About This Book
Background
The Clinical Data Interchange Standards Consortium (CDISC) started in 1997 as a global, open, multidisciplinary, non-profit organization focused on establishing standards to support the acquisition, exchange, submission, and archiving of clinical research data and metadata. The mission of CDISC is “to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of healthcare.”
CDISC standards are promoted as being “vendor-neutral, platform-independent and freely available via the CDISC website.” When one speaks of clinical research data, however, one particular vendor often comes to mind. SAS software has been used for analyzing, summarizing, and reporting clinical trial data since the early 1980s. The US Food and Drug Administration (FDA) has required that electronic data provided to them in marketing approval submissions be formatted in the SAS 5.0 transport file format. Although this format is now an open standard accepted by many types of software, it has played a role in establishing and maintaining SAS as the industry standard in the pharmaceutical industry for numerous tasks relating to clinical trial data.
The flagship standard developed by a CDISC working group is the Study Data Tabulation Model (SDTM). The term “tabulation” has its origins in the code of federal regulations (CFR) regarding what is required in New Drug Applications (NDAs). Specifically, 21 CFR 314.50 describes case report tabulations (CRTs) as “data on each patient in each study” that are “pertinent to a review of the drug's safety or effectiveness.” Originally, these tabulations were generated as listings on paper. However, by the late 1990s, electronic data sets were playing an increasing role in new drug reviews. As a result, the SDTM was developed as a standard data format for the electronic submission of these required tabulations.
Since the inception of CDISC, its bond with SAS and SAS users in the pharmaceutical industry has been a natural marriage. Over the past decade, as CDISC standards have built up momentum in terms of stabilizing and gaining regulatory approval and preference, SAS programmers have played an increasing role in the complete life cycle of clinical trial data—from collection, to analyzing, reporting, documenting, validating, submitting and archiving data, and all the steps in between. As such, the time seems right to provide an end-to-end handbook for SAS users in the pharmaceutical industry who are working with CDISC standards.
What’s New in This Edition?
When writing the first edition of this book, the FDA was still not requiring that marketing applications for new drugs and biologics be submitted electronically, much less that CDISC standards be applied to the data sets that accompanied fully electronic submissions. But the writing was on the wall, so to speak (or on the screens at industry conference presentations), that such changes were imminent. This was the motivation for that first edition—to help late adopters get on board with the someday-to-be-required CDISC implementation.
Then, in July of 2012, the FDA Safety and Innovation Act, or FDASIA, was passed, setting the wheels in motion for the requirement of electronic marketing applications including standardized study data. The Act deferred the details about the format of these soon-to-be-required electronic submissions to guidance documents, but it set a time table for them to take effect “beginning no earlier than 24 months after issuance of a final guidance.” In December 2014, “Providing Regulatory Submissions in Electronic Format – Standardized Study Data” was issued as a final guidance document, thereby setting December 2016 as the due date for official conversion to CDISC standards for future submission. The guidance document, as expected, specifies the use of both SDTM and ADaM datasets.
But these requirements by themselves were not uniquely motivating for a new edition of our book. As we were writing the first edition, we knew that the rapid evolution of CDISC standards would render at least part of the book outdated before it even came out. Perhaps most notable among these changes was the release and finalization of the Define-XML 2.0 standard, a more extensible version of the original standard for dataset meta-data. Many other changes have also since been released, including a host of new SDTM domains, a new version to the ADaM Implementation Guide (1.2), a new data structure for occurrence-related analysis data sets (the OCCDS), new ADaM validation checks (now on version 1.3), new Pinnacle 21 software, new therapeutic area standards, and, of course, new versions to the SAS and JMP software used to implement these standards. Many of these updates have been reflected within their respective relevant section within the book.
What hasn’t changed is the process by which we recommend that these standards be implemented. The use of CDASH at the collection stage is more important than ever, although mostly outside the scope of this book. The subsequent “linear” conversions from the raw, collected data to the SDTM and ADaM standards are still very much a basic tenet of that process. We also continue to espouse the virtues of establishing the metadata before the creation of the actual data that they describe. So from that perspective, the “end-to-end” organization of the book has remained largely unchanged.
Is This Book for You?
Any manager or user of clinical trial data in this day and age is likely to benefit from knowing how to either put data into a CDISC standard or analyze and find data once it is in a CDISC format. If you are one such person—a data manager, clinical and/or statistical programmer, biostatistician, or even a clinician, then this book is for you.
Prerequisites
It is assumed that the readers of this book have some basic understanding of SAS programming. It is also advantageous if the reader has some familiarity with the CDISC SDTM and ADaM models. If you do not have this knowledge, then there will be some portions of this book that will be more difficult to follow.
Purpose
This book has two purposes. One is to introduce readers to the end-to-end process for implementing CDISC standards on clinical trial data. The second is to introduce readers to tools based on SAS that cannot only facilitate the implementation process but also facilitate the ultimate goal of analyzing your data once it follows a CDISC standard. Some of these tools are actual SAS products. Some are SAS macros provided by the authors.
In order to achieve these goals, the authors have created fictional clinical trial data that will be used to provide examples of how to apply SAS tools to the various steps in the process along the way.
Organization and Scope of This Book
With the end-to-end concept in mind, this book is organized with a start-to-finish mentality for clinical trial data. Chapter 1 starts with an overview of the primary standards covered in this book, the SDTM and the Analysis Data Model (ADaM), and a discussion of considerations as to when each should be implemented. Chapter 2 is focused on what should be the first step to any big project, the specifications. Although many currently think of the creation of metadata and data documentation as part of the process that comes after building the datasets, the authors hope that the tools and tips provided here will facilitate the creation of a define.xml file as a tool for implementing SDTM standards before any of the actual conversion work is performed.
Chapters 3, 4, and 5 all cover SDTM implementation, but with different tools (Base SAS, SAS Clinical Standards Toolkit, and SAS Clinical Data Integration, respectively). Chapter 6 relates to ADaM metadata while Chapter 7 covers ADaM implementations using Base SAS. With regulatory, quality, and compliance concerns in mind, Chapters 8 and 9 cover CDISC validation using SAS software and Pinnacle 21 software, respectively. Chapter 10 is about analyzing data that have been structured to follow CDISC standards, with a particular focus on JMP Clinical, which has been specifically developed to work on SDTM and ADaM data. Finally, concluding the “end-to-end” process, Chapter 11 provides information on how to integrate your data from various studies into one integrated database and other steps required for providing your data in a regulatory submission.
Although many CDISC standards have stabilized, there are new standards on the horizon. Chapter 12 looks at some of these uncertainties, such as the Janus clinical trial data repository and HL7 messaging for CDISC content. Other topics relating to CDISC standards are covered here as well, such as the SEND model for non-clinical data and the BRIDG model for relating HL7, CDISC, and other standards, models, and semantics together.
What is not covered in this book are details, guidelines, and examples on how to put certain types of data into the CDISC models. These are details that CDISC therapeutic area working teams are most adept at dealing with. The SDTM implementation guide (IG), contains a wealth of knowledge pertaining to how, when, and where to put clinical trial data in SDTM domains. Similarly, the ADaM IG and associated appendixes have more information to help implementers decide how to build ADaM datasets.
Software Used to Develop This Book’s Content
As you might expect, the majority of the software used in this book is SAS software. The following software was used in the production of this book:
● Base SAS 9.4
● SAS Clinical Standards Toolkit 1.6
● SAS Clinical Data Integration 2.6
● JMP 11.2
● JMP Clinical 5.0
● Pinnacle 21 Community 2.1.0
Various versions of Internet Explorer and Chrome were used to render the define.xml files
Data and Programs Used in This Book
The majority of the source data for this book can be generated by the SAS programs found in Appendix A. There is some study metadata used to generate the Trial Design Model datasets for the SDTM that you can find in Microsoft Excel files on the author pages listed below. The metadata spreadsheets used for the ADaM and SDTM data can also be found on the author pages listed below. Finally, all programs used in this book can be found on the author pages as well.
Author Pages
You can access this book’s author pages at:
http://support.sas.com/hollandc
http://support.sas.com/shostak
The author pages include all of the SAS Press books that these authors have written. The links below the cover image will take you to a free chapter, example code and data, reviews, updates, and more.
Example Code and Data
You can access the example code and data for this book from the author pages listed in the previous “Author Pages” section. On the author page, select “Example Code and Data” to display the SAS programs that are included in this book.
For an alphabetical listing of all books for which example code and data are available, see http://support.sas.com/documentation/onlinedoc/code.samples.html. Select a title to display the book’s example code.
If you are unable to access the code through the website, send email to [email protected].
Additional Help
Although this book illustrates many analyses regularly performed in businesses across industries, questions specific to your aims and issues may arise. To fully support you, SAS Institute and SAS Press offer you the following help resources:
● For questions about topics covered in this book, contact the author through SAS Press:
◦ Send questions by email to [email protected]; include the book title in your correspondence.
◦ Submit feedback on the author’s page at http://support.sas.com/author_feedback.
● For questions about topics in or beyond the scope of this book, post queries to the relevant SAS Support Communities at https://communities.sas.com/welcome.
● SAS Institute maintains a comprehensive website with up-to-date information. One page that is particularly useful to both the novice and the seasoned SAS user is its Knowledge Base. Search for relevant notes in the “Samples and SAS Notes” section of the Knowledge Base at http://support.sas.com/resources.
● Registered SAS users or their organizations can access SAS Customer Support at http://support.sas.com. Here you can pose specific questions to SAS Customer Support; under Support, click Submit a Problem. You will need to provide an email address to which replies can be sent, identify your organization, and provide a customer site number or license information. This information can be found in your SAS logs.
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Acknowledgments
This book would not have been possible without the thorough review and thoughtful feedback of several individuals that we would like to thank and recognize for their contribution.
Internal SAS support:
● Editor: Stacey Hamilton
● Technical Publishing Specialist: Denise T. Jones
● Cover design: Robert Harris
● Copyeditor: Kathy Underwood (with marketing materials edited by John West)
Technical reviewers:
● Lex Jansen
● Nate Freimark
● Bill J. Gibson
● Geoffrey Mann
Jack would also like to dedicate this edition in memory of his father John and dog Susie. They taught him many lessons in how to do the right things and how to smell the roses, respectively.
Chris would like to dedicate this edition to all of the devoted CDISC volunteers who contribute so much of their time and energy to the worthy cause of developing data standards in our industry.