Regulatory submissions in clinical trials can be time-critical: a technical validation failure can stop progress before scientific review begins. This guide outlines the main types of regulatory submissions, what typically distinguishes them in practice, how to run the submission process with clear quality gates, and the common programme pitfalls that can derail timelines. It also covers what to expect after filing,including how to prepare for questions and maintain inspection readiness.
What is a Regulatory Submission?
A regulatory submission is the formal package of documents and data provided to a regulatory authority to support activities such as initiating a clinical trial or seeking marketing authorisation. Depending on region and purpose, submissions are reviewed by regulators such as the FDA, EMA, or national competent authorities.
Before scientific review, submissions typically undergo technical validation. This step checks whether the submission meets required structural, formatting, and data standards.
It is important to distinguish between:
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Technical rejection, where formal submission requirements are not met.
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Refuse-to-file decisions, which relate to overall completeness.
- Scientific or clinical deficiencies, identified later in the review process.
Technical validation happens early, which is why failures at this stage can halt progress quickly.
Types of Regulatory Submissions
Different submission types have different technical expectations, and misunderstanding these requirements is a frequent cause of rejection. Requirements can vary by authority, so teams should confirm local expectations before reusing formats or assumptions. Common examples include the following:
Clinical trial start submissions (CTA/IND)
These submissions support permission to initiate a clinical trial and are typically filed before the first participant is enrolled. They commonly include the protocol, key supporting evidence (including relevant preclinical information), informed consent materials, and information about the investigational product (including quality/manufacturing information), alongside ethics-related documentation where required. A frequent technical failure mode is misaligned versions (for example, protocol vs supporting documents) or missing required components for the chosen route.
Marketing applications(MAA/NDA/BLA)
These submissions seek marketing authorisation and typically expand the evidence package compared with trial-start filings, including broader clinical evidence alongside more complete quality/CMC information and pharmacovigilance planning. Technical issues often arise when cross-references and supporting files do not align across the submission structure, especially in multi-author builds.
Protocol amendments and substantial modifications
These submissions update how the trial is run (for example, changes to eligibility criteria, endpoints, or safety monitoring) and are typically filed when a change is considered ‘substantial’ by the authority. They commonly include the amended protocol with a clear rationale and any impacted documents (for example, updated informed consent where applicable). A common alignment failure is updating the protocol without updating dependent documents and artefacts consistently.
Safety and progress submissions during conduct
These submissions provide ongoing oversight during trial conduct (for example, annual reports/DSURs and updated Investigator’s Brochures, where applicable) and may be periodic or triggered. They typically summarise cumulative safety information, exposure, and trial status at a defined data cut. A type-specific risk is inconsistency between the stated data cut and the underlying source evidence used to compile the package.
Lifecycle variations and other dossier updates
These submissions update an existing dossier or approval (including quality/CMC updates, labelling, and other administrative or technical changes) and are filed when approved information changes. They typically describe what changed, why it changed, and which parts of the dossier are affected. A common route risk is using the wrong procedure for the change type, or providing insufficient traceability to impacted sections.
Post-approval commitments and post-market submissions
These submissions support ongoing obligations after authorisation and can include deliverables linked to commitments, surveillance, and benefit–risk maintenance over time. They often rely on consistent, auditable linkage between what was committed, what was done, and what is reported. A common risk is an incomplete audit trail across versions, supporting evidence, and published artefacts.
Responses during review (information requests)
Regulators may request additional information and clarifications during review, typically handled through point-by-point responses supported by evidence.
What is the Regulatory Process for Clinical Trials? Key Steps and Best Practices
Regulatory submissions sit within the wider clinical trial lifecycle, but the submission itself typically follows a repeatable operational pathway. A simple way to plan the work is to treat it as a staged process with explicit quality gates.
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Plan the submission
Confirm submission type, authority expectations, and the technical standards to apply (including data standards and file formats). Confirm the authority-specific checklist you will use (avoid reusing a generic template). - Compile and finalise content
Lock document versions, confirm cross-references, and align terminology across modules and datasets. Confirm the authority-specific checklist you will use (avoid reusing a generic template). - Publish the electronic package
Build the eCTD (or authority-specific electronic structure) and run link and structure checks. Run a publishing ‘dry run’ before the final package is frozen (structure, links, XML, file placement). Keep filenames lowercase where possible, unless specifically requested otherwise. - Validate study data and metadata
Run SDTM/ADaM/define.xml checks, confirm required files are present, and resolve high-impact issues. Use defined validation gates and review the highest-severity findings, not only the counts. Follow current guidance for study data submissions (for example, the Study Data Technical Conformance Guide) and use the latest applicable version. Check Study Tagging File (stf.xml) values against the study datasets (for example, STUDYID alignment) before publishing. For define.xml and study identifiers, check study-level metadata directly and do not rely on what is or isn’t displayed by default in a stylesheet view. - Submit via the relevant portal
Ensure the package meets portal constraints and local requirements (for example, EU CTIS workflows for clinical trials versus FDA electronic submission processes). - Respond after submission
Plan capacity and traceability for regulator questions, including quick retrieval of source evidence and version-controlled updates. - Archive and maintain inspection readiness
Retain validation outputs, decision logs, and final published artefacts in a controlled repository.
What are Common Regulatory Submission Pitfalls?
Common avoidable issues often sit outside the publishing tool itself and instead reflect programme control and cross-functional execution. These include:
Regulatory strategy and alignment
Unclear regulatory strategy can create late churn, particularly when target markets, indications, or data expectations are not aligned early.
Changing requirements
Requirements can change over time, so teams typically benefit from active tracking and clear decision logs.
Submission narrative coherence
A cohesive product ‘story’ can be hard to maintain across modules when many SMEs contribute, which can create avoidable inconsistency in how evidence is framed.
Document control and versioning
Weak document control (e.g. templates,versioning, late-breaking data handling) increases the chance of internal inconsistencies and technical validation errors.
Ownership, SME availability, and timelines
Lack of clear ownership, limited SME availability, and unrealistic timelines can push review and decision-making into the final days, increasing rework and risk.
Review workflow and sign-off
An inefficient review process such as unclear sequencing, sign-off, and unresolved comments can slow delivery even when content is broadly complete.
What Happens After You Submit?
Teams are often most effective when they treat post-submission work as a planned delivery rather than an exception. Rapid responses usually depend on controlled source evidence and clear ownership.
Inspection readiness can also become relevant during and after review, so maintaining clear documentation for decisions and validation outputs helps reduce scramble.
Where approvals lead to ongoing commitments, it helps to plan capacity for post-authorisation deliverables and surveillance work alongside the initial filing plan.
Conclusion
Regulatory submissions in clinical trials run more smoothly when teams match the submission type to the authority’s expectations, keep consistent and controlled, and use a staged process with practical quality gates. That combination can reduce avoidable technical rejection, limit rework, and protect timelines when questions arise during review.
Quanticate’s statistical programming team can support with submission readiness, including eCTD publishing checks, SDTM/ADaM and define.xml validation, and traceable delivery. Request a consultation and a member of our team will be in touch with you.
