Author: PD Dr. Ghazaleh Gouya-Lechner, Founder, Gouya Insights | Last reviewed: June 2026
Most CTIS submission failures are predictable. They follow consistent patterns across first-time sponsors, and they are avoidable if you know where to look before the review clock starts. What is covered here: Investigational Medicinal Product Dossier (IMPD) and Investigator’s Brochure (IB) errors, Part II national document failures, transparency and redaction missteps, and operational preparation gaps. Pharmacovigilance and post-authorisation requirements are outside the scope of this article.
Submitting a clinical trial application through the Clinical Trials Information System (CTIS) for the first time exposes every gap in your development program, your internal organisation, and your understanding of what European regulators expect.
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The sponsors who move fastest through CTIS review are not necessarily those with the most resources but those who start preparation well before their target submission date and treat pre-submission review as an important part of the work beyond formalities. The requests for information and resulting delays that derail first submissions almost always point to problems that existed long before the application was filed.
Part I of your CTIS application covers your investigational medical product and the scientific rationale of your trial. It is assessed through a coordinated process led by the Reporting Member State (RMS). Most requests for information (RFIs) come from Part I.
Mistake 1: Presenting preclinical data without translating it for human use
The Investigator’s Brochure (IB) is a clinical document. Its job is to give the investigators running your trial everything they need to conduct it safely and make informed clinical decisions. Regulators reviewing your IB want to understand what your preclinical findings mean for the humans who will be in your trial: what dose is safe to start with, what safety signals the clinical team should monitor, and where your animal models have limitations for predicting human response.
Sponsors who draft their own IB often produce a document that summarizes experiments chronologically rather than synthesizing it into a risk profile. When the clinical implications are not made explicit, reviewers will ask for clarification, and that triggers a request for information.
The fix: structure your IB around clinical questions, not experimental sequences. For each key non-clinical finding, include a section on what it means for dose selection, safety monitoring, and patient eligibility.
Mistake 2: Outdated or incomplete stability data
Insufficient stability data is one of the most frequently flagged deficiencies in the IMPD Part I review. Regulators need assurance that participants receive a product with consistent quality attributes throughout the study.
For a 12-month trial, stability data must cover at least 12 months under intended storage conditions. A shorter shelf life forces the use of multiple batches, adding operational complexity. Some trials also require an in-use stability study to evaluate product quality after opening, reconstitution, dilution, or preparation for administration.
The fix: before submission, confirm that your stability data covers the full planned shelf life. If gaps exist, extend ongoing stability studies or plan interim data updates, and document all changes clearly in the dossier.
Mistake 3: Insufficient comparability justification after manufacturing changes
If your investigational product has gone through any manufacturing changes since the original non-clinical studies, you need to demonstrate that the product used in the clinic is comparable to the product used in those studies. Sponsors frequently underestimate how much documentation this requires, or they include a brief statement rather than a structured comparability justification.
The fix: treat comparability as its own section of the IMPD. Document every manufacturing change, explain what analytical testing was done to confirm comparability, and be explicit about the implications for the clinical program. If gaps exist in the comparability data, acknowledge them and explain your risk mitigation approach.
Part II of your CTIS application is reviewed by each member state independently. Ethics committees have the most influence here, and country-specific requirements create the most variation between jurisdictions.
Mistake 4: Using a generic informed consent form across all countries
The informed consent form (ICF) is the document that trial participants sign before enrolment. It needs to explain the trial in plain language, address risks and benefits, and meet the specific requirements of the ethics committee and national legislation in each country where the trial runs. Sponsors running multi-country trials frequently produce one consent form and translate it, assuming a good translation is sufficient. It is not. Generic language around sample use, data sharing, or post-trial access is a consistent source of ethics committee questions across EU member states.
The fix: treat each country’s ICF as a distinct document. Start with a core template, then adapt it for each member state, addressing national requirements for consent, sample handling, and data protection. Build in time for country-specific legal review before submission.
Mistake 5: Documents that are too long and too technical for patients
Ethics committees assess patient-facing documents from the perspective of the patient. A consent form that is 30-page long, written in clinical terminology, and structured around regulatory requirements will not pass review without significant revision. Readability is a regulatory requirement under the Clinical Trials Regulation, not a stylistic preference.
The fix: before finalising any patient-facing document, have someone without a clinical background read it and explain back what they understood. If they cannot accurately describe the trial purpose, the main risks, and what they are agreeing to, the document needs to be rewritten.
Mistake 6: Ignoring secondary use of samples and post-trial access
Whether biological samples collected during your trial can be used for future research (secondary use) and whether patients can continue accessing the investigational treatment after the trial ends (post-trial access) are both required to be addressed in your Part II submission. Both are country-specific, and both are areas where sponsors often use generic language that does not meet national expectations.
The fix: address both topics explicitly for each country in the program. Review the relevant national legislation and ethics committee guidance for each member state, and ensure your consent form language reflects it. If post-trial access is not feasible given the regulatory status of your product, document what alternative support will be offered to participants.
These mistakes are organisational, not scientific. They consistently add weeks to first submissions and are entirely preventable with early planning.
Mistake 7: Assigning CTIS platform roles at the last minute
CTIS requires sponsors to assign specific roles within the platform before a submission can be managed: who can submit documents, who can view which parts of the dossier, who manages communications with the Reporting Member State. Sponsors who attempt to set this up during the submission window lose time they cannot recover.
The fix: set up your CTIS organizational account and assign all required roles at least four to six weeks before your target submission date.
Mistake 8: Underestimating how long it takes to prepare a clean dossier
The single most common mistake across first CTIS submissions is starting too late. Sponsors consistently underestimate the time required to resolve IMPD gaps, prepare country-specific Part II documents, develop a redaction strategy, and coordinate clinical, regulatory, legal, and manufacturing teams around a single submission deadline. For context, sponsors who have done this before routinely plan three to six months of preparation time before their target date, and they still find gaps during internal review.
The fix: begin preparation at least three to six months before your target submission date. Build in time for at least one internal review cycle before the dossier is finalized, and assume that gaps will be found during that review.
These mistakes relate to the CTIS transparency framework, which became fully applicable in June 2024. They carry less regulatory risk than scientific deficiencies, but are worth a brief review before submission.
Mistake 9: Misunderstanding what qualifies as confidential
Mechanism of action, trial design, and primary endpoints do not qualify as CCI simply because they have commercial value. CCI typically covers manufacturing processes, proprietary analytical methods, and specific commercial arrangements.
The fix: rather than relying on redaction, use document placement strategically. Not every CTIS document becomes public. The Investigator’s Brochure and the Investigational Medicinal Product Dossier are not published, so detailed proprietary information belongs there, while the protocol, which is public, can carry a general description.
What does CTIS stand for and when did it become mandatory?
CTIS stands for Clinical Trials Information System. It is the EU’s single entry point for submitting, managing, and publishing clinical trial applications under the Clinical Trials Regulation (EU) No 536/2014. Use of CTIS became mandatory for all new clinical trial applications in the EU in January 2023, with the full transparency framework applicable from June 2024.
What is the most common reason CTIS submissions get delayed?
The most frequent cause of delays is deficiencies in the IMPD and IB, particularly missing stability data, insufficient comparability justification after manufacturing changes, and preclinical findings that are not contextualized for human use. These trigger complex requests for information that can be challenging for the sponsor to answer within the defined timelines.
How many countries should I include in my first CTIS submission?
As few as possible. For a first submission, starting with a single country is often more practical than a multi-country application. A mono-national submission has fewer Part II documents to prepare, one ethics committee to manage, and a simpler operational footprint. Austria and Germany are both practical choices for early-phase trials given their efficient review timelines and well-established regulatory infrastructure. However, the optimal country strategy also depends on the clinical trial design. In studies involving patient populations with an expected slow recruitment rate, a multi-national strategy may be necessary to ensure timely enrollment. Additional countries can be added to the clinical trial via substantial amendments.
Can I fix mistakes in a CTIS submission after it has been submitted?
Some elements can be updated through the RFI during the submission process but can add complexity. Significant deficiencies in Part I documents, such as IMPD gaps, cannot be corrected quickly once the review process has started. The goal of pre-submission preparation is to minimise the need for amendments. Changes can also be made after approval by non-substantial (minor changes) or substantial modifications. However, they trigger additional costs and delays.
How do I know if my informed consent form will pass the ethics committee review?
Have someone without a clinical background read the document and explain back what they understood. If they cannot accurately describe the trial purpose, the main risks, and what they are agreeing to, the document needs revision before submission. Readability is a formal requirement under the Clinical Trials Regulation.
What happens if I do not submit a redaction strategy?
If commercially confidential information is not adequately protected in the documents submitted to CTIS, this information may become publicly available upon publication. Redaction strategies must therefore be implemented prior to submission, as changes after authorisation are difficult to implement and may not fully prevent disclosure of information already published
Do I need a regulatory affairs specialist to submit to CTIS?
For a first submission, working with an experienced regulatory professional is strongly advisable. The IMPD, IB, and protocol all require regulatory writing expertise and clinical interpretation. The country-specific Part II documents require knowledge of national requirements that varies significantly across EU member states. The cost of regulatory support at the preparation stage is consistently lower than the cost of a delayed or deficient submission.
What is the difference between a request for information and a rejection in CTIS review?
An RFI is part of the ongoing assessment and reflects that the application is still under evaluation. It introduces a defined sponsor response period within the overall timeline, during which the sponsor is expected to address identified deficiencies or provide clarification. In contrast, a rejection (or lapse/non-approval) represents a negative outcome of the evaluation. It occurs when the application cannot be approved based on the available data, either because deficiencies are not adequately addressed or because the sponsor fails to respond within the required timelines (usually 12 calendar days). In such cases, a new submission must be made. Importantly, RFIs do not suspend the review timeline but are integrated into the predefined timelines under the CTR, whereas rejection terminates the procedure.
References
[1] European Medicines Agency. CTIS Sponsor Handbook (March 2026) and Sponsor FAQ. https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/clinical-trials-information-system-ctis
[2] European Commission and Member States. Joint Recommendations on Recurrent Submission Deficiencies in CTIS Applications. EudraLex Volume 10. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-10_en
[3] European Medicines Agency. Clinical Trials Regulation (EU) No 536/2014. https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/clinical-trials-regulation
About the Author
PD Dr. Ghazaleh Gouya-Lechner is the founder of Gouya Insights and a cardiologist with over 20 years of hands-on clinical practice. She has worked across clinical development, regulatory strategy, and pharmacovigilance for both pharmaceutical and medical device companies. In 2017 she founded Gouya Insights, a CRO supporting early-stage biotech and medtech companies through clinical trials and drug development.
Nora holds degrees in law from Janus Pannonius University and in pharmacy from Semmelweis University, combining legal and scientific expertise. She is a certified Data Protection Officer with hands-on experience supporting GDPR compliance and contractual safeguards for biotech and pharma clients. With over 20 years in clinical research, she brings a pragmatic, risk-aware approach to data protection in global trials
