{"id":3283,"date":"2024-06-10T11:22:40","date_gmt":"2024-06-10T15:22:40","guid":{"rendered":"https:\/\/cytel.agencyukdev.com\/perspectives\/the-facts-in-the-case-of-subject-x\/"},"modified":"2024-08-22T06:19:54","modified_gmt":"2024-08-22T10:19:54","slug":"the-facts-in-the-case-of-subject-x","status":"publish","type":"perspectives","link":"https:\/\/cytel.agencyukdev.com\/fr\/perspectives\/the-facts-in-the-case-of-subject-x\/","title":{"rendered":"The Facts in the Case of Subject X"},"content":{"rendered":"

Over the past years, probably the entire last decade, there have been several discussions on how to handle multiple subjects\u201a\u00c4\u00f4 enrollments in CDISC data packages. Members of the CDISC SDS Multiple Subject Instances (MSI) team also shared some previews of future possible modifications of the SDTM standard to handle multiple subjects\u201a\u00c4\u00f4 enrollment,[i]<\/a><\/sup> and we might finally have something available with the upcoming future releases of the SDTM standard and Implementation Guidance (IG).
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Meanwhile, several sponsors and vendors have shared their experiences dealing with different scenarios of multiple subjects and, in some cases, provided alternative solutions,[ii]<\/a>[iii]<\/a>[iv]<\/a>[v]<\/a><\/sup> with the PHUSE \u201cSDTM ADaM Implementation FAQ Data Submission\u201d working group[vi]<\/a><\/sup> also providing some recommendations.<\/p>\n

This topic \u2014 without any clear direction and standard solutions and allowing no major conformance issues \u2014 is causing a lot of \u201cheadaches\u201d to sponsors and vendors. Nevertheless, the FDA requirements added in the October 2018 version of their Study Data Technical Conformance Guide (SDTCG) was also the source of extra stress to CDISC implementers. \u201cWhat? Another Demographics domain? DC domain what? What Observational Class should it be?\u201d<\/p>\n

The result is that, at least from the CDISC packages I\u2019m daily exposed to, everyone \u2014 vendors and sponsors alike \u2014 is interpreting the CDISC and FDA requirements in their own way.<\/p>\n

With this article, I will try to summarize this topic by providing a current \u201cstate of the art\u201d and some recommendations. I will focus specifically on two scenarios and as such will clarify what we mean by multiple subjects\u2019 enrollments:<\/p>\n

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  1. Multiple study subject enrollment<\/strong> is where a subject participating in a trial could also be subsequently enrolled in another trial where again the subject could have multiple failures or be successfully enrolled in the first attempt. The subject is assigned a new enrollment number as per the rule set up in the study.<\/li>\n
  2. Subject re-enrollment in the same study<\/strong> is where a subject in a single trial is allowed to be re-screened, meaning the subject is selected for participating in a trial, fails the screening, and at a later time might come back and go through the screening process again. Every time the subject comes in, the subject gets a new enrollment\/subject number.<\/li>\n<\/ol>\n

     <\/p>\n

    The case of a subject enrolled in multiple cohorts or study arms within the same study is not covered in this article,[vii]<\/a><\/sup> although many of the recommendations provided in this article apply to this scenario as well.<\/p>\n

    The question is: how can I represent this information in our CDISC datasets, for example in SDTM, so that we have a clear flow of the subject experience, while we maintain traceability and hopefully compliance with available standards and regulatory guidance?<\/em><\/p>\n

    Let’s look first at specific requirements from the SDTM IG and Health Regulatory guidance.<\/p>\n

     <\/p>\n

    Who is Subject X for CDISC and Health Authorities?<\/strong><\/span><\/p>\n

    The CDISC IG guidance clearly says, for example here in the below DM section, that it is a requirement to use the USUBJID variable to uniquely identify a subject in all studies within a submission involving the product<\/span><\/em>.<\/p>\n

    \"\"<\/p>\n

    Furthermore, the FDA in its SDTCG[viii]<\/a><\/sup> adds that an \u201cindividual,\u201d a study subject, should have the exact same unique identifier, thus the USUBJID variable, across all datasets, including between SDTM and ADaM, and that if a subject participated in more than one study, he or she should maintain the same USUBJID across all studies.<\/p>\n

    Similar requirements and additional clarifications can be found in both the FDA and the PMDA[ix]<\/a><\/sup> SDTCG.<\/p>\n

    \"\"<\/p>\n

    In addition to USUBJID, which is a unique identifier for the subject across all studies, we also need a SUBJID that uniquely identifies each subject that participates in a study. Also, if a subject is screened and\/or enrolled more than once in a study, then the subject\u201a\u00c4\u00f4s SUBJID should be different for each unique screening or enrollment.<\/p>\n

    \"\"<\/p>\n

    However, from the CDISC IG, including the latest IG 3.4, it is not clear how to handle data about individuals that are screened\/enrolled more than once in the same study. The only additional requirement is that in DM domain, only one record per subject, per individual, can be submitted, but it is unclear how we could represent demographics for subjects that have been enrolled more than once (SDTM IG 3.2 \/ 3.3 \/ 3.4 Section 5.2 \u201cDM Assumptions\u201d).<\/p>\n

    Let’s look now at a couple of scenarios on how to handle multiple enrollments.<\/p>\n

    Multiple study subject enrollment<\/strong><\/span><\/p>\n

    The following scenario shows how on study nr.2, USUBJID was carried over from study nr.1, while keeping SUBJID and SITEID the one assigned during enrollment in study nr.2.<\/p>\n

    \"\"<\/p>\n

    Of note, in this and all subsequent scenarios and examples, USUBJID is built by concatenating the study ID, site ID, and subject ID or enrollment number. For example, in study 1, the USUBJID was given the value of STUDY01 concatenated with the value 010, which is the site nr. where the subject was enrolled and 101 that is the subject number assigned during the \u201cprimary enrollment\u201d (I will come back later to the definition of primary enrollment). However, this is simply a convention as the CDISC IG doesn\u2019t mandate any standard derivation nor does the regulatory guidance, e.g., FDA SDTCG.<\/p>\n

    To achieve the USUBJID \u201cuniqueness,\u201d we need to be a bit \u201cprescient\u201d and plan in CRF some fields to check if a subject did participate to any previous study of the same \u201cproduct.\u201d<\/p>\n

    \"\"<\/p>\n

    The same is also applicable for rescreened subjects within the same study, the CRF should collect previous assigned screening\/enrollment numbers.<\/p>\n

    It is also recommended to mention in the Clinical Study Data Reviewer Guide (cSDRG) which previous studies a subject could have been already enrolled in and the reason.<\/p>\n

    \"\"<\/p>\n

    The same is true for submission projects where individual studies were conducted by other vendors or sponsors. It is recommended to check with the sponsor which studies could have subjects that already participated in previous studies. You will need to check if USUBJID was correctly implemented, because retrospective changes in individual existing study packages could be problematic, if not discouraged, and eventually adjustments can be done in the pooled datasets, either in the integrated SDTM or integrated ADaM.<\/p>\n

     <\/p>\n

    Subject re-enrollment in the same study<\/strong><\/span><\/p>\n

    Let\u2019s look now at a scenario where a subject might be screened several times in the same study (the figure below was taken from V. Poulsen and H. Pontoppidan F\u00f6h PHUSE-EU 2022 presentation).<\/p>\n

    \"\"<\/p>\n

    While subject XXX is finally enrolled after two failures, and eventually randomized, subject YYY failed twice and never came back. At each attempt, both subjects were given a new enrollment number and eventually some data needed for screening the subject might be collected and re-collected, e.g., vital signs.<\/p>\n

    Given the fact we must keep the same USUBJID when a subject is screened multiple times within the same study, this means in the DM domain we must decide from which enrollment the DM information should be derived. One approach could be as follows:<\/p>\n

     <\/p>\n