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By Alice
Dembner
Dr. David Trentham is the chairman
of the Department of Rheumatology at Harvard. He has used the antibiotic
Minocin for successfully for many with rheumatoid arthritis and scleroderma.
He decided to study the drug in those ages 6 to 14 and asked drug maker
Wyeth for a donation of $15,000 worth of the antibiotic. Wyeth, which
made $14 billion last year in total sales of drugs and other products,
had acquired a small company that supported Trentham's previous studies
of minocycline in animals and in adults. But this time, the answer was
an unequivocal no.
''While scientifically interesting,
the concept and design is not consistent with our current business objectives,''
wrote a company official in a letter that Trentham said stunned him.
While company officials later
said patient safety was the reason for the denial - the antibiotic can
cause some side effects, such as discoloration of the teeth - Trentham
believes the letter gave far more insight into the company's reasoning.
Trentham's translation of the
letter: If minocyline worked, it might compete with a blockbuster drug
called Enbrel that Wyeth now markets for both adult and juvenile rheumatoid
arthritis. Enbrel costs $1,300 per month for adults and has life-threatening
side effects, while Wyeth's brand of minocycline, called Minocin, costs
only $280 for an adult monthly dose, Trentham said. And unlike Enbrel,
minocycline is no longer under patent, so many companies could benefit
from the drug's success.
As rheumatologist Trentham
put it, ''It's a commercial decision, and it's unfortunate for the patients.''
Trentham said it was the first
time in his career that a drug company had turned down his request for
support of a study. But other researchers said denials are becoming more
common as the drug market becomes ever more competitive.
''It happens all the time,''
said Dr. Raymond Woosley, a prominent drug researcher who is vice president
of health sciences at the University of Arizona. ''They don't want you
to study their drug because of what you might find or how your finding
might affect another drug they're marketing. They want to control the
data on their drug.''
While companies have no legal
obligation to support research by doctors who don't work for them, many
scientists believe they have a moral responsibility to society.
''When a company refuses to
allow someone to do legitimate research on their drugs, we all lose out,''
said Sheldon Krimsky, a Tufts University professor who has studied relationships
between academic researchers and drug companies. ''Their
interest is in their market share, not in public well-being.''
A spokeswoman for Wyeth, however,
said economics played no role in the company's decision. ''The decision
was made primarily on safety,'' said Natalie de Vane. ''The company felt
there were newer medications that could be studied that didn't have the
side effects that this particular drug has. Minocin is contraindicated
in young children and there were very young children in this proposal.''
While minocycline carries an
FDA warning against use in children under 8 because of possible permanent
discoloration of teeth, Trentham said that is a far cry from the warning
on Enbrel, of serious and sometimes fatal infection or sepsis. Nonetheless,
Enbrel was approved by the FDA in 1999 for use in juvenile rheumatoid
arthritis for those patients who fail other treatments.
Despite the rejection by Wyeth,
Trentham is forging ahead. He secured a $20,000 grant from a small private
foundation, the Road Back Foundation, to fund lab fees for the six-month
study and will buy Minocin from Wyeth, and then charge study participants
or their insurers for the drug. But he said he worries that that will
make it much harder to recruit participants and will delay the study,
now scheduled to begin this summer. He plans to recruit patients across
the country who are not currently taking Enbrel or another treatment,
methotrexate.
''It's terribly important to
get to the bottom of whether Minocin works in children with juvenile rheumatoid
arthritis because of the benign nature of Minocin,'' said Trentham, who
is known as an antibiotic enthusiast.
Juvenile rheumatoid arthritis
affects up to 50,000 children in the United States, causing painful swelling,
stiffness and deformity of joints and sometimes stunting growth. While
some children outgrow it, others fight the disease their whole lives.
Doctors believe it is caused by a malfunction of the immune system and
typically treat children with anti-inflammatory drugs starting with ibuprofen
and moving to more potent drugs.
If minocycline works consistently
in children, Trentham said, it would also be a safer alternative to two
other common treatments for JRA - steroids and methotrexate. Steroids
can stunt a child's growth, and methotrexate, often used to treat cancer,
can be toxic to the liver and it can harm the immune system when given
in higher doses than usually given in children.
Some pediatric rheumatologists
said, however, that methotrexate is not as risky and minocycline is not
as safe for children as Trentham suggests. A cousin of tetracycline, it
commonly is used to treat severe acne. But it can discolor teeth and skin,
irritate the stomach, and, in rare instances, it can cause liver or kidney
damage and has been associated with lupus.
''We're able to control a large
number of our patients with currently available drugs,'' said Edward Giannini
of Cincinnati Children's Hospital, a senior scientist with an international
consortium that studies pediatric rheumatology treatments and helped test
Enbrel and methotrexate. ''I don't see much of a need to look at this
drug, because we feel it's only partly effective in adults. But there's
no harm in studying it.''
Concern about side effects
of methotrexate led Melanie Masala to bring her daughter, Gloria, to Boston
for treatment with minocycline. ''I was wondering which was worse, the
disease or the cure,'' she said.
With minocycline, Marsala said,
Gloria's transformation was ''incredible.'' As Gloria said: ''Before,
not many people liked to play with me because I couldn't do the things
they wanted to do. Now, I ride my bike, I rollerskate, I can jump, I can
even climb a little.'' And Trentham said she is growing again, catching
up to her classmates, without any medication side effects.
Scientists do not understand
why minocycline appears to help some arthritis patients. A national study
of 219 adults with rheumatoid arthritis, supported by the National Institutes
of Health and published in 1995, found, however, that minocycline significantly
reduced joint swelling and tenderness in more than half of patients, although
a dummy pill caused similar improvement in about 40 percent. Lederle Laboratories,
which then made Minocin, provided the drug and placebo free for the study.
Wyeth subsequently bought Lederle and helped market Enbrel, which chalked
up $900 million in sales last year.
Trentham, who was one of several
investigators for the NIH study, chose to use Minocin for his new study
for consistency, rather than other generic versions of the antibiotic
made by other drug companies.
Getting free drugs for research
is ''especially a problem when the company has a competing drug,'' said
Woosley, a professor of pharmacology and medicine. He and colleagues were
thwarted a few years ago, he said, when they wanted to study the side
effects of an older synthetic estrogen replacement. The company, which
he declined to name, refused because officials were worried the study
would focus attention on the side effects of a new drug they were developing.
''From a business point of
view, it makes sense. Why should they get involved in anything that might
harm them?'' said a Boston-area researcher, who requested anonymity because
he feared alienating companies from which he regularly seeks support.
''But the research community is trying to find out the truth, about mechanisms
and side effects of drugs and how they are best used clinically. And the
drug companies' posture impedes that. It's gotten worse year by year and
the last two years have been impossible.''
Boston
Globe June 25, 2002
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