First-Time-Right: Reduce Refuse-to-File Risk With Surgical Pre-Checks

Refuse-to-file letters rarely stem from brand-new regulations—they come from

missed basics: mismatched Module 2 summaries, incomplete tables, missing

signatures, or eCTD validation failures. The agency interprets an RTF as a signal

that the sponsor lacks control, and recovering from that label is painful.

This playbook turns RTF prevention into a rigorous, repeatable discipline. You

will run targeted checklists, stage mock filings, curate a living deficiency

library, and weave the insights back into authoring teams so issues are caught

before submission. The result is confidence in your file, faster approvals, and a

reputation for doing things right the first time.

Why first-time-right execution matters

Patient impact: RTF delays mean therapies stay off the market longer.
Financial consequences: Every month of delay burns cash and erodes

investor trust.

Regulatory relationships: Agencies keep score. Demonstrating mastery of the

basics earns goodwill for future interactions.

Internal morale: Teams that survive an RTF tend to burn out; preventing the

experience preserves talent.

Build your RTF defense system

1. Engineer a risk-weighted RTF checklist

Create a checklist that mirrors FDA/EMA refuse-to-file criteria augmented with

your historical findings. Organize it by module and stage of compilation:

Module 1 administrative elements (forms, signatures, user fees).
Module 2 summary consistency checks.
Module 3 validation of manufacturing narratives and supporting data.
Module 4/5 compliance with technical specs, datasets, and metadata.

For each item, define required evidence, owner, and verification method. Replace

simple checkboxes with dropdowns (Compliant, Needs Action, Not Applicable) and an

adjacent notes field for proof. Require attachments or links to authoritative

sources. During readiness reviews, focus on items marked Needs Action and enforce

closure with documented accountability.

2. Run disciplined mock filings

A dry run should feel like the real thing:

Compile a full eCTD sequence in a sandbox environment, including Module 1

components and metadata.

Validate using the same tools (Lorenz, GlobalSubmit, Extedo) and capture every

error, warning, and informational message.

Time each handoff from authoring to publishing to confirm process velocity.
Simulate governance meetings where findings are triaged and owners commit to

closure dates.

Record screen captures or detailed notes to build training material for future

filings.

Invite cross-functional participants—authors, reviewers, quality, and IT. The

mock filing is not just for publishers; it is a rehearsal for the entire program.

3. Curate a deficiency pattern library

Catalogue every deficiency you have faced plus publicly available agency

observations. Tag records with the module, root cause, product type, and

detection point (self-identified versus agency). For each pattern, document:

Preventive controls (e.g., additional review step, template update).
Diagnostic cues that signal the issue early.
Remediation playbook if it slips through (who to involve, turnaround targets).

Integrate this library into training for authors and reviewers. When they see a

scenario from the library, they immediately know the stakes.

4. Close the loop with continuous improvement

After every submission:

Debrief within 72 hours. What did the checklist miss? Where did the mock filing

expose surprises? Capture feedback before memories fade.

Update SOPs, checklists, and training modules with the new insights.
Log metrics (see below) and share them with governance to sustain sponsorship.

Technology accelerators

Check automation: Build the checklist inside your submission platform or a

structured SharePoint/Smartsheet board. Automate reminders and escalation when

due dates slip.

Validation scripts: Run nightly XML validation and hyperlink checks as

content lands in the publishing workspace.

Analytics dashboards: Surface open findings by owner, module, and severity

for leadership visibility.

Knowledge base tagging: Use metadata so the deficiency library is

searchable by keyword, dosage form, or manufacturing platform.

Metrics that prove you are RTF-ready

Percentage of checklist items documented with evidence before the mock filing.
Number and severity of findings uncovered during the mock versus post-mock

window.

Count of last-week document changes (aim for downward trend).
On-time completion rate for deficiency remediation actions.
Agency feedback trends (observations, 74-day letters) compared across cycles.

60-day rollout plan

Weeks 1-2: Analyze the latest agency correspondence, inspection outcomes,

and internal deviations tied to submission quality.

Weeks 3-4: Draft the RTF checklist with publishing, QA, CMC, and clinical

leads. Pilot on a high-risk section to test usability.

Weeks 5-6: Build the deficiency library shell, import historical records,

and align on metadata.

Weeks 7-8: Schedule and execute the first mock filing. Capture every

finding, assign owners, and integrate lessons into the checklist and library.

Change management essentials

Make leadership part of the solution—assign them to sponsor the mock filing and

publish the improvement metrics.

Train reviewers on how to document evidence properly; provide exemplars of

high-quality entries.

Recognize teams that close findings early. Public wins reinforce the behavior.
Embed RTF metrics into quarterly quality reviews so the program survives staff

turnover.

Frequently asked questions

How often should the checklist be updated? After every major submission or

whenever guidance changes. Treat version updates like controlled documents with

effective dates.

Do we need multiple mock filings? Programs with high complexity or new

technology platforms benefit from two runs—the first to shake out blockers, the

second to confirm fixes.

What about ex-US filings? Map global agency-specific RTF triggers into the

same framework and filter by region. Consistency reduces rework.

How do we keep momentum between submissions? Use the checklist during

major supplements, not just original filings, and review deficiency trends in

annual management reviews.

Sustain the win

Refresh the checklist and library after each submission, rotate mock-filing

facilitators, and brief leadership on defect prevention metrics quarterly. Make

RTF prevention part of onboarding for new regulatory and quality staff. When the

process becomes cultural muscle memory, you stop fearing RTFs—and regulators see

a sponsor that can reliably deliver high-quality submissions.