Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Quo vadis phase I trials in the EU?

Dr. Andreas Lippert (Abschlußjahr: 2017)

Summary
Language: English
Conducting clinical trials is probably as old as mankind itself. However, from the early stage e.g. in biblical times to James Lind’s first controlled trial to investigate the treatment of scurvy in 1747 until the present age, the scope and design of clinical trials has tremendously altered. Nowadays, novel designs such as the umbrella or basket will be contemplated. Any progress may also be associated with setbacks, especially in phase I/FIH trials when participants get SAE or die, as seen in the Bial disaster in 2016.
FIH trials are aporetic: they can be the beginning and end of the clinical development, which probably gives them a whiff of mystique. They not only mark the transition between the non-clinical and clinical phase, but also are the basis of reaching the sky as a blockbuster in the best case or a flop with non-approval in the worst case.
To avoid disasters, the study design needs to be carefully planned. In the aftermath of the TeGenero disaster in 2006, EMA issued the “Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products” (EMEA/CHMP/SWP/28367/07) in 2007. Lessons learnt from the Bial case and the scientific progress e.g. integrated protocols made the update of the current guideline inevitable. Both is now incorporated in the newly released “Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products” (EMEA/CHMP/SWP/28367/07 Rev. 1) being effective as off 1st February 2018.
With the new guideline, now totalling 22 pages (vs. 12 pages in the previous guideline), strongly focussing on the clinical section (10 vs. 3 pages), the quality and non-clinical ones nearly remain the same. The clinical section is divided into two parts: “Dosing selection for FIH and early clinical trials” and “Planning and conduct of FIH and early clinical trials”.
The first part was relocated from the non-clinical section to highlight its importance – selecting the starting dose in clinical use. This careful assessment is crucial for the safety of participants also for dose escalation using either SAD or MAD approach. All data derived from non-clinical trials needs to be taken into account for first dosing, and additionally all clinical data from the first participant resp. cohort on a real-time basis to dose further participants resp. cohorts. This also includes a check against predicted models and simulations.
The second part contains the newly incorporated integrated protocols with the option to combine SAD, MAD, DDI, and food effect part in one protocol. Overlaps between these parts may occur and need to be justified. This design is a huge progress but needs to be interpreted by resp. accustomed to HA/EC while the industry is advised to give more justification and transparency. The practical implementation of the integrated protocols is the key for the attractiveness of the EU for phase I/FIH trials in the next years. Based on the number of phase I trials between 2007 and 2016, the US has had a clear advantage so far.
All in all, the new guideline will make the EU a safer place for phase I clinical trials, in the future.
When innovation meets regulation, it is very important that a right balance will be found to keep the EU attractive as location for phase I trials and also to represent a counterbalance to the US. With France probably taking a more conservative approach as a consequence of the Bial case, and in the aftermath of Brexit, it will be up to Germany (BfArM and PEI) to play a key role pushing forward EU’s innovation resp. phase I trials.
Pages: 56