Com­bined stud­ies: CTAG and MDCG pub­lish spon­sors’ guide on safe­ty reporting

Spon­sors of stud­ies that fall under more than one EU reg­u­la­tion have a new prac­ti­cal ref­er­ence. On 11 Sep­tem­ber 2026, the Euro­pean Commission’s Direc­torate-Gen­er­al for Health and Food Safe­ty (DG SANTE) pub­lished the COMBINE Project 2 spon­sors’ guide on safe­ty report­ing in com­bined stud­ies. The guide is endorsed by the Clin­i­cal Tri­als Coor­di­na­tion and Advi­so­ry Group (CTAG) and the Med­ical Device Coor­di­na­tion Group (MDCG). It is not legal­ly bind­ing and does not rep­re­sent the Commission’s offi­cial posi­tion. 

The prob­lem

“Com­bined stud­ies” fall under two or more of these regulations:

• the Clin­i­cal Tri­als Reg­u­la­tion (EU) No 536/2014 (CTR)
• the Med­ical Devices Reg­u­la­tion (EU) 2017/745 (MDR)
• the In Vit­ro Diag­nos­tic Med­ical Devices Reg­u­la­tion (EU) 2017/746 (IVDR)

Each reg­u­la­tion sets its own def­i­n­i­tions, doc­u­men­ta­tion, time­lines and process­es for seri­ous adverse events (SAEs) and device defi­cien­cies (DDs). Until a ded­i­cat­ed legal frame­work exists, spon­sors must rec­on­cile all of them in parallel.

What the guide does

It builds on the ear­li­er COMBINE analy­sis report and:

• sets a com­mon def­i­n­i­tion of seri­ous­ness that works across all three regulations
• clar­i­fies what inves­ti­ga­tors and spon­sors each have to do
• rec­om­mends a sin­gle pro­to­col that inte­grates the Clin­i­cal Inves­ti­ga­tion Plan (CIP) or Clin­i­cal Per­for­mance Study Plan (CPSP)
• maps com­mu­ni­ca­tion flows between spon­sors in mul­ti-spon­sor studies
• lists nation­al report­ing routes in Annex­es 1 and 2

Open issues

The guide states that dou­ble report­ing remains unre­solved and requires leg­isla­tive har­mon­i­sa­tion. The MDR and IVDR also do not pro­vide for urgent safe­ty mea­sures out­side a sub­stan­tial mod­i­fi­ca­tion. Report­ing to ethics com­mit­tees is out of scope.

Source: CTAG, MDCG

Accom­pa­ny­ing this sub­ject we rec­om­mend the fol­low­ing con­tent on our website

• Upcom­ing UDI label­ing require­ments for Med­ical Devices
• EU guide­lines for jus­ti­fy­ing phtha­lates in med­ical devices updated