Modernizing the CDISC SDTMIG: making the IG more "transport format neutral"

 A few weeks ago, I had a long discussion, first per webconference, with follow-up per E-Mail, with the CDISC Standards direction, concerning the use of LOINC , SNOMED-CT, and UCUM, especially their absence in Therapeutic Area User Guides (TAUGs). We also had a long discussion about why the outdated SAS Transport 5 format is still used (and required by regulatory authorities) and why CDISC could not convince FDA, PMDA and NMPA to move to a modern format.

One of the statements that came in per E-mail and that struck me is the following (I cite):

"In the meantime the SAS v5 limitations are being used against CDISC as antiquated and something from the past".

I answered that I very well understand that this happens.
I however need to explain why I believe this is so, and especially why I believe (personal opinion) that this is justified.

If we take a look at the SDTM Implementation Guides (further abbreviated as SDTMIG, last version: 3.3, November 2018), then we see that it has so many statements and rules that are only there because of (the limitations of) SAS Transport 5. It looks as it never came up to the authors that other formats could be possible. For example, users of the SDTMIG that do not submit to the FDA, PMDA or NMPA, do NOT use SAS Transport 5 (SAS v5). CDISC promotes SDTM to be used in academic studies (with a reasonable amount of success), but academics really do not use SAS Transport 5. Furthermore, there is a good number of mapping tools on the market that do not use SAS Transport 5 for SDTM generation, but only "export" to SAS Transport 5 in the very last step. Behind the curtain, they use either XML, JSON, or "modern SAS".
I have seen quite a number of such studies (both academic and non-submission) using either CSV (comma-separated-values) or XML for storing and exchanging SDTM datasets and studies. So, SAS Transport 5 (also named "XPT") should only be one of the use cases, but the SDTMIG is written as if it were the only use case). 

Essentially, and ideally, "semantic" standards like the SDTMIG should be independent from the transport format used.
HL7-FHIR nicely demonstrates this: The FHIR specification is completely neutral towards any transport format. Examples are provided for 3 (modern) formats: JSON, XML, and RDF. People could however use FHIR with any other transport format (even CSV).

The SDTMIG specification is however written in such a way as that only SAS Transport 5 would be the only possible transport format, which is simply not true.

I do very well understand that submission to FDA and other regulatory authorities (who still require SAS Transport 5) is a major use case of SDTM, but it is not the only one.
As I want to make a positive contribution, I will make a few proposals here how the SDTMIG could be more "Transport format neutral", without loosing the use case of XPT-submissions. This could then counteract the statement "the SAS v5 limitations are being used against CDISC as antiquated and something from the past".

Let us start with section 4.2.1: Variable-naming conventions. The text is:
"Values of --TESTCD must be limited to eight characters and cannot start with a number, nor can they contain characters other than letters, numbers, or underscores. This is to avoid possible incompatibility with SAS v5Transport files. This limitation will be in effect until the use of other formats (such as Dataset-XML) becomes acceptable to regulatory authorities".

I propose to change this into something like:
"In the case of the use of SAS v5 transport files, values of --TESTCD must be limited to eight characters, nor may they contain other than letters, numbers, or underscores. In the case of the use of other formats such as CSV, XML or JSON, this limitation does not apply".

The next one (in the same section) is:

"Variable descriptive names (labels), up to 40 characters, should be provided as data variable labels for all variables, including Supplemental Qualifier variables".

My proposal is to update this into something like:

"Variable descriptive names (labels), not using more than 40 bytes when using SAS v5 transport files, must be provided as data variable labels for all variables, including Supplemental Qualifier variables".

Two major remarks here: first, the use of the wording "must" instead of "should", as the latter represents an expectation in non-US English, and secondly, stating "40 bytes" instead of "40 characters". Reason is that PMDA and NMPA have started requiring labels in Japanese / Chinese for certain datasets, which require up to 3 bytes per character, meaning that for SAS Transport 5, labels cannot be longer than 13 Japanese / Chinese characters.

I hope to be allowed to explain this further during a presentation at the next CDISC Japanese Interchange (I have submitted an abstract). I wrote already something down about these issues here and here. 

Another example where the SDTMIG implicitly assumes XPT, in Section 4.5.3:

"Sponsors may have test descriptions (--TEST) longer than 40 characters in their operational database. Since the --TEST variable is meant to serve as a label for a --TESTCD when a Findings dataset is transposed to a more horizontal format, the length of --TEST is limited to 40 characters (except as noted below) to conform to the limitations of the SAS v5 Transport format currently used for submission datasets. Therefore, sponsors have the choice to either insert the first 40 characters or a text string abbreviated to 40 characters in --TEST. Sponsors should include the full description for these variables in the study metadata in one of two ways: ..."

My proposal to make this more "transport format neutral":
"Sponsors may have test descriptions (--TEST) longer than 40 characters in their operational database. Since the --TEST variable is meant to serve as a label for a --TESTCD when a Findings dataset is transposed to a more horizontal format, the value of --TEST may not exceed 40 bytes in the case the SAS v5 Transport is used. In case another format such as CSV, XML or JSON is used, this limitation does not apply.
Therefore, but only in the case the SAS v5 Transport is used, sponsors have the choice to either insert the characters for the first 40 bytes or a text string abbreviated not taking more than 40 bytes in --TEST. ..."

Also remark that in the define.xml (as it is XML), there is no limitation for the length (nor in bytes nor in number of characters) for the labels. HL7-FHIR has shown us that values can be thousand of characters, in any language...

In Section 4.5.3.2 "Text Strings Greater than 200 Characters in Other Variables", the SDTMIG states:
"Some sponsors may collect data values longer than 200 characters for some variables. Because of the current requirement for the SAS v5 Transport file format, it is not possible to store the long text strings using only one variable. Therefore, the SDTMIG has defined conventions for storing long text string using multiple variables. For general-observation-class variables and supplemental qualifiers (i.e., non-standard variables), the conventions are as follows: ..."

I first propose to change the title of the section into "Use of SAS v5 Transport and text strings taking more than 200 bytes". The text can then be:
"Some sponsors may collect data values that take more than 200 bytes. In the case of the use of SAS v5 Transport, it is not possible to store the long text strings using only one variable. Therefore, the SDTMIG had defined conventions for storing long text strings using multiple variables when SAS v5 Transport is used. For general-observation-class variables and supplemental qualifiers (i.e., non-standard variables), the conventions are as follows: ..."

So, by changing the text slightly, it is both possible to accommodate for the use of non-ASCII characters (taking up to 3 or 4 bytes per character), as well for other formats such as CSV, XML, JSON.
Also remark that the following text snippets like "The first 200 characters of text should..." must then be changed into something like "The first 200 bytes of characters of text must ...". The reason is that the SAS-XPT limitation is not 200 characters, it is 200 bytes. Only in the case of ASCII, 1 character can be stored in 1 byte.

I will not try to listen every (of the hundreds of cases) where XPT is implicitly assumed here, like in section 5.1 "Comments", such as (but not limited to):
"When the comment text is longer than 200 characters, the first 200 characters of the comment will be in COVAL, ..."

to be replaced by something like:
"In the case of the use of SAS v5 Transport, when the comment text requires more than 200 bytes, then the characters for the first 200 bytes of the comment will be in COVAL, ...".

In the tables for the domains, we can then replace each instance of "The value in ... cannot be longer than 8 characters" and "The value in ... cannot be longer than 40 characters" into:
"In the case of the use of SAS v5 Transport, the value in ... cannot be longer than requiring 8 bytes" and "In the case of the use of SAS v5 Transport, the value in ... cannot be longer than requiring 40 bytes".
If that is not clear enough, one could even add: "In the case of other transport formats, this requirement does not apply".

Remark that with such updates / replacements, we "get two for the price of one", taking into account the new requirements of PMDA and NMPA for the use of "Asian" characters in some datasets, and  broadening the scope of SDTM, making it also more popular in the academic world as for non-FDA/PMDA/NMPA submissions. 

I hope these proposals can also lead to making other (modern) formats acceptable by regulatory authorities, even beyond FDA/PMDA/NMPA, as many are thinking that there is a 1:1 relationship between SDTMIG and XPT.

After having done so, nobody will be justified anymore to say that "CDISC is antiquated and something from the past" just because of the SAS v5 Transport format!

Reactions are of course always welcome!

 

 

 

 

 

 

 

 

 

 

SAS Transport 5, CDISC NMPA Submissions, and Chinese characters

 

A number of weeks ago, I was pointed to a publication of the NMPA, the Chinese regulatory authorities, about new guidelines for CDISC submissions. Although I am not mastering the Chinese language, I could find the following statement:

 

drawing my attention.

Essentially, it states: "It is recommended to use XPT version 5 (XPT V5 for short) or similar as the data submission format", followed by "The sponsor should explain the encoding used (such as utf-8, euc-cn, etc.) to avoid garbled codes in the submitted data set".

When I read this, I was pretty shocked. Reason is that SAS Transport 5 (SAS-XPT), a thirty year old format from the IBM mainframe time and that it only supports US-ASCII encoding. 

So I asked some colleagues whether they could provide me a translation of the full guidance, which I received, and which confirmed my first impression.

The text also states that all labels should be in the Chinese language, and that important information like the "adverse event term", or medication names should be in the Chinese language. 

So, what is problematic about this all?

This requires some explanation about encodings, i.e. the way characters are stored as bits and bytes. There are very many encodings, but the most used nowadays is "UTF-8", as it allows for "Unicode", i.e. covering all written languages in the world. Depending on the character to be stored, UTF-8 uses 1 to 4 bytes for a single character.
US-ASCII, usually simply designated as "ASCII", is a very old encoding, only supporting "English" characters. It uses 1 byte per character. Essentially, ASCII is a subset of UTF-8.

UTF-8 is a "variable-width encoding", meaning that either 1 byte is used, or several bytes are used, depending on the character. That makes it an extremely efficient encoding.

- 1 byte: ASCII characters
- 2 bytes: Other Latin alphabets: Greek, Cyrillic, Coptic, Armenian, Hebrew, Arabic
- 3 bytes: Chinese, Japanese, Korean (CJK)
- 4 bytes: less common CJK, historic scripts, mathematical symbols, emoji

So, for Chinese characters in UTF-8 (recommended by the NMPA), one needs 3 bytes for a single character.

The also mentioned EUC-CN encoding uses 2 bytes per character, but is not supported by many systems, and is limited in the number of chinese characters it supports ("Simplified Chinese").

What are the consequences of using Chinese characters in SAS-XPT for SDTM/SEND/ADaM?

The SDTM specification states that variable names and test codes may not be longer than 8 characters, and labels and test names not more than 40 characters. This limitation is due to the (by the FDA) mandated SAS-XPT format, and is not entirely correct. The real statement should be that variable names and test codes may not occupy more than 8 bytes. The statement "8 characters" is entirely based on the assumption that ASCII-encoding is used.

So, for Chinese characters encoded as UTF-8, this means that variable names may not longer than int(8/3) = 2 Chinese characters, and labels not more than int(40/3) = 13 Chinese characters.
For variable values, the limit becomes int(200/3) = 66 Chinese characters.
For variable names and test codes, there is no real problem, as NMPA probably accepts that the variable names and test codes are "English", i.e. use ASCII encoding.
A huge problem however occurs for variable labels.

For example, when I translate the label "Reported Name of Drug, Med, or Therapy", I get "报告药品报告药品名称,药物治疗" which is ... 14 Chinese characters. Or: "Dictionary-Derived Term for the Healthcare Encounter", translates as: "词典中针对医疗保健遇到的术语, also being 14 characters, i.e. taking 42 bytes, which is beyond the 40 byte limit. For CDISC test names, I haven't tried yet, but I suppose that some of them will, when translated to Chinese, be longer than 13 Chinese characters, and thus take more than 40 bytes. The reason for the 40-character (when using English, and supposing ASCII encoding) is that a test code becomes a column label when transposing, and labels may not be ...

Also questionable is what to do when a variable value takes more than 66 Chinese characters. How would one then need to split? Anyhow, such limitations are not of these times anymore, they were acceptable in the time of the punch cards, but we are living in the 21^st century now.

Another huge problem is that there are currently no viewers at all that support non-ASCII encoding in SAS-XPT files. The often used "SASViewer" (currently not available from SAS anymore) and the "SAS Universal Viewer" [https://support.sas.com/downloads/package.htm?pid=667] do not support any other encodings that ASCII for XPT files. This was confirmed to me by SAS Support. For example, when I load an XPT file with Chinese characters, I get:

Some stated that using SAS Transport Version 8 would take away all of the above objections and limitations. This is however not entirely true: also SAS Transport 8 assumes that all characters are encoded as ASCII, and does not support non-ASCII encodings like UTF-8 or EUC-CN. This also means that, just like for version 5, there are no viewers: when I would load a SAS Transport 8 file with Chinese characters into the SASViewer or SAS Universal Viewer, I would get the same result: the Viewer would not recognize the Chinese characters (as it assumes ASCII encoding), and the Chinese characters do not display correctly.

So, why did NMPA choose for SAS Transport 5?

Well, I asked them, but did not get an answer. So I asked the question to people that have good connections to the NMPA, like some members of the "China CDISC Coordination Committee" (C3C). From the discussions with these excellent colleagues, I got the strong impression that NMPA just wants to more or less copy the requirements of the FDA, except than for the use of the language. NMPA did not seem to have thought about (or not understood) what the consequences of using SAS-XPT are.

Are there better solutions?

Of course, there are - we are living in the 21^st century! Already in 2014, CDISC published the "Dataset-XML" standard, which was exactly meant as a replacement for SAS-XPT. It is based on XML, a modern, worldwide really open standard (i.m.o. SAS-XPT is semi-propriety), completely vendor-neutral (SAS-XPT isn't), and used in every industry, so not only in healthcare or clinical research (clinical research is the only industry still using XPT). XML supports any encoding, with the default encoding being ... UTF-8. XML does not have any of the limitations of SAS-XPT. Furthermore, Dataset-XML can be written and read by any modern software, including by SAS and by R statistical packages. Also other CDISC standards such as Define-XML and ODM are using the XML format. It is even so that Dataset-XML is based on both ODM and Define-XML, making it an "end-to-end" solution. That is also why the combination of Define-XML with Dataset-XML is often called "a marriage blessed in heaven".

So I also asked to my Chinese colleagues why NMPA is not recommending CDISC Dataset-XML format. The question that came back was whether FDA and PMDA already accept Dataset-XML. When I then explained about the Dataset-XML FDA pilot, and that the introduction of Dataset-XML has been put on ice, I got the answer (I cite): "If FDA/PMDA adopt XPT only, it will be difficult for NMPA (who has just joined ICH) to be the first agency to adopt dataset-xml. We may have to wait and see what decision other agencies to make".
What this has to do with ICH, I do not understand, as ICH does not mandate SAS-XPT format. Even the other way around, ICH's eCTD (electronic Common Technical Document) is based on ... XML.

For me it is clear that NMPA believes that by adopting/mandating SAS-XPT, it avoids risks. However, just the opposite is true: in my opinion, the use of SAS-XPT with Chinese characters will lead to huge problems at both the NMPA and at sponsors.

Some people asked me about my ideas about alternatives like using UTF-8 encoded CSV (comma separated values). So, I tested this and even added it to the list of supported formats in our famous SDTM-ETL mapping software. Such a CSV file then looks like (visualized in NotePad++):

Even such an extremely simple format would be a considerably better choice than SAS-XPT. When asked for a ranking for "suitability for Chinese characters in SDTM", I made the following table:

Transport format	Suitability Score
CDISC Dataset-XML	100
UTF-8 encoded CSV	50
SAS Transport 8	20
SAS Transport 5	10

Conclusions

SAS Transport 5 (SAS-XPT) format is the worst possible choice as a transport format for CDISC submissions to with Chinese characters to NMPA. It was developed for IBM mainframes (IBM mainframes did not support Chinese characters), and was never meant for anything else than "English" characters and ASCII encoding. It is not suitable at all for UTF-8 encoding and also never developed for that use case.

Several customers have come to me with questions about the new guidance of the NMPA and how to deal with it. My advice to them has been to negotiate the submission of their data sets in CDISC Dataset-XML format. If that is refused, they should propose UTF-8 encoded CSV, as that does not have any of the XPT limitations, is a simple format, and is still well readable by software packages such as SAS and R.