EMA to Revise Phase I Trial Guidance, Draft Expected in Late 2016

Regulatory News | 22 July 2016 | By Michael Mezher

The European Medicines Agency (EMA) on Thursday announced plans to update its guidelines on first-in-human (FIH) clinical trials following a trial incident in France last January that left one patient dead and five others hospitalized.

The proposed revisions come after EMA launched a review of FIH trials in late May. At the time, EMA said its review would be based largely on the findings of two investigations into the fatal trial, which was conducted by French contract research organization Biotrial, on behalf of Portuguese pharmaceutical company Bial.

With the announcement, EMA also released a draft concept paper for public consultation through 30 September 2016. EMA says the concept paper will "form the basis" for a draft revision to its current guidelines, which it expects to release in late 2016.

Concept Paper and Proposed Revisions

The proposed changes are laid out in the draft concept paper, which argues for revising the current guidelines to more closely reflect how FIH trials are currently conducted.

According to EMA, FIH trials have changed considerably since its guidance was published in 2007, and often involve more factors, such as multiple ascending doses (MAD), food interaction and multiple subject groups.

"The current guideline mainly focuses on non-clinical aspects of drug development and the use of animal data and reflects the practice at the time it was developed which focused on a single ascending dose (SAD) design for first-in-human trials," EMA writes. "Since then, integration of the non-clinical data available before FIH administrations and the pharmacokinetic (PK), pharmacodynamic (PD) and human safety data emerging during a trial has also evolved."

As such, EMA says plans to extend its FIH trial guidance to cover:

• Early phase clinical trial design (including single study or integrated protocol designs);
• Non-clinical aspects, such as:
  • integration of non-clinical pharmacology and toxicology data;
  • translation of non-clinical data to human use by extrapolation and verification;
  • the role of non-clinical data for the estimated therapeutic dose, maximum dose level, dose escalation steps, dose frequency and intervals; definition of stopping criteria; and identification of safety aspects to monitor;
• Clinical aspects, including:
  • integrated clinical trial designs and study endpoints including decision-making aspects;
  • clarification on the choice of trial subjects
  • rolling review of emerging human data during the study

  EMA Press Release

  Draft Concept Paper