ROCKVILLE, Md--In a move with very little precedent, the FDA Oncologic Drugs Advisory Committee (ODAC) recommended approval of a new indication for the bisphosphonate Aredia (pam-idronate disodium for injection) on the basis of a single clinical trial.
ROCKVILLE, Md--In a move with very little precedent, the FDA OncologicDrugs Advisory Committee (ODAC) recommended approval of a newindication for the bisphosphonate Aredia (pam-idronate disodiumfor injection) on the basis of a single clinical trial.
The new indication is for the treatment of bone metastases associatedwith multiple myeloma. The drug is already approved for use inhypercalcemia of malignancy (October 1991) and Paget's disease(September 1994).
The committee felt that even though the drug's sponsor, Ciba PharmaceuticalDivision, Ciba-Geigy Corp., presented only one phase III clinicaltrial, the need for the drug is so great and the adverse reactionssufficiently tolerable, that Aredia should be made available topeople with multiple myeloma.
James Berenson, MD, associate professor of medicine, Universityof California, Los Angeles, and chief of oncology, Veterans AdministrationMedical Center, told the panel that multiple myeloma is the secondmost common hematologic malignancy in the United States, with12,500 new cases each year. Sixty percent of patients are alreadyat stage III when they are first diagnosed.
Among the many clinical features of multiple myeloma are seriousskeletal complications such as osteoporosis, lytic lesions, pathologicfractures, osteopenia, and spinal cord compression. Treatmentwith analgesics, radiation therapy, surgery, glucocorticosteroids,and chemotherapy has been less than successful, Dr. Berenson said.
John Seaman, PharmD, director of clinical research, Ciba PharmaceuticalsDivision, described the randomized, double-blind clinical trialof Aredia vs placebo in which 392 patients with stage III multiplemyeloma participated. All had at least one lytic lesion.
The goal was to compare the effects of Aredia and placebo on spinalcord compression or collapse, pathologic fracture, and need forradiation to treat bone and prevent fractures. Pain, narcoticuse, bone lesion response, and quality of life also were evaluated.In general, all patients were receiving appropriate anticancerdrugs, most commonly melphalan (Alkeran) and prednisone.
During the 9 months of the trial, patients in the Aredia arm hadfewer skeletal-related events, a lower skeletal morbidity rate,and a longer time to the first skeletal-related event. They alsoneeded fewer analgesics and maintained their quality of life,Dr. Seaman said.
Patients in the placebo arm required more bone radiation for painrelief, and they had more bone morbidity and a greater numberof pathologic fractures. There was essentially no differencesin the two arms in radiographic bone lesion response and survivalrate.
The trial has just been completed and now has captured data fora total of 21 months, the company said. Final data from that portionof the trial is now being analyzed and will be submitted to theFDA when available.
At a dose of 90 mg of Aredia in 500 mL of 5% dextrose and watergiven over 4 hours once a month, serious adverse effects includedasymptomatic hypocalce-mia (two patients), allergic reaction (onepatient), transient skeletal pain, arth-ralgia, myalgia, and feveroccurring in the first 24 to 48 hours.
These effects occurred infrequently after the first or secondadministration of Aredia. Infusion site irritation and some minoreye problems (conjunctivitis and eye pain) were also seen.
There was no observed effect on liver and kidney function, althoughAredia is excreted more slowly in patients with very poor kidneyfunction. This phenomenon, however, should not have an effecton the administration of the drug, the company said.
The FDA recommends that future studies of Aredia concentrate onthe duration of treatment with the drug, the optimal time to beginAredia therapy, and its use in other malignancies such as breastcancer.
ODAC members were concerned about the fact that Ciba presentedonly one clinical trial, and that the planned clinical trial ofAredia for breast cancer has not yet been submitted. On the otherhand, the fact that the trial was both randomized and double blindlent a significant positive effect to the results, members ofthe committee said.
In addition, according to the FDA, there is precedent, albeitlimited, for approving a drug on the basis of one study.
The committee thus unanimously concluded that the trial did indeeddemonstrate that Aredia intravenous infusion, when given withstandard chemotherapy, is safe and effective for the preventionof skeletal morbidity in multiple myeloma patients with at leastone osteolytic lesion.