March 16, 2008
Cutting Dosage of Costly Drug Spurs a Debate
By ANDREW POLLACK
When a drug can cost more than $300,000 a year, the right dose becomes a matter of public debate.
The drug in question, Cerezyme, is used to treat a rare inherited enzyme deficiency called Gaucher disease. Some experts say that for most patients, as little as one-fourth the standard top dose would work, saving the health care system more than $200,000 a year per Gaucher patient.
“It is economic malpractice to give a much higher dose of an expensive drug than is required,” said Dr. Ernest Beutler, an authority on Gaucher disease at the Scripps Research Institute.
Some other Gaucher specialists argue otherwise, saying that skimping on the medicine could endanger patients.
But all sides agree on one thing. “Nobody would even be wasting their time talking about this if it were a cheap drug,” said Dr. Neal J. Weinreb, a Coral Springs, Fla., specialist in Gaucher (pronounced go-SHAY).
In that sense, the dispute over Cerezyme could be a sign of the increased scrutiny that dosing will receive as drugs become more expensive. Pharmaceutical companies have faced complaints for years over prices, but now they might have to defuse efforts to use less of their drugs to cut costs, and to rebut accusations that doses are inflated to bolster profits.
There are also economic and social questions about how much burden taxpayers and co-workers should be expected to bear; ultra-expensive drugs, especially in full doses, can raise the cost of everyone’s insurance.
With Cerezyme, which is made by Genzyme, the profits are sizable. Gaucher disease, which can have complications like ruined joints, is rare; only about 1,500 people in the United States are on the drug and about 5,000 worldwide. Sales of Cerezyme totaled $1.1 billion last year, making it a blockbuster by industry standards.
Genzyme is not the only company feeling some pressure. Some lung cancer doctors are using only half the approved dose of Genentech’s drug Avastin, after a recent study suggested the half-dose might be as effective as the full one, which can cost $100,000 a year.
In a letter to The Journal of Clinical Oncology last September, Dr. Ian E. Haines of MonashUniversity in Australia argued that the doses of all three Genentech cancer drugs — Herceptin, Rituxan and Avastin — appeared to be higher than necessary, perhaps to bolster sales.
Dr. David P. Schenkein, a Genentech executive, said the doses were chosen solely for maximum effectiveness in fighting cancer.
Scientists reported last year that a two-hour infusion of Schering-Plough’s anticlotting drug Integrilin worked just as well for some patients as the standard 18-hour infusion, saving hundreds of dollars per treatment.
And doctors are sharply reducing their use of anemia drugs sold by Amgen and Johnson & Johnson. While the cutbacks are mainly for safety reasons, the drugs’ multibillion-dollar cost to Medicare intensified scrutiny of the products.
In the case of Genzyme’s Cerezyme, higher doses are not harmful. It is only a question of how much of the drug is needed, given the cost.
Some experts say that patients who are given too little of the drug could suffer from the complications, which can occur without much warning.
“The risk is taken by the patient,” said Dr. Gregory Pastores, a Gaucher expert at New York University who tries to use a moderate dose.
Tina Chavers, 38, of Pensacola, Fla., said she wondered whether higher doses might have saved her hips, which were replaced a few years ago.
“There was no indication to tell us that I was going to lose my bones,” she said. “We just really thought my disease was very controlled.”
But a contrasting story is told by Carmie Stein of Akron, Ohio, who took the drug for 11 years until she switched doctors about four years ago. The new doctor said her condition was so mild that she did not need treatment.
“I really felt cheated,” Ms. Stein said of the years she took the drug, perhaps unnecessarily. Ms. Stein, a fitness buff, said she had felt healthier and more energetic since she stopped taking the drug.
Gaucher disease is an inherited deficiency of an enzyme the body needs to break down fats. The disease can cause vastly enlarged livers and spleens, anemia, low platelet counts, and bone pain and deterioration. Cerezyme is a synthetic version of the missing enzyme.
Genzyme, which became a leading biotechnology company because of Cerezyme, says that it has raised the price only once — 3 percent last year — since introducing the drug in 1994. The company says it needs the high price to make a sustainable business of serving such a small number of patients and to pay for research on new products. Genzyme also says it provides the drug free, if necessary, so that no one goes without the product because of its cost.
But critics say the company’s development costs were minimal, because the early work on the treatment was done by the National Institutes of Health, which gave Genzyme a contract to manufacture it. And analysts estimate the current cost of manufacturing the drug to be only about 10 percent of its price.
Insurers generally cover the drug because there are so few patients. But finding or staying on insurance can be difficult.
After Mitch and Jeannie Ware’s two daughters were found to have Gaucher, for example, the couple could not find private insurance. So the family had to move from Florida to Alabama in 2006, so Ms. Ware could take a job with a school system that provided insurance.
“Her job is worth three quarters of a million dollars” a year, Mr. Ware said.
The standard Cerezyme dose — an infusion of 60 units of the drug per kilogram of body weight every two weeks — was set in a clinical trial involving only 12 patients. Based on that trial, Ceredase, a nearly identical predecessor drug, was approved in 1991. Cerezyme, the same enzyme made differently, replaced it starting in 1994.
Dr. Beutler of Scripps said that it was reasonable to use a high dose in the initial trial to prove the drug worked. But after that, he said, “the reasonable thing was to cut back and see what you really need. It didn’t fit Genzyme’s business plan, so they never cut back.”
Dr. David Meeker, the president of the Genzyme division that sells Cerezyme, said the company thought doctors should determine doses specific to each patient. So there was no point in doing a clinical trial comparing different doses.
“Showing that 6 out of 10 got by with a certain dose doesn’t help us,” he said.
According to Genzyme, the average dose in the United States is 51 units per kilogram every two weeks. At that dose, it costs about $350,000 a year to treat an adult weighing 70 kilograms, or 154 pounds.
But the worldwide average, even factoring in United States patients, is 34 units. And in Israel, the standard dose is 15 units per kilogram every two weeks.
“Patients are doing just as well on a treatment that is 75 percent less expensive,” said Dr. Ari Zimran, an Israeli Gaucher expert.
A study in the journal Blood in 2006 compared patients in the Netherlands, where a low dose is used, to those in Germany, where a high dose is typical. In the usual measures of disease severity — liver and spleen size and blood counts — there was no difference between the groups. But the German patients did better in two indirect indices of bone health.
Dr. Pramod Mistry, a Gaucher expert at Yale who receives some research funding from Genzyme, said he was caring for some of Dr. Beutler’s former patients who had become “very, very sick” because of under-treatment.
One of them, Shauna Mangum, of Farmington, N.M., said she lived with pain after Dr. Beutler told her in 1994 that she did not need treatment. Now she is taking a high dose and says she can run five-kilometer races and play soccer with her children.
Dr. Beutler, who at age 79 no longer treats patients, said that Ms. Mangum’s case was mild when he saw her but might have worsened later.
Ms. Mangum began treatment in 2000, at a cost of more than $400,000 a year. The next year, the premiums for everyone in her insurance pool went up by $180 a month.
Dr. Mistry says patients are already under too much pressure to reduce their doses. “They have a tremendous sense of guilt,” he said, “that they are such a burden on society.”