http://www.nytimes.com/2001/02/11/health/11DRUG.html?pagewanted=all
To the New York Times:
It's unfortunate that it is
too late for Brooke Shrader and other children like her, but I'm sure the New
York Times would not want to overlook the well-known association between
rubella vaccine and both chronic and acute arthritis. The Institute of
Medicine, in their 1991 review of the safety of pertussis and rubella vaccines
found that "evidence is consistent with a causal relation" between
rubella vaccine and chronic arthritis, and "indicates a causal
relation" between rubella vaccine and acute arthritis.
Perhaps it would be better
to avoid arthritis altogether by more judicious use of vaccines, than to have
to solve the problems caused by them by using other drugs.
Sandy Mintz
Anchorage, Alaska
February
11, 2001
Children
Test New Medicines Despite Doubts
By
SHERYL GAY STOLBERG
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The federal government is the
driving force behind the change. In 1997, Congress offered pharmaceutical
manufacturers lucrative incentives to study their products in children. And in
December, the Food and Drug Administration began requiring companies to test
almost all new medicines in young people.
The testing is necessary,
experts say, because 80 percent of all medicines used in children have not been
adequately researched in them. Pediatricians often prescribe adult medicines
"off-label," without F.D.A. approval and without good information on
dosing and side effects.
"We are operating in a
vacuum," said Dr. Eric Kodish, who treats young cancer patients at Rainbow
Babies and Children's Hospital in Cleveland. He bases chemotherapy doses on
height and weight, but is cautious. "I might be able to treat their cancer
more aggressively, but I don't know how to safely do that," he said.
For children and their
families, the boom in pediatric testing has brought a chance of improved treatments,
but also the ethical dilemmas that accompany medical research.
Brooke Schrader, a 14-year-old
from Tarzana, Calif., has suffered from juvenile rheumatoid arthritis since she
was 4. By the time she was 11, she could barely walk; her mother, Deborah,
remembers carrying her around from room to room.
So when doctors at Children's
Hospital of Los Angeles offered to enroll Brooke, then a sixth grader, in a
study of a new biotechnology drug, her family jumped at the chance. In December
1997, she took the last spot in a clinical trial.
"It was at the point that
she was getting so bad that I could see my daughter being crippled," Ms.
Schrader said. "The risks were negligible compared to what I was seeing my
daughter go through."
But there were risks and uncertainties.
As part of the experiment, Brooke's twice-weekly injections of the new drug,
Enbrel, were switched to a placebo — fake medicine.
Brooke relapsed and was
eventually put back on the drug, which gained F.D.A. approval for use in
children in May 1999. In retrospect, she is glad she participated. "If I
gave up that opportunity and wasn't on this drug, I have no idea where I would
be now," she said. "Probably in a wheelchair."
Enrolling children in medical
experiments is a delicate business. In some cases, healthy youngsters are study
subjects, raising questions about whether they are being exposed to risks
without possible benefit. Some studies pay children to enroll. Rewards range
from toy store gift certificates to payments of $200 or more, and the practice
escapes federal regulation.
Doctors are also paid for
running the studies, receiving up to $2,000 for every patient recruited.
Although the money is typically designated to cover expenses, it may include a
profit.
"There's something
worrisome about parents getting money to enroll their kids in a study that has,
at the least, discomfort, and, at the worst, risk," said Dr. Norman Fost,
a professor of pediatrics and medical ethics at the University of Wisconsin.
"The same applies to physicians. There is enormous opportunity for profit
now because of the explosion of drug testing in children."
That
opportunity extends to the pharmaceutical companies, who under the 1997 law can
delay generic competion in exchange for pediatric testing. The law has meant hundreds
of millions of dollars in additional profits for the makers of such blockbuster
drugs as Claritin, the allergy medicine, and Prozac, the antidipressant.
No one knows precisely how many
children are involved in pharmaceutical research. But as a result of the 1997
law, the F.D.A. says, it has asked the industry for 332 "post marketing
studies" — those conducted after a drug is approved for adults — that
could involve more than 20,000 children.
So far, the agency said, 58
studies have been completed, compared with 11 between 1991 and 1996. And a
recent survey by the Pharmaceutical Research and Manufacturers of America, the
industry trade group, found that companies have 217 new medicines and vaccines
in clinical testing for children.
Testing medicines is more
complicated in children than in adults. Fewer youngsters are sick, so it is
difficult to find volunteers. Children metabolize medicines differently from
adults.
"We may expose a child to
a single dose of a drug, and then do a series of blood samples to determine
what concentrations are achieved in blood or urine," said Dr. Jeffrey
Blumer, chief of the division of pediatric pharmacology at Rainbow Babies and
Children's in Cleveland. "Then we use that information to determine the
dose."
In 1994, to promote more of
these studies, the National Institutes of Health began paying for a network of
specialized pediatric pharmacology units, including Dr. Blumer's. Today there
are 13, and they are busier than ever. Dr. Gregory Kearns, who runs the
pediatric pharmacology unit at Children's Mercy Hospital in Kansas City, Mo.,
said he would do more than 20 studies this year, twice as many as five years
ago. "Five years ago, with few exceptions, children were the afterthought
in terms of drug development," Dr. Kearns said. "Now infants and
children and adolescents have been catapulted to the forefront, and we are
demanding that society do what's right by them."
The Enbrel study, in which
Brooke Schrader participated, demonstrates the difficulties of conducting
pediatric research — and why pharmaceutical companies have often shied away
from it.
To begin with, the market for
pediatric medicines is small. Of the estimated two million Americans with
rheumatoid arthritis, fewer than 100,000 are children, half of whom would be
eligible for Enbrel, according to its manufacturer, the Immunex Corporation of
Seattle. Although not required to at the time, the company decided to study the
drug in adults and children simultaneously.
The reasons were twofold, said
Dr. Barbara Finck, the company's medical director. Immunex knew the F.D.A. was
pushing pediatric testing. And company officials thought Enbrel could be
approved as an "orphan drug," a lucrative designation given to treatments
for rare diseases. Orphan drug status entitles a company to tax credits and
seven years of "market exclusivity," or freedom from generic
competition.
The next question was how to
design the study. Typically, pharmaceutical experiments in adults are designed
with a placebo control: one group of patients gets the drug, the other a fake
treatment. But in sick children, Dr. Finck said, that design "is thought
to be unethical. So we were stumped."
They decided each of the 69
children enrolled would receive Enbrel injections for three months. Then, those
who responded well would be split into two groups. Half would continue on
Enbrel; the other half would get a placebo. If a child relapsed, he or she
would go back on the drug.
At Children's Hospital in Los
Angeles, one of nine centers that participated in the study, it was left to Dr.
Andrew Reiff, a pediatric rheumatologist, and Diann Wingert, a social worker,
to explain the study to families. Many of their patients are poor, Dr. Reiff
said, so he decided against offering financial compensation. "I don't want
to buy my patients for the trial," he said.
For parents, the study's
placebo design was less of an issue than Dr. Reiff and Ms. Wingert expected, at
least at first. But as the trial progressed, the placebo factor did become an
issue. Some parents suffered so much "anticipatory anxiety," Dr.
Reiff said, that they became convinced, incorrectly, that their children were
being given fake injections. In Brooke's case, she noticed a change within a
week.
"My ankles got really
swollen and it was hard to walk, and I was in so much pain," she said. For
her mother, the monthlong wait to be put back on Enbrel was agonizing.
"She had to be in a full-blown flare before they would put her back on the
drug," Ms. Schrader said. "It was very hard."
Brooke remains on Enbrel and
her disease is in remission, Dr. Reiff said. Others in the study were not so
fortunate. Two who were doing extremely well on the drug were switched to a
placebo, then back again, and never completely recovered; it is unclear why,
Dr. Reiff said.
In decades past, studies like
the one Dr. Reiff conducted were almost nonexistent. Pediatric pharmaceutical
experiments were generally limited to studies of new vaccines and antibiotics
that would be advertised for children.
"There was a lot of
controversy about whether children should ever be in trials," said Dr.
Dianne Murphy, associate director for pediatrics at the F.D.A.'s Center for
Drug Evaluation and Research.
In 1977, the American Academy
of Pediatrics called for more pediatric pharmaceutical testing. But
pharmaceutical executives did not have much interest in the tiny pediatric
market.
In the early 1990's, advocates
for pediatric AIDS patients began demanding testing in children, and the F.D.A.
tried to encourage more research, with little success. So in 1997, the Clinton
administration decided to make pediatric drug testing mandatory for nearly all
new medicines and biotechnology products.
The provision took full effect
in December, and the pharmaceutical industry is not terribly enthusiastic about
it. Marjorie Powell, a lawyer for the Pharmaceutical Research and Manufacturers
of America, said companies feared the rule would result in slower development
of drugs for adults.
But along with that stick,
Congress offered a carrot. As part of legislation changing the F.D.A.,
lawmakers enacted a "pediatric exclusivity" provision that offers
drug companies freedom from generic competition — in this case for six months
after a drug's patent expires — in exchange for studying how children respond
to medicines on the market for adults. The exclusivity applies to every
formulation of a drug, even if only one is tested, and even if the drug turns
out not to work in children.
"The investment can be
$100,000 in the study and the windfall is in the billions," complained
Bill Nixon, who heads the Generic Pharmaceutical Association, a generic
industry trade group. "That's why you see the proliferation of these
pediatric studies."
The provision has been
lucrative, said Carl Seiden, a pharmaceutical industry analyst with J. P.
Morgan Securities. Eli Lilly recently received the six-month extension for
Prozac, its antidepressant; Mr. Seiden estimated that the company would reap an
additional $1 billion in sales, $700 million of it profit. The same goes for
Schering Plough, which has received pediatric exclusivity for Claritin, the
allergy drug.
The F.D.A. estimates that over
20 years, pediatric exclusivity will cost consumers an additional $13.9
billion. Over that time, according to the agency's projections, brand-name drug
makers will gain $29.6 billion, the generic industry will lose $10.7 billion,
and drug distributors, including pharmacies, will lose $4.9 billion.
The provision is set to expire
next January, although the pharmaceutical industry and pediatric
pharmacologists are lobbying hard to retain it. Senators Christopher J. Dodd,
Democrat of Connecticut, and Mike DeWine, Republican of Ohio, have expressed
interest in renewing it.
But Senator Hillary Rodham
Clinton, Democrat of New York, said she thought the provision should be
narrowed to apply only to the drug formulation tested. And F.D.A. officials
said the incentive had failed in one respect: it did not spur testing of some
drugs widely used for children, including Albuterol, for asthma, and
Ampicillin, the antibiotic, because they lack patent protection.
Still, Dr. Murphy proclaimed
the provision a success. "It's moving the whole field of science
forward," she said.
There is so much movement that
pediatric researchers say they can barely keep up with the drug industry's
demand for new studies.
"Over the past 30 years in
adult medicine, an infrastructure has evolved for clinical testing of
drugs," said Dr. Ralph Kauffman, director of research at Children's Mercy
in Kansas City. "That infrastructure never developed for children."
Across the country, in cities
like Louisville, Ky., and Milwaukee, children's hospitals are expanding their
research units. In Ohio, the Children's Medical Center of Akron, a nonprofit
hospital, has spun off a for-profit business, Pediatric Clinical Trials
International.
And in Hartford, Kelson
Pediatric Partners, a company that manages pediatricians' offices, has recently
created a clinical trials network. Company officials declined to be
interviewed, but the company's Web site advertises "urban and suburban
populations of infants, children and adolescents" and "high volume
practices."
That kind of advertising
worries Dr. Kauffman. "Suddenly this demand is out there," he said,
"and there are dollar signs attached, and everybody sees an
opportunity."