Super pricey therapies

‘Orphan drugs’ for rare diseases can cost $1 million per patient per year
By Heather Ennis
TORONTO | A proliferation of expensive new drugs may be creating a new class of patients—those with relatively rare disorders and pockets that are too shallow to foot the bill.
According to some doctors who treat these patients, health regions, drug companies and provincial and federal drug plans have been playing hot potato with the costs of the drugs, which can approach $1 million per year for a single patient.
For some suffering from rare disorders—including Gaucher’s disease, mucopolysaccharidosis type 1(MPS-1) and Fabry disease—emerging enzyme therapies represent the only hope of living a long and normal life, the doctors say, and Canada has already taken too long to come up with a plan to help them.
“When you start talking about the amount per patient, people are really surprised,” said Dr. Robin Casey, a Calgary pediatric geneticist who specializes in treating patients with rare disorders. “But the total cost to a country is not a big percentage of the total cost.”
A relatively new phenomenon, so-called orphan drugs began to appear after the U.S. government devised an incentive plan to bring more therapies for rare diseases to market. Because orphan diseases affect so few people, pharmaceutical companies had been showing little enthusiasm for pouring millions of dollars into developing drugs with limited profit potential. As a counterbalance, the U.S. Food and Drug Administration dangled a seven-year market exclusivity to anyone who achieved regulatory approval for a drug used to treat a condition that affects fewer than 200,000 people nationwide. Unlike patent protection, this exclusivity means other drugs can’t enter the market for that condition during the seven years. After that, the drugs started coming.
Hurler-Schie syndrome
In April, the issue hit Canadian headlines when Mackenzie Olsen, a 10-year-old Alberta boy suffering Hurler-Schie syndrome, took his story to the media. He had been receiving Aldurazyme (laronidase), a therapy specifically designed for his rare condition, on a complimentary basis while the company that developed it was completing the trials necessary for regulatory approval. Once they got the nod to distribute the drug, patients and physicians were left scrambling to find an alternative funding arrangement.
Hurler-Schie syndrome is a form of MPS-1—a lysosomal storage disease. The disease has varying degrees of severity, and Mackenzie’s case falls somewhere in the middle of the continuum.
“The natural history is that these children are usually diagnosed when they’re three or four years of age and traditionally have reasonably intact intelligence,” said Dr. Casey, who is Mackenzie’s physician. “They do go on to have severe debilitating disease and most die in their early teens or 20s.”
Weekly enzyme injections let patients lead fairly normal lives but they also carry a hefty price tag. In Mackenzie’s case, the drug costs approximately $17,000 per week. “He’s a fairly heavy boy,” said Dr. Casey.
Though he has lost approximately half of his sight and hearing, Mackenzie was able to go to school and lead a relatively normal life for the duration of the trials, said Dr. Casey.
“He’s been on therapy now for about four years and has done very well,” he said. “The problem for Mackenzie has been trying to find somebody who would pay the costs involved.”
Mackenzie’s not alone. There are fewer than a dozen patients with MPS-1 in Canada at any given time, said Dr. Casey, and many are waiting for various agencies to decide who—if anyone—should pay for their care.
First Nation care
Because Mackenzie belongs to a First Nation, his health needs are a federal responsibility and are normally covered through the non-insured health benefits program (NIHB) at Health Canada. Anticipating the termination of Aldurazyme clinical trials, Dr. Casey applied in October 2004 to the NIHB to have Mackenzie’s treatment covered.
“I applied knowing we had about a four-month period before he would run out of enzyme,” he said. “At the end of February we received a notice from them that they were not going to cover him pending a review by the Common Drug Review (CDR).”
A direct appeal to federal Health Minister Ujjal Dosanjh proved fruitless.
“I wrote him a long letter explaining what was going to happen to this boy. Just before the end of March I received a reply from them indicating they were going to stand by their previous decision.”
The free supply of Aldurazyme dried up, leaving Dr. Casey with no options and a very sick patient. Two Alberta First Nations groups provided enough money to cover the treatment until the end of March. Dr. Casey cut Mackenzie’s dose and the funding lasted nearly a month longer.
An 11th-hour agreement with the Calgary Health Region has given Mackenzie access to his therapy until the CDR expert panel makes its funding recommendation to Canadian public drug plans.
Aldurazyme has been sent to the CDR for review and a recommendation is tentatively due in early July. However, if past recommendations are any indication, it doesn’t look good for Mackenzie or other patients with the same disease.
The Canadian Expert Drug Advisory Committee of the CDR has reviewed two enzyme replacement therapies for Fabry disease: Agalsidase alpha (Replagal) and Agalsidase beta (Fabrazyme). They have also considered an oral alternative to enzyme replacement therapy (ERT) infusions for Gaucher’s disease. All have resulted in negative recommendations.
In December 2004, Fabrazyme was resubmitted to the expert panel and is currently being reconsidered.
“The bottom line is that those three drugs, which are in use elsewhere around the world and are paid for in various ways, are not going to be available in Canada because there’s no recommendation for funding,” said Dr. Casey. “Unless the patient has a private insurance plan that will provide coverage, they’re not going to get the drug.”
Cost effectiveness
The CDR is not designed to make decisions based on ethical or compassionate grounds, said the chairman of the expert panel. It provides recommendation to the various drug plans based on cost effectiveness, which each public payer can veto.
“We can’t just be 100% advocates and say we absolutely want this, we don’t care what the costs are and we don’t care what’s happening with the cost of health care,” said Dr. Andreas Laupacis, chairman of the expert review panel and CEO of the Institute of Clinical and Evaluative Science.
“If the decision-makers want to make a decision that cost-effectiveness isn’t going to be the overriding issue here, and for other reasons funds the drug, I can live with that. I have no problem with that.”
Knowing provincial drug plans often choose to follow the expert panel’s recommendations, the decisions can be difficult, said Dr. Laupacis, particularly when the drugs he’s asked to review are prohibitively expensive for the vast majority of Canadians.
“It’s emotionally much more difficult to sit on a committee like this and say, ‘On the basis of cost-effectiveness, we don’t think this drug is cost-effective,’ and realize the reality is there’s almost nobody out there who can afford the Fabry drugs themselves,” he said.
“If the drug plans then follow that, it essentially means patients aren’t going to get the drug. That’s a tough emotional thing to deal with.”
But somebody has to do it, said Dr. Laupacis, and it’s better to have the issue in the hands of medical professionals than sending new and expensive drugs to a panel of health economists, he said. “I would much rather have some docs advising the government what to fund than some folks who have had no involvement with health care whatsoever.”
Attacks from all sides
Despite hurtful words and messages coming from those who want free access to these costly therapies, Dr. Laupacis is committed to the process. He said it is important to maintain a quality, sustainable health system.
“Some of these advocates, when the negative recommendation came out, basically accused us of sentencing patients to death,” he said.
“Sitting on these committees, you do feel like you’re sitting there in target practice. Physicians, who understandably advocate for patients with these diseases, attack you. Patients attack you. I get e-mails with pictures of people with Fabry disease. At the same time, ministries of health grumble because the drug budget has gone up 15%.”
There are at least two parts to a cost-effectiveness analysis, said Dr. Laupacis, and orphan drugs with big price tags are falling short on effectiveness. He said he takes issue with the number, length and quality of the trials he has been given to guide his decision.
“When we first looked at the drugs for Fabry disease there really was no evidence from high-quality clinical trials that these drugs really impacted on clinical outcomes,” said Dr. Laupacis. “A lot of our reason for (our) recommendation was based on the fact that we hadn’t been provided with convincing evidence.”
Some advocates of public funding for orphan drugs agree, but the problem isn’t with the trials, they say. The CDR just wasn’t built with these kinds of therapies in mind, and they should be considered separately from drugs for more common disorders.
Dr. Joe Clarke, a pediatric clinical geneticist at the Hospital for Sick Children in Toronto, has proposed an alternative way to process therapies for rare diseases. He suggests the criteria for coverage be relaxed in the case of expensive drugs for rare diseases and that continued study and monitoring be prerequisites for funding. By lowering the bar, patients can gain access to new therapies while more and better evidence is collected.
Other countries, including Australia and several in Europe, have taken this approach, he said.
“Overall, they’re not a big chunk of the health-care budget,” said Dr. Clarke. “We have to provide this if it’s available, and we have to pay the price.”
Using criteria similar to those used by Health Canada to approve drugs for sale in this country may be more appropriate, said Dr. Clarke. So far, all ERT drugs have been given the go-ahead by the Therapeutic Products Directorate, which tends to look for evidence of biological effect rather than clinical outcomes or cost.
Meeting the CDR criteria just isn’t possible for most orphan drugs, said Dr. Clarke. The diseases they treat look very different in different patients, so selecting and measuring a clinically meaningful endpoint is often a struggle. “Hardly two patients have the same disease,” he said. “You need a much more dramatic improvement to make your point.”
The rate of orphan drug development isn’t likely to slow, said Dr. Clarke, who is urging the federal government to come up with a new scheme to handle them sooner, rather than later.
“There are ethical imperatives not to stand by and watch someone die if you have it in your power to save them,” he said. “It’s a much more complicated thing than simply counting the beans.”