Questions About Protocol After Death in French Trial

Pascale Solère

January 29, 2016

Questions continue to swirl around the recent death of a healthy volunteer taking part in a phase 1 trial in Rennes, France.

Bial, the Portuguese pharmaceutical company developing Bia 10-2474, and Biotrial, the medical research center approved by the French Health Ministry to carry out the clinical trial, are now under fire, and an investigation is under way.

New information released January 27 by L'Agence nationale de sécurité du médicament et des produits de santé (ANSM), France's national drug safety agency, shows that all patients in the high-dose group began taking that dose — 50 mg/day — at the same time on Wednesday, January 6.

This is against European Medicines Agency recommendations from the Committee for Medicinal Products for Human Use governing phase 1 trials, established in 2007, that suggest leaving a sufficient gap between participants before incremental increases in dosing to mitigate risk in first-in-human trials.

French Health Minister Marisol Touraine, left, and Professor Gilles Edan, the chief neuroscientist at Rennes Hospital, address the media during a press conference held in Rennes, western France, January 15. Source: David Vincent/AP

The recommendations came out of analysis of causes and risk factors of another accident in a phase 1 trial in the United Kingdom in 2006. This analysis showed that increasing the observation time before treating the next study patient could significantly reduce the risk for a catastrophic accident or series of accidents.

Nearly 10 years after the accident in the United Kingdom, the events in Rennes raise the question of whether simple compliance with these best practices could have prevented or mitigated the outcome. Of the patients hospitalized, at least four have demonstrable brain injury on imaging.

On their website, the ANSM has released a chronology of the preclinical and early clinical testing of the drug used in this trial. It outlines findings from four previous cohorts of eight patients, each of whom took multiple ascending doses ranging from 2.5 to 20 mg. No adverse events were reported to ANSM for any of these previous trials, the document notes.

On Wednesday, January 6, the eight men taking part in the fifth cohort took their first 50-mg dose of the investigational drug, 19 days after the end of cohort 4. On Sunday, January 10, the fifth day of taking the 50-mg dose, the first patient began to show neurologic symptoms that were thought at first to be a stroke. He was hospitalized that evening.

On Monday, January 11, the seven remaining volunteers received their sixth 50-mg dose in the morning. At the hospital, however, the hospitalized volunteer deteriorated and fell into a coma. At that point, Bial and Biotrial decided to discontinue the trial, the ANSM document said.

Between Wednesday and the following Friday, however, five of the remaining seven patients treated with the investigational agent were hospitalized; the two not hospitalized were receiving a placebo, early reports noted. Biotrial informed ANSM of these serious adverse events on Thursday, January 14, the ANSM statement notes.

Investigation Underway

According to the newspaper Le Parisien, questions are being raised about the pharmaceutical manufacturer Bial.

This "flagship of the Portuguese pharmaceutical industry," the newspaper notes, was founded in 1924, and now has 950 staff worldwide. Its drugs are on sale in 58 countries, and in 2014 it achieved sales of €200M, according to data from Reuters.

After news of these serious new developments broke, the Portuguese Health Minister, Adalberto Campos Fernandes, personally defended the company against reports in the media.

Yet, the Parisien further reports, "a corruption investigation is under way. Bial is suspected of having bribed at least 500 doctors, paying them to prescribe its drugs. Last summer, search warrants were issued for its headquarters and for several other sites. About fifteen staff members and a health consulting firm would seem to be involved."

Of the three organizations — Bial, Biotrial, and the ANSM — Bial has the greatest access to the data related to the trial.

The ongoing investigation will address four main questions:

  1. Did Bial provide the French national drug safety agency with all the preclinical data to which it had access?

  2. How did Bial and Biotrial jointly manage the monitoring and analysis of this phase 1 trial, as it progressed, in particular the choice of doses, dose escalation and the intervals between the patients, tolerance levels, and the various subtests of this phase 1 trial, which in fact actually comprised four studies?

  3. Did Bial and Biotrial inform the Rennes University Hospital — to which the victims were admitted — have all the relevant information needed to treat them?

  4. Why did Bial and/or Biotrial wait until the evening of Thursday, January 14, before notifying the Health Ministry, even though the man admitted to the hospital in late afternoon of Sunday 10 was already brain-dead and four other patients had been experiencing severe and potentially irreversible neurologic problems since Monday, January 11?

Biotrial, created in 1989 by its current CEO, Jean-Marc Gandon, a pharmacist, is the largest of France's four laboratories specializing in phase 1 trials. It has 55,000 volunteers on its books and conducts 20 to 25 trials simultaneously. Its turnover is €35M, of which 90% is from exports, according to the Ouest-France newspaper. A large majority of its customers, such as Bial, are from outside France.

However, even for Biotrial, winning the contract for a protocol such as this is not routine. The 1BIAL35 trial was to have included at least 128 individuals. The cost per subject in this phase 1 trial, excluding the participant fee (by far the least expensive aspect), is high. It includes numerous clinical and biological checks, the doses of the drugs and its metabolites, and the calculations and pharmacokinetic and pharmacologic analyses/interpretations required, in addition to the operating budget of the phase 1 trial center itself.

The budget is significant, and the contract is attractive, particularly because the company is expanding on the other side of the Atlantic, especially in the United States.

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