US researchers faced with cancer-drug shortfall struggle to keep trials on track.
Potential cancer treatments are loitering in the wings as clinical trials are delayed by widespread shortages of common chemotherapy drugs.
The I-SPY 2 Breast Cancer Clinical Trial, for example, a high-profile experiment aiming to test the use of certain molecular markers to guide cancer treatment, was designed to allow researchers to adapt the study's protocol in response to early results. But principal investigator Laura Esserman, an oncologist at the University of California, San Francisco, is finding it harder to adapt to the shortages.
Faced with a dearth of the decades-old chemotherapy drug doxorubicin — a result of manufacturing delays and increased demand — Esserman's team substituted the drug epirubicin. However, finding an alternative when supplies of paclitaxel dried up proved more challenging. The logical substitution was a medication called abraxane, but there were insufficient safety data on combining that with other drugs used in the trial. Instead, Esserman's team encouraged hospitals involved in the trial to use abraxane for patients not enrolled in I-SPY 2, freeing up more of the limited supplies of paclitaxel for trial participants.
According to the University of Utah's drug information service, 198 drug shortages had been reported in the United States by late August this year, 15 of which are cancer drugs required for clinical research. More than 150 trials sponsored by the US National Cancer Institute (NCI) involve drugs that are in short supply. "If there was ever a national cancer-research emergency, this is it," says Robert Comis, president of the Coalition of Cancer Cooperative Groups, based in Philadelphia, Pennsylvania.
Shortfalls stack up
Since 2007, drug shortages in the United States have been growing in number, driven by the consolidation of generic drug makers, a tendency by hospitals and wholesalers to order medicines on demand rather than stockpile supplies, and a spate of manufacturing problems ranging from mould contamination to the presence of glass particles in injected drugs. With one-quarter of the year left to go, shortages are already nearing 2010's tally of 211, and hospitals have had to ration dwindling stocks. Edwin Choy, an oncologist at Harvard Medical School in Boston, says that he has had to switch patients who were doing well on one drug to another treatment. "Sometimes their cancer progresses after the switch," he says. "It's horrible."
Although most of the shortages affect old, generic drugs, clinical trials often use these staples, either as controls or in combination with experimental medicines, including the genetically targeted drugs that many hope will revolutionize cancer care. Diane Colaizzi, executive adviser to the Coalition of Cancer Cooperative Groups, says that, typically, investigators in the NCI's cooperative groups — which unite cancer researchers across many sites to conduct large clinical trials — will not enroll new patients in a trial unless they can ensure that the patient will be able to complete their treatment. "We don't want to disrupt treatment once it starts," Colaizzi says.
Consequently, enrolment in clinical trials — already often a long and difficult process — can grind to a halt. A trial testing a combination of chemotherapy and antiretroviral drugs for the treatment of advanced AIDS-related Kaposi sarcoma is expected to be on hold for at least a year. Meanwhile, Robert DiPaola, an oncologist at the Cancer Institute of New Jersey in New Brunswick, says that the doxorubicin shortage delayed a cancer trial testing an inhibitor of a family of DNA-repair enzymes called PARP proteins by five months. "It is particularly frustrating at a time when cancer researchers are under pressure to shorten the time it takes to start and conduct clinical trials," he says.
And clinicians are not always able to amend their trial protocol by substituting an alternative drug, as Esserman did for I-SPY 2, cautions Colaizzi — particularly when the trial will be submitted to the US Food and Drug Administration as part of an application for drug approval. And even when it is an option, researchers aren't always sure how to interpret data from trials that changed protocol midstream, says James Hoffman, medication outcomes and safety officer at the St. Jude Children's Research Hospital in Memphis, Tennessee. "There's no doubt that there are going to be analytical challenges because of all of these changes," he says.
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Ledford, H. Drug shortage slows clinical trials. Nature (2011). https://doi.org/10.1038/news.2011.570