A secret Nigerian government report concluded that the drug manufacturer Pfizer undertook an “illegal trial of an unregistered drug” when the company enrolled nearly 100 Nigerian children with meningitis in a trial testing its antibiotic trovafloxacin (Trovan) against ceftriaxone during a 1996 meningitis epidemic.
Families of the children, their attorneys, and the media have been seeking the results of the report for five years without success until the report was leaked last week to the Washington Post (7 May, sect A: 1) by a source who asked to remain anonymous because of “personal safety” concerns.
The Washington Post article said that “aspects of the affair remain mysterious, such as why the report remains confidential.” The head of the investigative panel behind the report, Abdulsalami Nasidi, a virologist and senior Nigerian health official, told the Washington Post he did not know why the report was never released. The panel was set up in 2001 to determine whether the trial was conducted legally (BMJ 2001;322:194).
A class action suit filed on behalf of the children’s families in a federal court in New York alleges that Pfizer did not inform families that trovafloxacin was an experimental treatment and that it failed to obtain informed consent (BMJ 2001;323:592). The lawsuit was dismissed last summer after a judge decided that the US court did not have jurisdiction to hear it, a decision the plaintiffs are appealing.
Court documents filed by the plaintiffs said that “most tragically, Pfizer purposely … low-dosed the control drug” and did not tell families that free, approved treatment was available at the same hospital from Médecins Sans Frontières.
The plaintiffs cited, in turn, a whistleblower lawsuit filed by Juan Walterspiel, a former associate medical director of Pfizer’s central research division, who had responsibility for international protocol development. Dr Walterspiel claimed that Pfizer fired him after he warned the company—before and after the study was conducted—that the study methods employed by Pfizer in the Nigerian trial were “improper and unsafe.” Dr Walterspiel’s action has since been settled.
Pfizer issued a news release on 7 May after being shown the Nigerian government report. It said: “Trovan unquestionably saved lives, and Pfizer strongly disagrees with any suggestion that the company conducted its study in an unethical manner.”
Pfizer stated that it “conducted this trial with the full knowledge of the Nigerian government and in a responsible way consistent with Nigerian law.” The news release also stated that local nurses had explained the experiment to parents of children being treated and had obtained their verbal consent. “Trovan achieved the highest survival rate (94.4%) of any treatment available at the Kano Infectious Disease Hospital, including ceftriaxone (93.8%),” the company added. “For patients receiving treatment at the hospital who were not in the Pfizer program, the survival rate was 89.9%.”
Elaine Kusel, attorney for 30 plaintiff families, said Pfizer’s claim that trovafloxacin outperformed ceftriaxone and community treatment was meaningless, because the children in the trial were not properly randomised. “They [the researchers] simply picked kids out of a line of families waiting for care outside the hospital.”
Critics who question the study’s methodology and data have been stymied by Pfizer’s failure to publish the study. Pfizer acknowledges that the only occasion on which it presented the results was at a meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy in New Orleans in 1996.
In response to queries by the BMJ , Pfizer denied the allegations made by the plaintiffs in the lawsuit. Although the Pfizer spokesperson Bryant Haskins admitted, in an email message, that the daily doses of ceftriaxone given to the children in the study had been reduced by two thirds, from 100 mg per kg to 33 mg per kg, he claimed they still “significantly exceeded the recommendations of the WHO.”
“There is no FDA [the US Food and Drug Administration] approved dose for ceftriaxone for treating epidemic meningococcal meningitis,” he said, adding that the doses used by Pfizer far exceeded the dose needed to kill meningococcus in cerebrospinal fluid. As for how children had come to be recruited to the study, Mr Haskins said that triage nurses sent children suspected of having meningitis to a building where their parents were offered the option of participating in the study.
“If any parent preferred that his or her child be treated by [Médecins Sans Frontières],” he added, “the child was immediately taken to the appropriate building.”
As for why Pfizer didn’t win FDA approval to use trovafloxacin to treat meningitis in light of its claimed superiority, Mr Haskins said, “Pfizer won approval from the FDA to use Trovan for more than a dozen indications.
“After discussions with the agency, the company withdrew its claim for the treatment of epidemic meningococcal meningitis primarily for regulatory reasons; for example, a requirement to have brain stem auditory evoked response assessments at post-study follow up visits was impossible in the primitive setting in which the trial was conducted.”
Trovafloxacin was withdrawn from European markets after reports of fatal liver disease and since 1999 has been recommended only for emergency use in the US.