Programming considerations for trials focusing on Personalised Medicine

Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose.

The number and range of medications already referencing pharmacogenomics can be found at Drugs@FDA, providing an extensive list  of therapeutic products with pharmacogenomic information found in the drug labelling, with a few of these medications shown in the table below.  The labelling for some, but not all, of the products includes specific actions to be taken based on the biomarker information.

 

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From a programming perspective how is this highly-specialised data to be handled for storage and presentation?

CDISC SDTM

The Study Data Tabulation Model (SDTM) provides a general framework for describing the organisation of data collected during clinical trials.  The CDISC PGx team has developed draft guidance SDTMIG for Pharmacogenomics/Genetics (SDTMIG-PGx) to provide some direction.

CDISC introduction to SDTMIG-PGx

Version 1.0 of SDTMIG-PGx (Provisional) was released on 2015-05-26.  SDTMIG-PGx describes standards to guide the organization, structure and format of gene-related tabulation datasets submitted as part of a product application, such as a new genetic test, to a regulatory agency.  SDTMIG-PGx v1.0 supports the structured capture and reporting of genetic changes associated with diseases or other conditions, called genetic biomarkers, from patients and of the microorganisms that comprise patients’ microbiomes.  It contains information on biospecimen handling for isolation of genetic material and many examples of genetic variation, genotyping and gene expression data formatted using SDTM.

Relationships to Other Standards

SDTMIG-PGx intended to be used in concert with the SDTM and SDTM implementation guides (IGs).

Note that the SDTMIG-PGx stands on its own.  The genetics domains are not anticipated to be incorporated into the SDTMIG.

Known issues

Genetic data tends to be complex with multiple concepts and relationships which must be maintained.

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The standards and examples are limited by the experiences of data collected.

A full list of known issues is presented in SDTMIG-PGx section 1.6 covering: Complexity & Variability; Standardization & Nomenclatures; Modelling Concerns.

SDTM Domains

The domains introduced are intended to hold data that fall into one of three general categories: data about biospecimens; data about genetic observations; and data that define a genetic biomarker or assign it to a subject.

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PB and SB are special-purpose domains.

BE belongs to the general observation class of Events; BS, PF, and PG to the general observation class of Findings.

RELSPEC is a special-purpose dataset.

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Variables used in PGx data

PGx introduces new variables plus pre-existing variables of special interest:

  • Specimen-related variables
    • --DTC “Date/Time of Collection” (not the date/time of assessment)
  • Variables for identifying pathogens
  • Variables for defining observations
  • Variables for reporting genetic variation

General-use variables without additional notes or guidance are no included.

SDTMIG-PGx examples

Section 3

SDTMIG-PGx contains examples for the Biospecimen domains.

Section 4

Pharmacogenomics/Genetics domains.

SDTMIG-PGx Appendices

PGx data collection and data analysis is likely to be a new topic to programmers.

Appendix B

Contains a glossary of terms used.  Additional definitions can be found in the CDISC Glossary available at http://www.cdisc.org/glossary/index.html.

Appendix C

Contains an overview of genetic concepts, covering: Biospecimen Collection; Handling and Quality; Key Genetic Concepts, Genetic Variation; Gene Expression.

Conclusion

SDTMIG-PGx v1.0 provides a framework for the transformation of PGx data to a structure compliant with the concepts of SDTM.  Due to limited exposure to PGx data to date the standards and examples will develop towards maturity.

By utilising the existing SDTM concepts and framework for these data the move to Analysis Data Model (ADaM) datasets for the reporting is facilitated.

SDTMIG-PGx v1.0 has been released for provisional use, since it introduces new variables and constructs added to SDTM v1.5, and to allow operational testing and evaluation of this standard by the CDISC user community.

Note that the FDA still has not officially announced that sponsor should submit genomic data with SDTMIG-PGx.