Lax monitoring by Pfizer of a paediatric clinical trial involving its atypical antipsychotic Geodon (ziprasidone) meant that “widespread overdosing” of study participants at multiple sites “was neither detected nor corrected in a timely manner”, the US Food and Drug Administration says.

The FDA has published a warning letter it sent earlier this month to Martin Mackay, Pfizer’s senior vice president, global research and development, citing “significant violations” discovered during inspections of a number of clinical investigators conducting the trial.

The agency did not name the trial nor the drug under investigation. But Pfizer has confirmed that it involved Geodon for the as yet unapproved indication of paediatric bipolar disorder.

The warning letter relates to an FDA inspection conducted between 4 May and 3 June 2009, although the problems identified date back to a previous inspection in the spring/summer of 2005. According to the letter, Pfizer became aware that patients were being overdosed in July 2006, but through a data management unit rather than its study monitors.

The company subsequently identified sites at which dosing errors had occurred and took steps to remedy the situation, including suspending enrolment at certain sites, retraining all of the trial sites and study monitors on correct dosing procedures, and stepping up monitoring of drug accountability to 100% for all sites.

However, an internal Pfizer document from October 2007 referred to overdosing of another six paediatric subjects in the trial, occurring in June, July and August 2007 – “several months after Pfizer retrained study monitors on correct dosing procedures”, the FDA’s warning letter notes.

It also highlights other deficiencies, such as failing to ensure that the trial was conducted in accordance with the general investigation plan and protocols in Pfizer’s Investigational New Drug application; and failing to keep participating investigators informed about new observations on Geodon discovered or reported by Pfizer, “particularly with respect to adverse effects and safe use”.

Paediatric application

While Pfizer says it is addressing the issues raised by the FDA, the warning letter is unlikely to help the company’s efforts to secure a paediatric indication for Geodon, currently approved in the US for the treatment of schizophrenia and acute manic or mixed episodes of bipolar disorder.

In June 2009, the FDA’s Psychopharmacologic Drugs Advisory Committee concluded that Geodon and two other atypical antipsychotics – AstraZeneca’s Seroquel (quetiapine) and Eli Lilly’s Zyprexa (olanzapine) – were effective and “reasonably safe” for use in children and adolescents.

However, there were nine abstentions on the safety vote (which went 8 to 1 in favour) for Geodon in 10 to 17 year-olds with bipolar disorder, and concerns have been raised about the drug’s effect on heart rate in particular.

Geodon is already used off-label by US physicians in the paediatric population. Last September it was one of the drugs named in Pfizer’s US$2.3 billion settlement with the US Department of Justice over illegal promotion of off-label uses for the company's products.

Ensuring compliance

In a statement, Pfizer said it "continually enhances our systems for managing clinical trials" to ensure compliance with good clinical practice and regulatory agencies worldwide.

The company "recognises the seriousness of the issues cited by the FDA and is committed to fully addressing FDA’s concerns", it added, noting that many of the items cited by the FDA "were first uncovered and reported to the FDA by Pfizer as far back as four years ago as part of our ongoing clinical trial monitoring and quality assurance processes".

Since that time, the company has instituted a number of new measures to improve the monitoring and execution of clinical trials, including oversight of clinical investigators, it pointed out.

"Pfizer has communicated with the FDA about our conduct of clinical trials and, over the next two weeks, will provide an outline of new and existing processes for preventing similar issues with Pfizer clinical trials in the future," it commented.