BLA submissions | Studies which start after 2016-12-17 (December 17th, 2016) |
Commercial INDs and amendments, except for submissions described in section 561 of the Federal Food, Drug, and Cosmetic Act | Studies which start after 2017-12-17 (December 17th, 2017) |
Note: dates for other versions, updates, etc. follow a different implementation timeline (notably, removing the distinction between IND and NDA/BLA after SENDIG 3.1); please see the "When new study types or versions of the SEND Implementation Guide are brought online, when will they be required?" question below. Note:
Examples:
|
eCTD Sections |
---|
The Electronic Common Technical Document (eCTD) page (which can be reached from the Study Data Standards page as well) has several resources for submission, including the Technical Rejection Criteria for Study Data. This is the definitive source for which sections of the eCTD are applicable for submission of data (including SEND datasets). Currently this is specified as WILL APPLY and WILL NOT APPLY. The Electronic Common Technical Document Specification (eCTD) including the full list of possible sections in which a study may be submitted can be found in the ICH eCTD Specification |
Documents |
---|
These requirements to produce SEND datasets for FDA hinge around the following documents:
For more information, see the following FDA pages: The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) is working to adopt CDISC standards including SEND. At the April 2014 CDISC Europe Interchange, plans were presented for adoption at some point after FY2017. For more information see the following PMDA page: When new study types or versions of the SEND Implementation Guide are brought online, when will they be required?
After new standards or updates are published, pending an evaluation by CDER, CDER will add the standard to the Study Data Standards Resources page with a timeframe for requirement. The timeframe for these will be at least 12 months after the standard/version is added to the page, and will apply only to new studies. It is expected that larger scale additions (such as completely new subject areas) will have a longer timeframe for Sponsors to implement and ramp up before it becomes required. Note:
Example - below gives an example of a standards update and the resulting requirement date...
Then...
When will new Controlled Terminology be required? Note that this stipulation applies to CT active at the time of the creation of the SEND package for the study. For instance, if a SEND package is created for a study in 2013 and not submitted until 2017, the CT to which it must adhere is the CT active at the time of the packaging (e.g., 2013 or shortly before it). There is no requirement to retroactively update past studies with CT that comes out after finalization. Visit the SEND CT page to get the most recent CT. When can SEND replace TUMOR.XPT in FDA submissions? How do I know whether SEND is mandatory for any given endpoint?
In other words:
However, this is purely speaking to what is mandatory. The FDA has stated on numerous occasions that they still would prefer to receive data for both of the above exceptions (e.g., via custom domains or to have packages for non-required study types if they have fitting domains). Please contact cder-edata@fda.hhs.gov for additional advice about such a submission. Is SEND mandatory for study types that were not piloted? For studies I submit with SEND datasets, what is the FDA's recommendation for including non-SEND datasets? (e.g., custom domains) What is the status of the FDA pilots (CDER, CVM, CBER)? Please see the Study Data Standards page for pilot status. How will the FDA use SEND files? Is SEND only a U.S. requirement? As far as the European Medicines Agency (EMA) goes, the Clinical Trial Advisory Group on clinical trial data formats (CTAG2) is working on advising the EMA on clinical data formats, where it is leaning toward CDISC standards (although if it accepts, it would likely follow a similar progression as the FDA, with a 2-3 year pilot. Here is a link to the recommendations CTAG2 provided the EMA: Final advice to the European Medicines Agency from the clinical trial advisory group on Clinical trial data formats. As of 2016, PMDA has put forward a schedule for requiring SDTM on the clinical side and plans to explore the nonclinical side as well (with possible pilot). |
Technical Rejection Criteria |
---|
As a reminder, the Technical Rejection Criteria are available on the eCTD resources page. When do the Technical Rejection Criteria go into effect? Which TSPARMCDs are required by FDA? There are new variables added in the base SDTM after the SENDIG was published. Will FDA accept submissions with these not included? Is the TS.xpt file for studies that start before 2016-12-17 required beginning on 2016-12-17? As to officially posted policy, if you submit SEND after 2016-12-17, TS is required (see "When is it ok to include a simplified vs full TS?" question for more details). For legacy cases (e.g., only the report), then only the short version TS is required (single row TS; no DM or Define). All other studies should have a full TS. The Technical Rejection Criteria can be found on the eCTD page. On this page is a TRC Self-Check Worksheet you can follow to check what you need. |
GLP vs Non-GLP |
---|
Does SEND cover non-GLP studies? Short answer is yes. Whether SEND is required is irrespective of whether the study is GLP or Non-GLP. So, if this type of study would be SEND-applicable if it were GLP, then it's also applicable for it as non-GLP. |
21 CFR Part 11 |
Does 21 CFR Part 11 apply? Minimum requirements wise, it is per study and case that would dictate whether GLP Validation (and 21 CFR Part 11) apply (e.g., if used for pre-final purposes to affect study decisions, etc.). Many choose to validate the software producing all datasets (with 21 CFR Part 11 coverage inherent) even if used for a mixture of cases, as the intent to use them may vary, and it's easier to validate the single process. |
Protocol, Report, QA, QC Impact |
---|
How will my study reports from a CRO change when SEND files are used? Should SEND be listed in the Protocol or treated only as a contract deliverable? Please see the Handling of SEND in Study Documentation page for more details and discussion around this question. Should SEND datasets be sent through QA review? Please see the Handling of SEND in Study Documentation page for more details and discussion around this question. What QC should be applied to SEND datasets? Please see the Handling of SEND in Study Documentation page for more details and discussion around this question. Will the study director's signature on the report also indicate accountability for the SEND datasets? Please see the Handling of SEND in Study Documentation page for more details and discussion around this question. What documentation is required for SEND datasets created retrospectively (after report finalization)? Please see the Handling of SEND in Study Documentation page for more details and discussion around this question. |
Working with SEND Files |
---|
What's in a SEND Package? What is a SEND File? What is a SEND dataset? If I receive a SEND file (i.e. from a CRO), how do I open it/view my data?
When opened, they appear similarly to Excel workbooks. Various other vendors have products that will allow you to view SEND datasets as well. These tend to be more robust in visualization/analysis capabilities and enabling of review. How can I create a ts.xpt file with the Study Start Date?
What should the catalog (dataset) name be for the SAS Transport files? Will the XPT files be replaced with something easier to work with, like XML? Does the FDA mandate or endorse use of a specific validator like the one from Pinnacle 21? Are there publicly available sample SEND datasets? Here is a list of places to obtain sample datasets:
There are also many examples in the SENDIG of domain records. |
SEND Implementation |
---|
For more information on implementation and SDTM/SEND basics, check out the SEND Implementation - SEND Fundamentals page. |
What to Include in a SEND Dataset or SEND Package? |
---|
Should I include all variables shown in the implementation tables in my dataset? Should I include pretest/stock animals in a SEND dataset? What study types can/should I use SEND for or include in my SEND package? |
Model Questions |
---|
Does the order of rows in a domain file matter? Does the order of columns in a domain file matter? Does the value of --SEQ matter? What is --GRPID used for? I have to make a SUPP domain entry because the entry in my domain field exceeds 200 characters. What do I use for QNAM if the domain variable is already 8 characters (like LBREASEX)? How are records which are scored (like some clinpath, dermal, or neurotox tests) supposed to be presented? Why is QEVAL expected in SUPP-- domains, but --EVAL is permissible in all other domains where it is present? If animals are scheduled to have findings in the future (e.g., at terminal sacrifice) and the animals are removed from the study early (e.g., unscheduled sacrifice), how should findings be represented (e.g., with VISITDY, --STAT, and --REASND)? When the protocol is amended during the study to change planned activities, when/how should VISITDY be populated? How should the --DTC/--DY variables be populated in cases where --STAT=NOT DONE? The following statement is from the CDER Data Standards Questions Team: "It is our position that the STUDYID variable should be populated with the identifier used during the course of the conduct of the study (in this example, the CRO study ID) and that the TSVAL when TSPARMCD=SSPONSOR should be the sponsor’s identifier." |
Working with CROs |
---|
What Should I Ask My CRO? A number of considerations arise when initiating a conversation with another organization around SEND file production. The SEND between Organizations page has an extensive "Points to Consider" question list to help smooth this process. |
Working with Multiple Files/Studies/Versions |
---|
Should the SENDIG and/or CT version used be the same for all studies in a submission? What do I need to do when collating datasets for a domain?
How is versioning handled for different versions of a SEND package for a study? In a number of operational cases, it is necessary or useful to be able to tie together records between a current version and the version prior, such as for the detection of deltas. There are a couple options for this:
|
Misc |
---|
Are calculated results reported in SEND?
Why are there entries in SEND files such as body weight gains and organ weight ratios, when that information can be derived from information in other SEND files? How do I manage unscheduled data (i.e., data collected in an unscheduled interval)? How do I indicate derived records?
SENDIG 3.1 and beyond describes this in more detail. |
Controlled Terminology (CT) and Formats |
---|
For more information on Controlled Terminology, check out the SEND Implementation - CT Fundamentals page. |
Working with Versions of CT |
---|
How frequently are controlled terminology files updated? Where can I find the most recent controlled terminology? Where can I find old controlled terminology versions? Should the controlled terminology version used be the same across a single study? Should the controlled terminology version used be the same for all studies in a submission? How do I know what version of controlled terminology was used with a dataset? How do I get the Pinnacle 21 Validator to validate against a particular version of CT? |
Mapping Questions |
---|
Does the case of the controlled terms matter? Do I need to change my units when mapping to ORRESU? Are all controlled terminology for tissues in the singular form (KIDNEY)? What do I do if I have terms that are used in our organization that do not map to controlled terminology? The implementation guide mentions "ISO 8601 format" and "ISO 8601 character format". Is there a difference? How are --TEST and --TESTCD related? What do I do when I have two different --STRESU values for the same --TEST? |
Numerical Data (Measurements Data) |
---|
I collect Body Weight in kilograms for Male and in grams for Female. How do I have to export the data in SEND?
So, in the example given in the question, --ORRES would be the result as collected (in kg for males and g for females), and if your reported tables would all be in terms of kg (in other words, you choose to standardize to kg), then your standardized results would be the results in kg form (e.g., males as is and females converted). Do I have to convert my results to different units for --ORRESU and --STRESU? What do I do when the precision differs between collection and reporting? In the SEND implementation guide, in the CDISC notes for the --STRESN variable for some domains, it mentions "continuous or numeric results". What is a continuous result in this context? How do I handle clinpath results which are above or below limits of quantification (BLQ), such as <1.0? The SENDIG discusses this under the ORIGINAL AND STANDARDIZED RESULTS section. Briefly, this value is not actually a numeric value, so --STRESN should be left null. However, a value of 1 may actually be used in calculations; the guide directs how to populate a --CALCN variable (usually as a SUPP-- variable) to contain this information. |
Categorical Data (Findings Data) |
---|
I have food consumption observations on my study such as "reduced food intake". How do I report these data in SEND? What do I do with clinical observations modifiers that do not have a specific variable for them (like color)? If I have a comment for FW domain and my data are pooled, how do I set the USUBJID in SEND CO dataset? |
Define File |
---|
Basics |
What is a define file? Must one be sent with each SEND package? Can the define file be submitted as PDF or does it need to be XML?
|
Viewing / Style Sheet |
What is a Style Sheet for define? Opening a define.xml by itself is not really human-readable. A style sheet is a companion file to define that gives instructions to a browser on how to represent the xml file in a nice way. Style sheets can take on many flavours, and no one style sheet out there is "definitive" - it is mainly a matter of preference. Where can I get a stylesheet to view my define.xml with? |
Codelist |
Must the define file contain the mapping from source field(s) to Controlled Terminology field(s)? What variable should be associated with a codelist in define.xml?
Codelists are not generally needed for:
Other variables should be considered on a case-by-case basis and included if a codelist could provide value to the user of the SEND data What terms should be included in a codelist? Can a define.xml codelist contain all terms from the CDISC Published Controlled Terminology Codelist? How should sponsor-specific extensions to official CT be handled? Must the define file contain definitions for sponsor-specific controlled terminology (where no official CT exists)? In a define.xml CodeList, when should a Display Value (Decode) be included with a term?
In a define.xml Codelist, what should be in the Display Value (Decode) entry for a term?
See SENDIG 3.1 Section 4.3.4 regarding use of coded result values in SEND datasets. When and how can you use one define.xml Codelist with multiple variables? |
Value-level Metadata |
What is value-level metadata? When should value-level metadata be included in define.xml? Which variable(s) should be described in value-level metadata?
|
Calculated Variables |
Must the define file contain the formulae for calculated measurements? Any variable with an origin type=Derived must have a documented derivation method in define.xml. |
Dataset Keys |
What makes up a good dataset key?
|
Comments |
What does the SENDIG 3.0 say about define.xml comments?
Some less common cases are also discussed:
Some other, even less frequent cases are as follows:
|
nSDRG |
---|
What is an nSDRG? Must one be sent with each SEND package? What is the proper format of an nSDRG? Does it need to contain anything specific? |
Describing Conformance Issues - Section 5 |
What kinds of information do Reviewers find useful in this section? Do you expect that explanations of issues in section 5, when impacting data content are referenced or further explained in the dataset explanations (section 4.2)? Are there some examples of what has been seen in nsdrg and considered “too technical”? (in messages or explanations of validation issues.) Should all validation issues be described in this section, including those determined to be “false”? (false = errors or warnings that result from bugs in Pinnacle 21 Community or other validators that may be used. Some examples of common rule breaks that are false in nature: Errors: DD0059, DD0028, DD0024, DD0064. Warnings: FDAN037, FDAN169, FDAN212, FDAN218, FDAN341, DD0029, PCO497.) Are there particular domains which need special consideration regarding the handling of conformance issues (such as MI and Tumor data – where there are a lot (14) of business rules)? Do people who do “data loading” use the nsdrg? Is the FDA tracking validation rule violations by quantity and/or rule ID? Are trends emerging to suggest certain rules could be either A) impractical for companies to adhere to, or B) too vague in meaning. For example, high variety of explanations could indicate wide misunderstanding of the rule or its application. |
Domain Specifics |
---|
Trial Summary |
When is it ok to include a simplified vs full TS? For standard study types (e.g., single/repeat dose carcinogenicity, etc.), i.e., the eCTD sections as outlined in Electronic Common Technical Document (eCTD) page (which can be reached from the Study Data Standards page):
How do I generate a simplified TS? This page contains some information and has a link to a Simplified TS creation guide: In addition, several tests were supplied to the FDA in July 2021. The results of these tests are here: https://phuse.s3.eu-central-1.amazonaws.com/Advance/Nonclinical/Testing+Simplified+TS+Examples+Against+FDA+Technical+Rejection+Criteria+Webinar.pdf. The summary learning points are:
|
Trial Design |
Is the Trial Design (TE, TA, TX, TS) meant to be planned or actual? Is it acceptable to use "Last day of element" as the endrule in TE? |
Exposure |
Do I have to submit each dose?
|
PK Domains (PC and PP) |
Can PK data be put into SEND format? Is there a specific template or type of file to upload for PK data? How do you populate PCTESTCD/PCTEST vs. PPCAT?
The above points tend toward the most common cases. The Technical Conformance Guide has more information on populating these domains. How Do I Handle PK Data or Analysis with CROs/External Labs? |
Use of SEND Packages by the FDA/Industry |
---|
What data mining opportunities will SEND enable? What software is used by reviewers to visualize and review SEND data? What exactly needs to be included in a complete SEND package that is ready to submit to the FDA?
In addition, for the submission, the following are generally needed:
|
SEND Future |
---|
See this link for the Nonclinical Standardization Roadmap group's roadmap, a general (but not binding) indication on relative priority of domains: Is Safety Pharm included in SEND? Is DART / Repro Tox included in SEND? Will SEND be developed to cover neurotox studies? Will SEND be developed to cover phototox studies? Will SEND be developed to cover genetic tox studies? Is Anti-drug Antibody (ADA) expected? Is Flow Cytometry expected? How to model Cytokine and Immune Response Data? In the meantime, the CT exists for some of these endpoints for two cases:
If you are looking to model the data, PHUSE subteams have covered some recommendations for Biomarkers and ADA in white papers:
Are other endpoints being developed? When will the XPT files be replaced with XML? Will SEND be developed to cover veterinary records (treatment recommendations and observations from the exams)? |
Suggesting Changes |
If you see an error or have a suggested change for improving the CDISC SEND standard, Enter your comments using JIRA as sescribed on the page https://wiki.cdisc.org/pages/viewpage.action?pageId=68949529. If you don't already have an account, select the option to signup for an account. |
Open Questions |
---|
The following are open questions, without an answer at present. Most involve the Change Control Tracker (CCT) for an answer from the larger SEND team or others. My study data does not have all of the matching elements for SEND; what do I do? What should be done when the only variable distinguishing records is the unit (e.g., --ORRESU)? |
Known Issues |
---|
See the Known Issues page. |
Submitting a New Issue |
---|
If you have exhausted the above and think there is an issue with the SENDIG, new issues may be submitted in the CDISC JIRA. Steps:
Example of a good description: "In SENDIG 3.1, section 6.3.1.1, page 65, BW domain, Assumption #2 states "Body weight gains are submitted in the Body Weight Gain domain", but this is not descriptive enough. |