The Complete Guide to Clinical Data Submissions:
CDISC Standards, TMF Compliance, and Electronic System Validation

In global clinical trials, accurately distinguishing between clinical data standards sdtm (SDTM) and ADaM is the first step toward a successful submission. According to industry definitions, SDTM is used to structure and display data frameworks, while ADaM is specifically prepared for statistical analysis datasets. For life science companies, a core pain point often lies in sdtm programming and terminology consistency during data conversion. The consequences of non-compliance are severe. FDA guidance explicitly warns:

FDA may refuse to file for New Drug Applications (NDAs)… whose study data do not conform to the required standards specified…[1].

To avoid this, companies must strictly adhere to the controlled terminology within cdisc sdtm standards. NCI explains the origin of these standards:

CDISC partners with NCI (EVS) to develop and support controlled terminology for all CDISC standards initiatives…[2].

This means every variable must be defined using specific controlled terminology. As stated in relevant literature:

The Study Data Tabulation Model (SDTM) is a universally accepted and standardized framework… Variables within each domain are defined and coded using specific controlled terminology…[3].

In practice, a Statistical Analysis Plan (SAP) often “locks” specific terminology versions, such as the MedDRA version used in clinical sas sdtm processes. A real-world SAP shows:

The following CDISC standards will be used… Terminology Standards. CDISC SDTM 2020-09-25… MedDRA v22.1…[4].

Therefore, it is advisable to introduce strict Subject Matter Expert (SME) review mechanisms during localization and enforce consistency using terminology management tools, as compliance must be verifiable. Indeed, the validation process often involves automated tools:

Data coding is also mapped to the SDTM controlled terminology. OpenCDISC module will be run to confirm compliance…[5].

The integrity of the trial master file (TMF) is a focal point for regulatory inspections. When building a compliant tmf, handling multilingual documentation is a common pitfall. According to FDA regulations on Drug Master Files:

The DMF must be in the English language. Whenever a submission contains information in another language, an accurate certified English translation must also be included.[6].

This means any non-English source files must undergo strict certified translation. Furthermore, with the rise of Remote Regulatory Assessments (RRAs), record security and formatting have become paramount. The FDA specifically notes in its Draft RRA Guidance:

Specifically, see the Draft RRA Guidance’s discussion of records security, file format… and language translation.[7].

Inspectors will directly access specific records within the TMF during audits. FDA Inspector guidelines instruct:

Review the sponsor’s monitoring reports and other records related to monitoring that may be located in the, trial master file (TMF)…[8].

However, a common industry issue is the lack of standardized filing practices. An industry report points out:

Failure to Standardize TMF Filing Practices…. One TMF can contain thousands of documents…[9].

To ensure “auditability” and avoid regulatory issues, it is advisable to maintain a detailed change log, ensuring every amendment and decision is traceable. As experts suggest:

Maintain a change log so every amendment, annotation, and decision is traceable; this prevents conflicting translated versions…[10].

This also applies to eCRF validation documentation, which is typically maintained in the TMF:

The documentation related to the validation of the eCRFs will be maintained in the Trial Master File (TMF).[11].

Given information security risks, adopting an ISO 27001-compliant closed-loop system to manage the translation workflow of such sensitive data is a prudent choice.

cdisc standards are not static; they update periodically as therapeutic areas evolve. For sponsors, the biggest challenge lies in ensuring submitted data conforms to the latest fda cdisc requirements. Ignoring this carries immense risk. The FDA explicitly states it may refuse to file non-compliant electronic submissions:

FDA may refuse to file… any electronic submission whose study data do not conform to the required standards specified in the…[12].

This compliance requirement is not a one-time check but requires continuous attention to changes in the standards catalog. The FDA notes that SDTM is updated periodically:

FDA is supporting efforts to develop clinical terminology standards… The SDTM will be updated periodically…[13].

This means old terminology files are completely replaced by new versions, and using outdated terminology can lead directly to validation failure. Update notices released by CDISC confirm this:

Current Controlled Terminology Release – Update 24 June 2016…. These terminology files replace all older SDTM and SEND files…[14].

In this dynamic environment, it is recommended that companies adopt systems capable of dynamic terminology management, using technology to extract the latest terms from official sources and sharing them in real-time with all linguists to ensure cdisc compliance is always up-to-date.

When preparing for an fda submission, handling multilingual content must follow specific regulatory pathways. First, the ground rule is clear: all critical Drug Master Files must be submitted in English. FDA guidance mandates:

The DMF must be in the English language. Whenever a submission contains information in another language, an accurate certified English translation must also be included.[15].

Beyond technical documentation, subject-facing informed consent forms are also strictly regulated by 21 cfr. If subjects do not understand English, the FDA allows the use of translated short forms:

In accordance with the requirements of 21 CFR 50.27(b)(2), informed consent is documented using a short form that has been translated… This presentation may be an oral translation…[16].

Moreover, the convergence of standards among global regulatory agencies is a significant trend. NCI notes that CDISC resources can be used for submissions to multiple agencies:

…submissions to regulatory agencies (like the U.S. Food and Drug Administration, Japanese Pharmaceuticals and Medical Devices Agency, and others)…[17].

This internationalization is also reflected in ICH’s work, such as the M1 work plan which includes multilingual translations of MedDRA guidelines:

Release of Chinese, Korean, and Spanish translations of “MedDRA Term Selection: Points to Consider”…[18].

Given that submission materials often involve complex XML structures (like eCTD in ind and nda), it is advisable to seek partners with full-process engineering support to handle XML/DITA formats directly, thereby avoiding formatting errors and compliance risks associated with manual copy-pasting.

As clinical trials become digital, the use of electronic systems like epro, ecoa, and econsent is expanding. The FDA collectively categorizes these as regulated electronic records:

Electronic systems and records include: …electronic patient-reported outcomes (ePRO)… electronic clinical outcome assessments (eCOA), electronic informed consent (eIC) systems…[19].

In localizing these systems, the core challenge is ensuring translated content is culturally appropriate and accurately understood by subjects, which directly impacts icf compliance. 21 CFR 50.20 explicitly requires:

In order to meet the requirements of 21 CFR 50.20, the consent document must be in language understandable to the subject.[20].

Low-quality epro translations can lead to catastrophic consequences. Industry reports warn:

Poor translations can have drastic impacts… result in invalid or unusable data, rejection of submissions to ethics and regulatory authorities…[21].

To ensure scientific validity of data, strict Linguistic Validation must be performed. Standard processes typically include:

For consent forms, PROs… perform formal linguistic validation: forward translation, reconciliation, back-translation… and cognitive interviews…[22].

However, the industry still faces challenges with a lack of concurrent translation guidelines:

The scientific literature currently lacks recommended guidelines on the process of concurrent translation…[23].

To bridge this gap, it is recommended to follow an integration process involving multi-step validation, including screenshot reviews and cognitive interviews:

…eCOA integration process which includes… two forward translations, reconciliation, back translation,… screenshot review, cognitive interviews…[24].

Implementing such in-depth cultural consultation and validation is key to ensuring patient understanding and data integrity.

When selecting clinical systems, it is essential to distinguish between the functions of ctms and edc. The industry typically defines them as:

A Clinical Trial Management System (CTMS) is a platform used to manage the operational aspects… An Electronic Data Capture (EDC) system is designed to collect and manage clinical trial data…[25].

Although functionally different, both face software localization challenges, particularly with ecrf as the front-end interface of the EDC. A critical risk is the incompatibility of translated eCRF terms with backend database fields. The FDA recorded a real-world failure case:

… additional CV disease and heart failure terms were identified in the eCRF system. InForm. These were not consistent with the reported stratum in IVRS…[26].

Such inconsistencies can lead to stratification errors and may even require additional on-site language support. One trial protocol mentioned establishing a help desk for this:

To ensure the safety of study patients… provide medical translation service (if necessary)…[27].

Since data is captured via eCRF—as stated in the protocol

The data for this study will be captured on electronic case report forms (eCRFs) using an EDC system (Bioclinica 5.5).[28]

—the eCRF interface language must be precise and tested. It is advisable to use professional eclinical software localization engineering services capable of handling .rc, .json resource files and performing GUI testing to ensure the interface is free of corruption or truncation, thereby guaranteeing data capture accuracy.