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The Trial Summary Domain Puzzle

Author: Genpro Statistical Programming Team

 

Trial Summary Domain [TS domain] – A jigsaw puzzle among the SDTM Trial domains where we need to put together the pieces of the study in a structured way to get a complete picture. This domain is often challenging either in determining the number of parameters required or in getting the required value of the parameters. This blog is a complete guide to the so-called “head-ache TS”. We will discuss the complete structure, required parameters, and the source of values for the parameters.

The TS domain is a trial-level domain that helps to get a complete overview of the clinical trial such as the protocol title, phase, and trial objectives. FDA made TS a “must-have” item for e-submission, even if the study started prior to December 17, 2016. The trial Summary domain has changed significantly since SDTM IG v 3.1.3. New variables have been added to have more control over data. Information presented in a standardized way helps reviewers to have a complete idea of the study quickly and easily.

Challenges

Creation of TS dataset is often troublesome for many statistical programmers.

  • We don’t have a one pot solution for all the parameters. Information of TS parameters comes from different sources:

1.  Study Protocol (trial phase, protocol title, trial objectives).

2. Clinical Datasets (Study start /end date, Actual Number of Subjects).

3. Dictionaries or terminologies (such as CDISC CT, Registry Identifier, Unique Ingredient Identifier).

  • Collecting the above information is manual and time-consuming.

Structure

A trial design domain that contains one record for each trial summary characteristic. This domain is not subject oriented. The domain is composed of fixed structure and a list of variables which cannot be extended. We can see the same in section 7.4.2 of SDTMIG v 3.3.

Like other general observation class, TS domain also have STUDYID and DOMAIN. TSSEQ is slightly different from what it means for other domains in general observation class. TSSEQ indicates just the several possible values of trial summary parameters.

The name, code name and value of the parameters are stored in TSPARM, TSPARMCD and TSVAL respectively. To make the minimum set of variables consistent across all sponsors, new variables have been included from SDTMIG v 3.1.3 onwards. These variables are TSVALCD, TSVALNF (if applicable), TSVCDREF, TSVCDVER.

  • TSVALNF stores value called “null flavor” used mainly when TSVAL cannot be filled.
  • TSVALCD stores any controlled terminologies associated with parameter’s values.
  • TSVCDREF holds the name of the reference terminology from which TSVALCD is taken.
  • TSVCDVER contains information about the version of the reference terminology.

Unlike the general observation classes, if the value in TSVAL has more than 200 characters, additional values can be stored in TSVAL1-TSVALn based on the length.

Putting together the Puzzles

By now, we have an overview of how the TS Domain looks like. The one thing that makes TS domain complete is TSPARM. But for this we need an enthusiastic and research-oriented mind.

Populating TSVAL for some TSPARM(CD)’s need consulting the protocol, SAP and other study related documents. Some TSVAL requires controlled terminologies while some can be entered without any controlled terminologies like the study title. Some other requires external sources like clinicaltrials.gov, NCI Term Browser, dnb.com, FDA Substance Registration System etc.

The following table provides detailed information of all the required TSPARM needed as part of submission. We make the process easier to map the TS domain by providing information’s like the expected values, source of the parameter value, any special considerations etc. As mentioned in SDTMIG v 3.3, TSPARM and TSPARMCD are extensible so we can have more parameters added based on the study design.

The column Desired states whether the parameter is required or not. The value “Y” means the parameters must be included and either TSVAL or TSVALNF needs to be populated. The value “Conditional” means the parameter is required based on the study design. For example, if in a study there is protocol specified treatment to be taken in addition to the investigational therapy(ADDON=Y), then the parameter CURTRT, should be included with either TSVAL or TSVALNF populated.

TSPARMCDTSPARMTSVCDREFDesiredTSVALFormats/ CodelistSource or External LinkAdditional Notes
ACTSUBActual Number of

Subjects

YNumber
ADAPTAdaptive DesignCDISCYNo or YesTextProtocol
ADDONAdded on to Existing TreatmentsCDISCYNo or YesTextProtocol
AGEMAXPlanned Maximum

Age of Subjects

ISO 8601YTextProtocolIf maximum age specified is 80 years, then TSVAL=P80Y
AGEMINPlanned Minimum Age of SubjectsISO 8601YTextProtocolIf minimum age specified is 18 years,

then TSVAL=P18Y

COMPTRTComparative Treatment NameUNIIYSRS Preferred Substance Name (or Device Name)Texthttps://fdasis.nlm.nih.gov/srs/srs.jsp
CRMDURConfirmed Response

Minimum

Duration

ISO 8601ConditionalTextProtocolFollow the same format as in AGEMAX
CTAUGCDISC Therapeutic Area User GuideConditionalTexthttps://www.cdisc.org/Include all specific Therapeutic Area Guides used, if any. Use as many rows as needed.
CURTRTCurrent Therapy or TreatmentConditionalSRS Preferred Substance Name (or Device Name)Texthttps://fdasis.nlm.nih.gov/srs/srs.jspUse when ADDON=Y. Use as many rows

As needed.

DCUTDESCData Cutoff

Description

YTextDescribe the basis of data cutoff

like “Database lock”. We can use

the variable TSGRPID to relate

DCUTDTC to DCUTDESC.

DCUTDTCData Cutoff DateISO 8601YTextIf data cut-off is based on database lock

Then give the date of lock. We can use

the variable TSGRPID to relate

DCUTDTC to DCUTDESC..

EXTTINDExtension Trial

Indicator

YNo or YesTextProtocol
FCNTRYPlanned Country of

Investigational Sites

CDISCYISO 3166-1 alpha-3 Country CodeTexthttps://en.wikipedia.org/wiki/List_of_ISO_3166_country_codesUse as many rows as needed.
HLTSUBJIHealthy Subject

Indicator

CDISCYNo or YesTextProtocol
INDICTrial

Disease/Condition

Indication

SNOMEDConditionalSNOMED CTTexthttps://ncit.nci.nih.gov/ncitbrowser/pages/vocabulary.jsf

 

For a healthy volunteer study,

TSVALNF = ‘NA’.

INTMODELIntervention

Model

CDISCConditionalIntervention ModelText/C99076Protocol/ https://clinicaltrials.gov/ 

Used when STYPE =” INTERVENTIONAL”

INTTYPEIntervention

Type

CDISCConditionalIntervention TypeText/C99078Protocol/ https://clinicaltrials.gov/Used when STYPE=” INTERVENTIONAL”
LENGTHTrial LengthISO 8601YTextProtocolPlanned length of observation for a single subject.

Follow same format as AGEMAX

NARMSPlanned Number of

Arms

YNumberProtocol
NCOHORTNumber of

Groups/Cohorts

YNumberProtocol
OBJPRIMTrial Primary

Objective

YTextProtocolUse as many rows as needed.
OBJSECTrial Secondary

Objective

YTextProtocolUse as many rows as needed.
OUTMSEXPExploratory

Outcome Measure

ConditionalTextProtocolUse as many rows as needed.
OUTMSPRIPrimary Outcome

Measure

YTextProtocol Use as many rows as needed.
OUTMSSECSecondary Outcome

Measure

ConditionalTextProtocolUse as many rows as needed.
PCLASPharmacologic ClassConditionalMED-RTTexthttps://ncit.nci.nih.gov/ncitbrowser/pages/vocabulary.jsf?dictionary=MED-RT&version=2020_09_08Use if STYPE = ‘INTERVENTIONAL’ and

where applicable for INTTYPE.

PDPSTINDPediatric Postmarket

Study Indicator

YNo or YesTextProtocol
PDSTINDPediatric Study

Indicator

YNo or YesTextProtocol
PIPINDPediatric

Investigation Plan

Indicator

YNo or YesTextProtocol
PLANSUBPlanned Number of

Subjects

YNumberProtocol
RANDOMTrial is

Randomized

CDISCYNo or YesTextProtocol
RANDQTRandomization

Quotient

ConditionalNumber Includes percentage of subjects that are planned

to be exposed to investigational treatment. For

example, if in a study the subjects are

randomized in  1:1:1 ratio and one of the

treatment is Placebo then TSVAL is 2/3=0.67.

Value ‘1’ denotes all subjects  randomized to  the

Investigational treatment.

RDINDRare Disease

Indicator

YNo or YesTextProtocol
REGIDRegistry IdentifierClinicalTrial

s.gov

YIdentifierTextClinicalTrials.gov or EUDRAC

(https://clinicaltrials.gov/).

 Use as many rows as needed.
RLPSCRITRelapse CriteriaConditionalTextProtocol
SDMDURStable Disease

Minimum Duration

ISO8601ConditionalTextProtocol
SENDTCStudy End DateISO 8601YTextThe date on which the final data item for a

clinical Study was collected from the last study

participant  (that is,last subject, last visit, or as

otherwise defined in the study protocol).

SEXPOPSex of ParticipantsCDISCYSex of ParticipantsText/C66732Protocol
SPONSORClinical Study

Sponsor

DUNSYData Universal Numbering System or D-U-N-S(DUNS)Texthttps://www.dnb.com/ 

 

SDTMVERSDTM VersionYTextThe value should be the exact term listed in the

FDA  Data Standards Catalog. If multiple SDTM

Versions are used for a study, each version

should be listed as separate rows.

SDTIGVERSDTM IG VersionYThe value should be the exact term listed in the

FDA  Data Standards Catalog. If multiple SDTM

Versions are used for a study, each version

should be listed as  separate rows.

SSTDTCStudy Start DateISO 8601YTexthttps://clinicaltrials.gov/The earliest date of informed consent among any

Subject (Date/Time of Informed Consent,

RFICDTC) that enrolled in the study. For studies

conducted without informed consent (ie.

emergency use) use  the date of treatment.

Dates for subjects who were  screen failures are

not included.

STYPEStudy TypeCDISCYStudy TypeText/C99077https://clinicaltrials.gov/
TBLINDTrial Blinding

Schema

CDISCYTrial Blinding SchemaText/C66735
TCNTRLControl TypeCDISCYControl TypeText/C66785Protocol
TDIGRPDiagnosis

Group

SNOMEDConditionalSNOMED CTTexthttps://ncit.nci.nih.gov/ncitbrowser/pages/vocabulary.jsfUse when HLTSUBJI = ‘N’
TINDTPTrial

Indication Type

CDISCConditionalTrial Indication TypeText/C66736Protocol/https://clinicaltrials.gov/
THERAREATherapeutic AreaCDISCYTextProtocol/https://clinicaltrials.gov/
TITLETrial TitleYTextProtocol/https://clinicaltrials.gov/
TPHASETrial Phase ClassificationCDISCYTrial Phase ClassificationText/C66737
TRTInvestigational

Therapy or

Treatment

UNIIConditionalSRS Preferred

Substance

Name (or

Device Name)

 

Texthttps://fdasis.nlm.nih.gov/srs/srs.jspUse If STYPE = ‘INTERVENTIONAL’.
TTYPETrial TypeCDISCYTrial TypeText/C66739Protocol/https://clinicaltrials.gov/

 

For QT submissions or important information related to ECG is available, we can include TSPARM related to ECG. The above table describes the required and most used TSPARMs. Also, there are more TSPARMs available in SDTM CT, which we can include based on our study.

The NULL FLAVOR (TSVALNF)

There are situations where we cannot find values for the required parameter TSVAL. If we keep TSVAL column blank, pinnacle 21 will throw an error. What can be done in this situation? This is where TSVALNF comes into picture.

The values that can be used to populate TSVALNF called null flavour, provides additional information when TSVAL is null. The controlled terminology for this null flavour is in ISO 21090 standard, “Health Informatics – Harmonized data types for information exchange. Consider the TSPARAM’s AGEMAX and AGEMIN which are required parameters. The main reason behind inclusion of NULL FLAVOR in this scenario is that most of the protocol do not specify an upper limit for the age of subject. So, we cannot populate TSVAL and hence TSVALNF needs to be filled. There are around fourteen items/values in NULL FLAVOR which are detailed out in section 7.4.2.1 of SDTMIG v3.3. The most used values of NULL FLAVOR are listed below:

  • PINF (Positive infinity) – Positive infinity of numbers. Usually used when there is no maximum age specified
  • UNK (Unknown) – A proper value is applicable, but not known.
  • NAV (Temporarily unavailable) – Information is not available at this time, but it is expected that it will be available later. For example, study end date when the study is ongoing.
  • NA (Not applicable) – No proper value is applicable in this context.

Please be careful that both TSVAL and TSVALNF are not populated at the same time. TSVALNF is populated only when corresponding TSVAL is not available.

CONCLUSION

SDTM Trial summary domain provides a high-level overview of the clinical trial. It is an important part of e-submission. Besides being a confusing domain, once created this is the most informative Trial Domain as we get a full picture of the Clinical trial from a single piece. The complete information on TS domain can be found in SDTMIG v3.3 and FDA Study Data Conformance Guide. Appendix B which includes the Required TS parameters for submission will be excluded from SDTMIG v3.4 onwards and will be completely available in FDA Study Data Conformance Guide.

REFERENCES

  • Study Data Tabulation Model Implementation Guide v 3.3
  • https://www.pharmasug.org/proceedings/2016/DS/PharmaSUG-2016-DS11.pdf

Tags:

  • CDISC
  • SDTM
  • TS Domain
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