Following last year’s success, Daniela DragoCarlos Langezaal and Fortunato Fred Senatore were back to conduct another interactive session. Attendees gathered into groups to discuss and propose regulatory strategies based on a number of scenarios, three of which will be described here.


  • Carlos Langezaal, Senior Director, Global Regulatory Affairs, Bristol Myers Squibb, USA
  • Daniela Drago, Expert Consultant, NDA Partners, USA
  • Fortunato Fred Senatore, Medical Officer and Clinical Team Leader at the Division of Cardiology and Nephrology Office of New Drugs, CDER, FDA, USA


In this scenario, the company had filed a Phase 1 first in-human CTA with a recombinantly expressed, humanised super-agonist monoclonal antibody. The study design involved the dosing of six healthy male volunteers with an investigational medicinal product and two dosed with placebo. The audience was asked to choose one of two options:

A: Volunteers would be dosed with a 10-minute spacing between volunteers; or

B: volunteers would be dosed one day apart.

The majority of the audience chose option B – which was confirmed as the correct answer. Unfortunately, in real life it was option A that had taken place, and subjects started experiencing cytokine storms one hour after dosing.

5M4A5680_TOPRA Symposium 2022_Day 3_20221019

Carlos Langezaal and Daniela Drago


This scenario involved a company which had a compound in early development. Non clinical testing showed a potential signal of QT prolongation. The audience was tasked to make a recommendation for the clinical development plan. The options were either to:

A: Conduct a TQT study after proof of concept, or

B: determine the validity of the signal in Phase 1.

In this case, after a short deliberation, Option B was confirmed as the correct answer as the QT prolongation signal should be validated in a Phase 1 study in line with current ICH guidance (ICH E14).


The final scenario involved a situation where a drug was already approved in the EU as an adjunct therapy in the treatment of seizures. The sponsor had evaluated the drug in a well designed, Phase 3 non-inferiority trial as mono therapy vs the gold standard. The adjudicated outcome demonstrated that the lower bound of 95% confidence interval crossed the non inferiority margin, on which the sponsor had reached agreement with the rapporteur.

The sponsor considered that it missed the criteria based on a higher than expected and historical treatment response of the gold standard. The audience was tasked to decide whether the applicant should file for an extension of the indication to include monotherapy. The majority of the audience, in this case, was in favour of submitting an extension variation.

This was correct, since a dose for monotherapy was established and while the lower bound of 95% confidence interval was crossed, this was only minimal, and the high response rate demonstrated that the drug was indeed effective. As the safety profile was acceptable and it provided an alternative option to patients, the new indication was approved in the EU. The same, however, cannot be said for the US