The Day 120 List of Questions and the clock stop are integral procedural steps in the scientific assessment of a marketing authorisation application within the centralised procedure. Following the initial assessment phase, the committee consolidates the outstanding issues into a list of questions; the active assessment clock is stopped to allow the applicant to prepare the responses. This constitutes an intended part of the procedure, not a statement of deficiencies or a preliminary decision against approval.
Integration into the Centralised Assessment Procedure
The active assessment period for a regular centralised marketing authorisation application is generally up to 210 days. Rapporteurs and co-rapporteurs review the dossier, submit their assessment reports, and incorporate comments from other committee members. After this initial scientific phase, the committee determines what information is still required to conclusively assess quality, safety, efficacy, and the benefit-risk balance.
The Day 120 List of Questions summarises these points in a structured manner. It may concern aspects of the clinical development program, statistical analysis, product quality, non-clinical data, the risk management plan, or product information. This provides the applicant with a binding framework for subsequent submissions. A precise and complete response is essential because it informs the subsequent assessment by the rapporteur teams and scientific committees.
Clock Stop and Resumption of Assessment
With the List of Questions, the active assessment clock is stopped. During this clock stop, the applicant prepares the responses and the necessary revised documentation. This time does not count towards the active 210 days. The clock stop therefore does not create a legally unregulated deferral, but rather separates the regulatory assessment time from the time the applicant requires for substantial supplementary submissions. The scope and quality of the responses influence how quickly the assessment can be resumed.
Upon receipt of the responses, rapporteurs and co-rapporteurs assess the supplementary information. Further outstanding issues may be addressed in a Day 180 list. Depending on the circumstances, the committee may also request an oral explanation from the applicant. The CHMP adopts its opinion no later than Day 210 of the active assessment period. The procedure thus involves a recurring rhythm of assessment, questions, response, re-assessment, and committee decision.
Distinction from Deficiency Letters and Accelerated Assessment
The Day 120 List of Questions is not a statement of deficiencies in the sense of a final rejection. It documents the regular information requirements after the initial assessment of a comprehensive marketing authorisation dossier. Even a well-prepared application can raise questions, as the scientific assessment must examine the consistency of all evidence and its implications for the proposed use. An opinion on the benefit-risk balance is only issued after the assessment is complete.
The process is also to be distinguished from accelerated assessment. Accelerated assessment can shorten the active assessment period if approved by the CHMP. However, lists of questions and clock stops remain elements of the scientific interaction within the assessment procedure. They are not superseded by an application following a shortened timeline. It remains crucial that additional information is submitted in a scientifically robust and regulatorily consistent manner.
The responses must adhere to the specific wording of the questions and transparently indicate changes in the dossier. A response letter without the underlying data, analyses, or revised modules is generally insufficient. The project team should therefore determine, even before submission, how potential follow-up questions regarding key endpoints, safety data, manufacturing information, and product information will be processed, reviewed, and formally submitted. This preparation can significantly improve the quality of the dialogue during the clock stop.
Relevance for clinical trials
For clinical trials, the greatest operational pressure often arises not from the designation of a day, but from the preparation of scientifically robust responses. Databases, analysis programs, study reports, safety evaluations, and documentation of protocol deviations must be controllably accessible. If re-analyses, additional subgroup assessments, or updated safety data are required, clear responsibilities and a documented quality process are necessary. Incomplete or contradictory responses can trigger further questions and prolong the overall duration of the procedure.
Full-service CROs like Mediconomics support the preparation and coordination of response packages through project management, data management, biostatistics, pharmacovigilance, medical writing, and regulatory affairs. This includes tracking each question, defining data sources and responsible parties, ensuring scientific consistency across modules, and timely preparation of clinical summaries, tables, analyses, and justifiable rationales.
Frequently Asked Questions (FAQ)
Is Day 120 a calendar day after submission?
It refers to a day of the active assessment period. Times during a clock stop for applicant responses are not counted.
What happens after the responses are submitted?
The rapporteur teams assess the supplementary information; subsequently, further outstanding issues can be addressed, and an oral explanation may be requested.
Can a List of Questions also concern quality or safety data?
Yes. The list can concern all dossier sections relevant for the scientific benefit-risk assessment.
Regulatory References
- Regulation (EC) No 726/2004, Article 6 – forms the framework for the examination of centralised marketing authorisation applications.
- Regulation (EC) No 726/2004, Article 8 – concerns the CHMP opinion on the application.
- Regulation (EC) No 726/2004, Article 14(9) – regulates the accelerated assessment to be distinguished.
- EMA procedural guidance on the evaluation of medicinal products – describes assessment phases, lists of questions, and clock stops.