When completed phase I submissions still raise questions
A phase I clinical study can be well prepared and still trigger questions from the FAMHP. That may be frustrating, especially when the protocol is complete, the investigator’s brochure (IB) has been reviewed and the clinical rationale is known inside the sponsor team. By the time a request for information arrives, timelines are tight, internal teams are stretched and every clarification adds pressure.
This is often where problems start. What is obvious to the people who have worked with the compound for years is not always obvious to the regulator reading the submission for the first time. A toxicology finding that feels explainable internally may look underdeveloped in the IB. A dose-escalation plan that makes sense to the clinical team may not fully clarify how PK calculations and modeling outputs informed these decisions. A stopping rule may be present but still leave room for interpretation when the study is actually running. In early-phase research, that gap matters, because regulators expect to see how uncertainty is handled.
The regulator is looking for the line of thought
For first-in-human and other phase I clinical trial submissions, the FAMHP reviews whether the required sections are present and whether the logic between them holds.
- Does the non-clinical package support the proposed starting dose?
- Do the exposure limits connect back to the right toxicology and pharmacology data?
- Does the PK sampling schedule match the expected profile of the investigational medicinal product?
- Are the stopping rules clear enough for real decisions, not just for the protocol text?
These are practical questions and they often sit in the space between disciplines. The toxicologist may focus on whether a finding is relevant. The clinician may focus on how to monitor it. The regulatory team may focus on whether the language meets EU CTR expectations. The study team may focus on whether the design works at the site. The submission needs to bring those views together. If it does not, the regulator may ask for the missing connection.
What we saw in Belgian phase I submissions
Our phase I consultants reviewed Part 1 RFIs received from the FAMHP for phase I clinical trial applications conducted at our clinical pharmacology unit in Belgium since the implementation of the EU Clinical Trials Regulation.
One theme stood out: many RFIs were not about big scientific disagreements. They were about points that could have been clearer before submission. Protocol questions often came back to safety, dosing strategy, regulatory alignment, eligibility criteria and pharmacokinetics. In the investigator’s brochure, questions often related to how toxicology, PK or pharmacology findings were interpreted and linked to the proposed clinical study.
This is useful for sponsors, because it means there is room to act before filing. The test is simple: would an external reviewer understand why this clinical choice is reasonable, based only on what is in the submission?
For a deeper breakdown of the RFI themes and practical considerations behind them, download our full paper: Regulatory insights from phase 1 clinical trials: a comprehensive analysis of Part 1 RFI trends and best practices.
When internal logic stays internal
Small and emerging biotech companies often carry deep knowledge of their compound, but less experience with the regulatory submission process. That combination creates a specific risk. The team knows the answer, but the document does not always spell it out.
For larger pharma companies, the challenge is different. The knowledge is there, but it may sit across several teams, documents and versions. The final submission can become technically complete, yet still feel fragmented to a reviewer.
Both situations can lead to avoidable RFIs.
Where SGS can help before the question is asked
Many CROs support document preparation, submission logistics and study execution. That remains essential. But, especially for first-in-human and early pharmacology studies, sponsors need someone to challenge the scientific logic before the regulator does.
Our phase I consultancy goes beyond coordinating the submission or setting up the study at our clinical pharmacology unit. Before filing, we help sponsors pressure-test whether the protocol, investigator’s brochure and supporting data tell one coherent story. We look at the submission as a regulator may read it: asking not only whether the required information is present, but whether the rationale behind key decisions is clear. That means challenging points such as dose justification, exposure thresholds, dose escalation process, safety monitoring, stopping rules, eligibility criteria and the clinical relevance of non-clinical findings.
By combining our regulatory review experience, clinical pharmacology expertise, and phase I operational insights, we help identify where internal assumptions have not yet been made clear enough for external review. By applying lessons from real FAMHP RFI trends, we help sponsors strengthen phase I clinical trials before submission. This helps reduce avoidable regulatory questions, supports smoother study authorization, limits the risk of review delays, conditional approvals or non-approval, and give teams greater confidence as they move into execution.
Read the full white paper
Our full paper gives a more detailed view of recurring FAMHP RFI themes in Belgian phase I submissions. It covers protocol-related questions, investigator’s brochure findings and practical observations on dose strategy, safety oversight, pharmacokinetics, toxicology interpretation and regulatory completeness.
Download the paper to see where RFIs most often arise and what sponsors can do before submitting a phase I clinical trial application in Belgium.
