Dozens of cancer drugs have been in short supply in recent years as manufacturers closed factories, stopped making products, or halted operations because of quality control problems. Researchers have struggled to quantify the effect shortages have had on patient care, and an article published Wednesday by the New England Journal of Medicine advances that effort.
When a factory closure in 2010 resulted in the shortage of a key drug used to treat children and adolescents with Hodgkin's lymphoma, doctors thought a comparable drug already on the market would provide a suitable substitute. But a study found that the people who received the substitute were more likely to relapse, requiring more aggressive care and sometimes suffering severe side effects.
The article — said by the authors to be the first to document the effect on patients of a specific shortage — illuminates how little is known about what the lapses in drug supply will mean for people's health.
"These are business issues and manufacturing problems that are ongoing and have very real effects on patients," said Erin Fox, who tracks shortages as director of drug information at University of Utah Hospitals and Clinics. "A lot of patients had their regimens altered, and I think we are just starting to see what the impact of those shortages was."
After what she called a "perfect storm" of production problems in 2010 that interrupted drug supplies from several major manufacturers, Fox said the situation appears to be getting better and the rate of new drug shortages has slowed. Still, her office is tracking 296 active shortages, including 30 chemotherapy drugs.
In the case reported in the New England Journal, Denmark-based Lundbeck, the sole maker of mechlorethamine, stopped production and announced an extended shortage in April 2010. A spokeswoman for the Food and Drug Administration said the company lost its contractor and had to set up a new facility to make the drug, marketed as Mustargen.
A group of researchers, including some from Boston, had been testing the toxicity and long-term effects of a treatment regimen that included Mustargen when they learned of the shortage. The oncologists leading the study replaced it with cyclophosphamide, which is widely used in a similar regimen to treat adult and pediatric cancers, and continued the study. Of all the substitutions made during recent shortages, this one looked as if it would have the least consequence, said Dr. Michael Link, professor of pediatrics at Stanford University School of Medicine and an author on the paper.
"This was a no-brainer," said Link, who also is past president of the American Society of Clinical Oncology .
But, the researchers suspected that more children treated with the substitute were relapsing. When they looked at the data, accounting for severity of illness and the amount of time each child was tracked after treatment, they found those who received Mustargen had an 88 percent chance of being cancer free for at least two years. That chance was less, at 75 percent, for those treated with cyclophosphamide.
All patients who relapsed survived, but they required aggressive treatments such as a stem cell transplant that made them more likely to be infertile or have other cancers later in life — risks that might have been avoided if it weren't for the shortage, said Dr. Monika Metzger, lead author and an oncologist at St. Jude Children's Research Hospital.
The Postle family of East Kingston, N.H., knows the implications firsthand. Isabella Postle was 11 when she was diagnosed with Hodgkin's lymphoma at Dana-Farber Cancer Institute in early 2010. Her doctor, Dr. Amy Billett, director of the joint pediatric lymphoma program for Dana-Farber and Boston Children's Hospital, was involved in the study with Link. The Postles had already decided to pursue the treatment regimen that included Mustargen when the shortage occurred.
After undergoing about three months of chemotherapy with the substitute, the family learned it hadn't worked, said Frank Postle, Isbella's father. She would need more chemotherapy and a stem cell transplant. An infection put her in intensive care for more than a week, and she required months of isolation in the hospital and at home. Now, she is cancer-free but still closely monitored by her doctors, Postle said. "This was not a small impact to her life and our family," he said.
Drug makers are entitled to make a profit, he said, but they "carry a little bit of a moral obligation, not only for adults that have cancer but for these kids who have their whole life in front of them. A few percentage points could mean a whole lot."
Link said the results of the Mustargen substitution were eye-opening. Doctors thought they had a good alternative, but the data showed otherwise. When other critical drugs became unavailable for months — for example, cisplatin or doxorubicin, which are important in treating testicular and breast cancers affecting many more people — there were no clear substitutes and there has been little documentation of the consequence for patients.
Many of the major cancer drug shortages have eased or been resolved in recent months, Link said. Lundbeck was producing Mustargen again in October and the drug was readily available by November, according to tracking by Fox's group. (Lundbeck recently announced plans to sell its Mustargen product and other drugs to another manufacturer.)
The FDA has taken steps to mitigate the effects of shortages, including pushing manufacturers to notify the government when they expect a supply interruption. But, Link said, the changes don't go far enough to prevent future shortages.
"We have no confidence that we have a durable solution," he said. "The worry is, when's the next one going to happen?"