Monday July 16, 2001

Shortcomings Seen in Asthma Drug Trial Death

By Kate Fodor

NEW YORK (Reuters Health) - A 24-year-old woman who died
after taking part in a Johns Hopkins University asthma study
was not fully informed of the risks involved, a committee
formed to investigate the death said in a report to the federal
government's Office of Human Research Protection.

The informed consent form signed by Ellen Roche and other
healthy volunteers was ``inadequate'' and ``should not have been
approved'' by the Institutional Review Board responsible for
overseeing the research, according to Dr. Lewis Becker, a
Hopkins professor of medicine who led the university's internal
review of the trial.

During a press briefing on Monday, Becker said that his
committee--which included six other Hopkins faculty members and
three outside consultants--believes the consent form should
have made clear that hexamethonium, one of the drugs
administered in the study, is not approved by the US Food and
Drug Administration (FDA) and is no longer in clinical use.

In addition, the form should have stated that hexamethonium
delivered by inhalation, as it was in the study, ``was only used
experimentally, never clinically,'' and that serious adverse
events or death were possible, Becker said.

Roche developed a cough after inhaling hexamethonium as
part of the trial. The cough turned into respiratory distress
syndrome within a month, and she died of progressive
hypotension and multi-organ failure on June 2nd.

Had the study's lead researcher, Dr. Alkis Togias, been
aware of published reports of toxicity associated with
prolonged intravenous delivery of hexamethonium, that
information also should have been included in the consent form,
according to Becker. But he said that Togias had not seen the
reports before starting the study, and that the committee was
divided about whether he was at fault for not discovering them
during the standard literature review he conducted.

Becker stressed that even if the toxicity data had turned
up in time, it would not have been a reason for calling off the
study. The data ``come from 50 years ago, when the drug was
given for prolonged periods of time intravenously,'' he pointed
out, noting that the adverse events were rare and occurred in
people who were already ill and had received the drug for more
than a month.

However, the committee faulted the Institutional Review
Board overseeing the trial for not asking Togias to submit an
Investigational New Drug (IND) application to the FDA before
starting the study. Because the FDA has access to more data
than appears in the published literature, such an application
might have led to better information about hexamethonium's
potential toxicity.

But while INDs are required whenever unapproved drugs are
evaluated as potential therapies, it is less clear whether they
are always necessary for studies such as this one, in which
hexamethonium was used only to challenge the lungs as a way to
gain more information about asthma.

Becker noted that the Institutional Review Board had asked
the FDA for advice about INDs several times in relation to this
and at least one similar study, but had been told only that the
issue was complicated and the agency was formulating its
position.

Along with its complaints about the consent form, the
committee echoed a number of concerns raised by an FDA review
of the Hopkins study earlier this month. A cough developed by
one of the participants given hexamethonium before Roche
received her dose was not reported to the review board, and
changes made to the drug formulation were not cleared with the
review board, the report notes.

During the press briefing, Johns Hopkins Vice Dean for
Research Dr. Chi Dang reported that an external review of the
study is slated to begin near the end of the month. In the
meantime, the university is scrutinizing its clinical trial
procedures and has already begun to implement changes,
including contracting with external advisors to evaluate its
Institutional Review Boards, Dang said.