IND vs IMPD: Building One Data Package That Satisfies Both FDA & EU Regulators

Executive snapshot

Filing separate first-in-human (FIH) dossiers for the United States and Europe can drag an early-stage program six-plus months behind plan. A harmonised approach—one Common Technical Document (CTD) “master” that slots into both the FDA Investigational New Drug (IND) sequence and the EU Clinical Trials Regulation (CTR) portal (CTIS)—cuts review-cycle queries by ~35 %, lets you open US/EU sites in lock-step, and shows investors a globally scalable package. This article maps the IND and IMPD/CTA frameworks side-by-side, pinpoints six technical gaps that still trip sponsors, and provides a 16-week workflow, case metrics, and ready-to-use check-lists so you can move from pre-clinical data-lock to parallel safe-to-proceed / CTA authorisation in as little as 63 days.

Introduction

Historically, FIH studies followed a sequential path: submit an IND under 21 CFR 312 [1], wait for the FDA’s 30-day review, and then assemble country-specific IMPDs under Regulation (EU) 536/2014 [2]. Today, with investor pressure for parallel site activation and advances in digital publishing, one integrated dossier is feasible—if done correctly from the start.

Despite both systems relying on the CTD structure, regulatory differences remain. The FDA process focuses on a 30-day clinical-hold clock and eCTD format. In contrast, the EU CTR enforces a 60-day joint review (with potential clock-stops) and mandates data publication via CTIS [11]. Below is a comparative overview:

Key axis	IND	IMPD / CTA
Non-clinical depth	Two-species, 28-day GLP tox + full ICH S7A/B [8][9]	Selected studies may be waived if justified
Starting-dose rationale	Default NOAEL → MRSD [4]; MABEL/PAD optional	EMA FIH Guideline 2017 [3] requires MABEL/PAD only for high-risk assets
CMC granularity	High-level Phase 1 specs; stability commitment acceptable	Batch-release specs + QP declaration required up-front

A harmonised package therefore means adopting the strictest requirement, documenting justified regional deviations, and structuring every file so it drops cleanly into both eCTD and CTIS. Done well, you eliminate duplicate authoring, reduce regulator questions by a third, and keep US/EU Phase 1 timelines in lock-step.

Regulatory foundations — quick reference

Feature	FDA IND	EU IMPD + CTA
Governing law	21 CFR 312 [1]	Regulation (EU) 536/2014 [2]
Submission gateway	eCTD (CDER/CBER)	CTIS single portal
Clock-stop review	30-day silent approval unless clinical hold	60 days + clock-stops for RFIs
Primary dossier element	CTD M1-5	IMPD + admin/ethics annexes
Transparency	Confidential	Auto-public disclosure (deferrals possible) [11]

Where IND & IMPD still diverge—and how to bridge each gap

Non-clinical safety depth

FDA invariably expects two-species 28-day GLP tox; EU may waive selected studies. Bridge: write to the higher bar and attach a one-page waiver memo for EU reviewers.

Starting-dose algorithm

Both regions default to NOAEL → MRSD [4]; EMA’s FIH guideline [3] requires MABEL/PAD only for immune agonists, stimulators, or novel modalities. Bridge: use a single risk-grid slide-deck—page 1 risk table, page 2 MRSD worksheet, page 3 MABEL/PAD if triggers met.

Clinical-pharmacology & DDI package

Small molecules: Follow FDA [5] + ICH M12 [6]; defer transporters if PBPK shows low risk.

mAbs/Proteins: Assess cytokine-mediated CYP effects per FDA 2023 guidance [12].

Peptides/Oligos: Transporter screens if MW <5 kDa [7].

ATMPs: Focus on immunogenicity and conditioning regimen interactions [10].

CMC depth & QP certification

IND allows high-level specs; EU needs batch specs + QP declaration. Bridge: create an IMPD-style spec table and drop the same PDF into IND M3.

Electronic format & transparency

IND eCTD is private; CTIS auto-publishes. Bridge: generate a “public copy” PDF with automated redactions alongside the master file.

Clock-management

FDA clarifying RFIs typically arrive day 14-21; EU RFIs day 40-50. Bridge: a colour-coded gap matrix and a 2-page pre-IND briefing lock the plan before filing.

The single-data-package workflow

Week	Milestone	Owner	Output
0-1	Kick-off audit & gap map	Reg-lead	Airtable tracker
1-2	Critical-path alignment	PM	Locked Gantt
2-8	Living gap matrix + modality-flagged DDI table	CP/PK lead	SharePoint “single source”
6	Compile CTD once; auto-populate IND M1 & IMPD Annex I	Med writer	Draft dossier
8	CTA submission via CTIS; IND queued	Publisher	eCTD & CTIS packages
6-10	FDA 30-day review	—	Rapid RFI response
8-16	EU 60-day review	—	Coordinated RFI response
10-16	Simultaneous “May Proceed” + CTA authorisations	—	FIH Go

Common pitfalls & pro tips

Pitfall	Time lost	Quick fix
“We’ll localise later.” Two versions emerge.	4-6 weeks	Write once; track change-log.
Country-specific ethics annexes forgotten.	4 weeks	Annex checklist by Week 4.
Stability spec mismatch.	10-day FDA hold	Use IMPD spec table in IND.
CTIS public copy not scrubbed.	Reputation risk	Automated redaction script.

Frequently asked questions

1. Can I file an IMPD verbatim as an IND? No—administrative forms, US-specific REMS text, and eCTD hyperlinks differ.
2. How do I handle protocol divergence after approval? Maintain one “master” protocol and track amendments in a single log referenced in both dossiers.
3. Does Project Optimus change dose-finding only in the US? No—EMA’s revised oncology guidance is aligned; use the same exposure–response slides.
4. Will eCTD v4.0 change CTD structure? Structure stays; v4.0 adds an XML backbone and two-way messaging—tag v3.2.2 sequences now to future-proof.

References

1. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312
2. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX%3A32014R0536
3. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-and-mitigate-risks-first-human-and-early-clinical-trials-investigational-medicinal-products-revision-1_en.pdf
4. https://www.fda.gov/media/72309/download
5. https://www.fda.gov/media/135586/download
6. https://database.ich.org/sites/default/files/ICH_M12_Step4_Guideline_2024_0521_0.pdf
7. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions-revised_en.pdf
8. https://database.ich.org/sites/default/files/S7A_Guideline.pdf
9. https://database.ich.org/sites/default/files/S7B_Guideline.pdf
10. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-clinical-aspects-medicinal-products-containing-genetically_en.pdf
11. https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trial-regulation/transparency-rules
12. https://www.fda.gov/media/140909/download