What does the new COMBINE guidance cover?

The document was produced as part of Project 2 of the COMBINE programme. It covers combined studies, i.e. those conducted simultaneously under the CTR (536/2014) and the MDR or IVDR.

It does not replace the MDCG 2020-10 and MDCG 2024-4 guidance. It differs from them on only one point: reporting deadlines. It is also not legally binding.

When is an event considered serious, given that each regulation defines it differently?

The guide proposes a common denominator. In a combined study, a serious adverse event (SAE) is defined as an event that leads or could have led to:

  • death,
  • a life-threatening condition,
  • hospitalisation or its prolongation,
  • persistent or significant disability or incapacity,
  • a congenital anomaly or birth defect.

Added to these are criteria specific to the MDR and IVDR. The first is chronic disease, which is particularly relevant in the case of implants. The next is foetal distress, foetal death or a congenital physical or mental impairment or birth defect, as well as a medical or surgical intervention to prevent permanent impairment of a body structure or function.

The last is a patient management decision resulting in death or an imminent life-threatening situation.

The authors acknowledge that the device-related criteria are not legally binding for the medicinal product part of the study. However, they assume that a medical assessment in accordance with ICH E2A will lead the investigator to the same conclusions anyway.

What does this mean for the investigational site?

For the investigational site, this entails three obligations:

  • reporting an SAE to the sponsor immediately, within 24 hours at the latest;
  • assessing causality separately for the medicinal product (IMP), the investigational medical device or IVD (IMD/IIVD), the comparator and the investigational/study procedure;
  • reporting a device deficiency (DD) even if no harm has occurred but could have occurred.

The sponsor may not alter the investigator’s assessment. If they disagree with it, they must set out their position in a comment on the report.

What are the deadlines following harmonisation?

  • 24 hours: the investigator reports SAEs and DDs to the sponsor.
  • 7 calendar days: the sponsor reports to all national competent authorities (NCAs) responsible under the MDR/IVDR any SAEs that may be related to the device, comparator or procedure, as well as reportable DDs. MDCG 2020-10 stipulated 2 days for events indicating an imminent risk of death, serious injury or serious illness that require prompt remedial action. The new deadline has been aligned with that for fatal or life-threatening SUSARs.
  • 15 calendar days: the sponsor reports events affecting the benefit-risk balance via CTIS as an unexpected event.
  • 60 days from the data lock point (DLP): the sponsor submits an annual safety report (ASR). This may include a line listing of IMD/IIVD-related SAEs with IMDRF coding.

Dual reporting

The same case may still be reported to both EudraVigilance and the competent authority for medical devices.

The sponsor may delegate these responsibilities to an external entity. Whilst this simplifies the logistics, it does not resolve the issue, and the authors explicitly state that legislative changes are required.

The EUDAMED module on clinical investigations and performance studies is not yet operational; therefore, in Poland, reports from clinical investigations of medical devices are submitted to the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (URPL) at incydenty@urpl.gov.pl.

The annexes to the guidance document show that national requirements can be more extensive. Germany, for example, expects quarterly periodic reports.

What should be checked in the documentation right now?

  1. Do the protocol and the CIP/CPSP form a single document (the recommended model) or are they fully consistent with one another?
  2. If there are several sponsors, is there a communication plan specifying who receives which SAEs?
  3. Does the SAE form require a causality assessment to be carried out for each product separately?
  4. Do the SOPs take into account the new 7-day deadline?
  5. Are you familiar with the national requirements in every country where you are conducting the trial?

Read more

COMBINE programme Project 2: Safety reporting in combined studies – Sponsors’ guide