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Data Standards: Considerations for Regulatory Submissions

Drug applications go through comprehensive reviews of both nonclinical and clinical study data. Historically, these datasets were structured according to the Sponsors’ preferences rather than by standardized criteria, which caused many challenges for regulatory reviewers. As technological advancements have led to more data being recorded on digital platforms, data package standardization and the enforcement of these standards by regulatory authorities have become necessities.

The Clinical Data Interchange Standards Consortium (CDISC) is a nonprofit standards development organization that works with individuals from multiple regulatory agencies, including the U.S. Food and Drug Administration (FDA), as well as academic and industry partners, to develop global data standards for nonclinical and clinical studies. 

CDISC standards underly the requirements for all data packages submitted to FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Per CDISC standards, tabulated data are provided as SEND and SDTM domains for nonclinical and clinical packages, respectively, while ADaM specifications are utilized for clinical analysis datasets.

Data standard requirements were implemented by the FDA starting in 2016. As summarized in the table below, data for studies submitted in support of marketing applications must follow CDISC requirements if they started after December 17, 2016 including:

  • New Drug Applications (NDAs)
  • Biologics License Applications (BLAs)
  • Abbreviated New Drug Applications (ANDAs)

Study data presented in commercial Investigational New Drug Applications (INDs) must be CDISC-compliant if the study started after December 17, 2017. If a sponsor fails to follow these guidelines, the FDA may refuse to file the application. Importantly, because of the one-year gap between requirements for marketing applications and INDs, there may be some studies where CDISC is not required for the IND but will still be required for the marketing application.

Timelines for Data Standards Implementation

Type of Application Study Start Date After
NDA, BLA, ANDA December 17, 2016
Commercial IND December 17, 2017

While many sponsors are aware of these implementation requirements, new specifications are regularly released that can catch some drug developers off-guard. Many of the recent updates pertain to regulations regarding SEND datasets in addition to rules for specific domains, such as the trial summary (ts.xpt) domain. These are discussed in more detail below.

SEND Regulations

Initial SEND regulations only pertained to single-dose toxicology, repeat-dose toxicology, and carcinogenicity studies submitted to CDER (CBER currently does not require SEND datasets but will accept them for submissions). Starting on March 15, 2019, however, SEND datasets were required to follow a new implementation guide (Version 3.1) that additionally supports cardiovascular and respiratory safety pharmacology studies. With this new regulation, these additional studies must now also be SEND-compliant if the study start date is after March 15, 2019 for NDAs, BLAs, and ANDAs or after March 15, 2020 for INDs.

Furthermore, SEND modifications are expected to be implemented in the future. Because of this and given the typical rolling implementation timelines, it is important for sponsors to assess the studies in their pipeline and continually monitor for updated data reporting standards to ensure that their submissions are compliant with current regulations.

Note that data standards for nonclinical data packages are irrespective of GLP status; therefore, both non-GLP and GLP studies must comply with these regulations.

Studies and Timelines for SEND Implementation for CDER

Type of Application  Type of Study Study Start Date After
NDA, BLA, ANDA Single-dose Toxicology, Repeat-dose Toxicology, Carcinogenicity December 17, 2016
Cardiovascular and Respiratory Safety Pharmacology March 15, 2019
Commercial IND Single-dose Toxicology, Repeat-dose Toxicology, Carcinogenicity December 17, 2017
Cardiovascular and Respiratory Safety Pharmacology March 15, 2020

Trial Summary Domains

Trial summary domains are one of the most commonly overlooked datasets for submissions. This dataset contains basic study information such as the study title, objectives, and number of subjects; most importantly, though, it includes the study start date. There are different rules regarding trial summary domains depending on the type of application and whether the study is clinical or nonclinical. Fortunately, the FDA has provided multiple guidelines to aid sponsors in determining the requirements for their specific programs. Among these are a list of technical rejection criteria and a self-check worksheet (note: in order to display properly, the worksheet may need to be downloaded and opened using a PDF viewer).

Trial summary domains must be submitted for all nonclinical studies that fall within the required SEND study types, but they are only required for clinical studies if other “.xpt” data are submitted. The extent of information required within the domain, however, is different depending on the study start date. As of September 2019, the technical rejection criteria did not include cardiovascular or respiratory safety pharmacology studies. CBER submissions do not require a trial summary domain for nonclinical studies as SEND is not yet required for this division.

Studies and Timelines for Trial Summary Domains

Study Type Study Start Date Application Type Criteria to Follow (CDER)
Nonclinical Prior to or on December 17, 2016 NDA, BLA, ANDA Simplified TS domain required
Prior to or on December 17, 2017 Commercial IND Simplified TS domain required
After December 17, 2016 NDA, BLA, ANDA Full TS domain required
After December 17, 2017 Commercial IND Full TS domain required
Clinical Prior to or on December 17, 2016 NDA, BLA, ANDA Simplified TS domain required if other “.xpt” datasets submitted
Prior to or on December 17, 2017 Commercial IND None
After December 17, 2016 NDA, BLA, ANDA Full TS domain required
After December 17, 2017 Commercial IND None

Conclusions

As many sponsors can attest, the preparation of CDISC-compliant datasets is time-consuming and costly. It is important to consider current and future data regulations when planning studies for your development program. To help navigate the complexities of data management, the FDA has compiled Study Data Standards Resources

  • Data Standards Catalog: Provides a list of different data standards, versions, and dates for implementation
  •  Study Data Technical Conformance Guide: Provides technical recommendations for the submission of standardized animal and human data
  •  FDA Guidance: Providing Regulatory Submissions in Electronic Format — Standardized Study Data: Provides regulatory details for data standards

The world of data standards is constantly evolving. Find out how Nuventra can assist with your data needs today! 

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