FEDERAL PROBES REVIEW APPROVALS OF DIET DRUGS

The welter of lawsuits over a pair of controversial diet pills has
yielded an unexpected side effect -- two federal investigations
assessing whether any wrongdoing occurred during the approval process
of Redux and Pondimin.

The Federal Bureau of Investigation has begun a probe into the
interactions between the Food and Drug Administration and American
Home Products Corp., which withdrew both drugs in 1997 over serious
health concerns.

The inquiry, reported last week, also has prompted the FDA's Office of
Criminal Investigation to renew a 2-year-old case into how Redux was
approved in 1996, and whether the Madison drug maker properly conveyed
data about heart and lung damage.

The FDA would not comment on any investigation, and an FBI spokesman
said the agency doesn't have an "open case," a term for a formal
criminal investigation. American Home denied acting improperly or
concealing information at any time from regulators.

But sources familiar with the inquiry and knowledgeable of FDA
procedures say these examinations will take a wide-angle view of a
highly complex and nuanced process by which Redux paperwork traveled
through offices and laboratories in France, New England, New Jersey
and, ultimately, Maryland, where the FDA is based.

These sources said the investigators would likely review:

A series of confusing events surrounding a pair of 1995 meetings that
were held by an FDA advisory panel to review Redux and determine
whether it should be approved.

Whether all side-effect data was fully disclosed to the FDA,
including patient reports from the early 1990's in Europe, where Redux
was originally sold by a French drug maker.

American Home's procedures for reporting side effects. The drug maker
was cited in 1997 by the FDA for miscoding data about heart-valve
damage and reporting it late.

Interactions between FDA officials and American Home employees during
the multiyear approval process.

"As a scientist I can say that we have long been waiting for this,"
said Lewis Seiden, a professor of neuroscience at the University of
Chicago. "Some of us have never been able to understand how these diet
pills were approved in the first place. It's always been a puzzler."

Beyond rattling investors over the stability of a major drug maker,
the inquiries are expected to call into question whether the FDA,
which is mandated to protect public health, upheld its end of the
bargain at a time when America was hungry for diet drugs.

In the mid-1990s, the approval of the drugs was seen as a litmus test
for an agency deemed uncooperative and sluggish by the pharmaceutical
industry and members of Congress. The approval also roiled the
scientific community.

Since the drugs were withdrawn, more than 4,100 lawsuits have been
filed against American Home seeking individual damages or payments for
medical tests by those who took the pills but haven't suffered harm.

One massive trial is under way in New Brunswick to determine whether
American Home must pay for medical tests for an estimated 94,000 New
Jersey residents. But the publicity over the FBI inquiry may prompt
the drug maker to seek a mistrial this week, sources said.

Lawyers for diet-pill users charged that American Home concealed
side-effect data about Redux and Pondimin, which was also known as
fenfluramine, one-half of the fen-phen weight-loss cocktail.

The fen-phen combination was never approved by the FDA, but a 1992
study finding they reduced weight when used together helped boost sales.

Phentermine, the other half of fen-phen, is still sold. The Redux
approval was important to American Home because Pondimin, its chemical
cousin, faced generic competition while Redux had patent protection
for several years, which would shield it from copycat versions.

Before any lawsuit accused American Home and its executives of
misleading regulators, doctors and consumers, a cadre of respected
scientists had misgivings about the pills.

Their doubts began with research that showed mice and monkeys suffered
brain damage when given slightly higher doses of the drugs than would
be taken by humans. The extensive but cloistered FDA review process
was rife with debate about the side effects attributed to the diet
pills. Along the way, heated scientific discussions pitted two widely
known scientific rivals against each other.

One was Mark Molliver, a neuro-scientist at Johns Hopkins University,
who attended Harvard Medical School. He became the drug's fiercest
critic after his research found that rat brains were damaged after
Redux was ingested.

His opponent was Richard Wurtman, a neuroscience professor at the
Massachusetts Institute of Technology and founder of Interneuron
Pharmaceuticals Corp., which licensed Redux to American Home. He
rejected any research suggesting the drug was unsafe.

Wurtman did not return calls for comments about federal
inquiries.

Molliver, reached last week, said, "It's about time."

They never clashed publicly. But their competing views were the
subject of hot debate during a pair of 1995 meetings held by an FDA
advisory panel, which reviewed Redux and eventually recommended the
agency approve the drug for use.

The sequence of events that took place at these meetings is expected
to be reviewed by the FBI and the FDA's own investigators.

At the first meeting in September of that year, the presentation by
Molliver and some colleagues shocked the committee. Committee members
hadn't been briefed on the negative data as they had been on other
issues. An FDA official later said the lapse was an
"oversight."

Eventually, the panel voted 5 to 3 to reject Redux until American Home
and Interneuron could prove consumers wouldn't be at risk. Shortly
after the vote was taken, three members went on to other
engagements.

After they left the meeting, Dr. James Bilstad, the FDA official who
oversaw drug evaluation, asked those still present to vote again. The
remaining members voted 3 to 2 to approve the drug. Because they
didn't constitute a quorum, however, another vote was required.

The next meeting was scheduled for November, on the same day as an
important gathering of neuroscien-tists, precluding Molliver and
others from attending. Sources said the FBI and FDA investigators are
interested in the timing of the votes.

At the November meeting, American Home was accused by panelists of
inadequate testing methods. It turned out, however, that two members
who did not remain for the entire debate had voted in favor of the
drug. Redux was approved by a 6 to 5 vote.

Two weeks ago, one panel member, Dr. Roger Illingworth of Oregon
Health Sciences University in Portland, gave sworn testimony in a
deposition about a change of heart. Had he been given additional
information about Redux, he said, he wouldn't have voted for approval.

In particular, he testified that he would have liked to have seen a
letter from a prominent pulmonary specialist expressing concern about
the drug's propensity for causing lung damage. The letter was never
circulated to panel members, according to sources.

The government investigators are expected to review such events and,
in the process, could answer a question posed by Dr. Leo Lutwak, an
FDA official, who in 1998 complained that certain data about brain
damage weren't revealed to the agency.

"My questions are who knew what and when?" he wrote in a January 1998
memo to other FDA officials during the period when the agency first
examined the Redux approval. "Why weren't we informed in an
appropriate manner and within an appropriate time frame?"

The New Brunswick trial is expected to resume this week and could
continue for up to a month.

The government inquiries are preliminary, but a decision is expected
within the next month or so as to whether a formal investigation
should be opened. If that occurs, the government would begin a more
detailed effort, including subpoenas for documents from American Home
and other parties.