Fatal Clinical Trial Helps Spur Revision of European Guidance

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By John T. Aquino

July 21 — The European Medicines Agency (EMA) July 21 released proposed changes to its guidance on first-in-human (FIH) clinical trials in the wake of a trial-related death in January.

The changes are outlined in a concept paper that the agency released for public comments, which are due by Sept. 30.

The review of the guidance was partly prompted by the death of one participant and the hospitalization of five others in a phase I FIH clinical trial in Rennes, France, in January (10 LSLR 02, 1/22/16).

Ironically, the incident parallels the near-fatal injuries in a London-based clinical trial in 2006 that spurred the EMA to issue the guidance in 2007.

The EMA noted in the concept paper that the revision also was prompted by changes since 2007 in the integration of non-clinical data that are available before an FIH trial and the pharmacokinetic (PK, what happens to the drug in the human system), pharmacodynamic (PD, the relationship between the drug and the patient's response) and human safety data emerging during the trial.

Broader Scope of Studies

Mark Barnes of Ropes & Gray LLP, Boston, told Bloomberg BNA in a July 21 e-mail, “Additional attention to how to design first-in-human trials safely and with optimal attention to PK and PD data and data from animal models, is welcome, particularly in light of the dawn of the use of gene therapy agents as disease treatments.”

Barnes added that when the guidance is revised, “[W]e can expect not only additional regulatory attention to early phase studies but also additional attention to late phase, post-approval studies, all to gather more, better and more timely information about safety issues.”

Areas of Consideration

The concept paper outlines discussion points for consideration in revising the 2007 guidance:

  •  extending the guidance to early phase clinical trials, including single-study or integrated protocol designs;
  •  extending the non-clinical aspects of the guidance to address points such as better integration of PK and PD data evaluated using current PK/PD or physiologically-based pharmacokinetic modeling and data from the toxicology testing into an overall risk assessment for FIH and early clinical trial administration, and translation of non-clinical data to human use by extrapolation and verification of assumptions made; and
  •  extending the clinical part of the guidance to address points such as integrated clinical designs and study endpoints including decision-making aspects, extending the guidance's scope beyond single ascending dose FIH trials to incorporate other early phase trials and designs, clarification on the choice of trial subjects and overall dose/exposure range and scheme, including stopping rules.

The concept paper was prepared by an EU-wide expert group that includes experts from national authorities that authorize clinical trials in the EU, and it was adopted by the EMA's Committee for Medicinal Products for Human Use.

U.S. FDA Monitoring Incident

The drug being tested in the January incident in Rennes was for mood disorders and was developed by Portuguese-based pharmaceutical company Bial, with the test conducted by Biotrial, a clinical research organization based in Rennes.

The EMA document was guided by the findings from two in-depth investigations into the Rennes trial, one carried out by the Temporary Specialist Scientific Committee set up by the French medicines agency ANSM, and the other by the Inspection générale des affaires sociales, the French inspector general for social affairs.

The U.S. Food and Drug Administration commented that catastrophic adverse events in phase I studies conducted in the U.S. are extremely rare due to the safety data the agency requires for submitting an investigational new drug application (10 LSLR 03, 2/5/16).

It added that it is collecting and reviewing safety data in connection with the Rennes trial and working with the EMA and ANSM.

Parallels 2006 Incident, Aftermath

The events in Rennes that helped spur the revision of the guidance parallel those that prompted its creation in 2007.

In April 2006, in the London-based FIH trial of TGN412, a monoclonal antibody developed as a medicine to treat leukemia and other autoimmune diseases, all six volunteers suffered multiple organ failure, requiring intensive therapy.

A working group was established that produced a report , which resulted in a revision of the Association of British Pharmaceutical Industries' guidance for phase I clinical trials and the current EMA guidance, “Guidelines on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products,” in 2007.

Comments on the concept paper's proposals should be sent by Sept. 30 to FIH-rev@ema.europa.eu.

To contact the reporter on this story: John T. Aquino in Washington at jaquino@bna.com

To contact the editor responsible for this story: Randy Kubetin at rkubetin@bna.com

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