In the short life of Sam Grady, dates are divided into two categories: days that came before the 3-year-old's July 1 diagnosis of leukemia and the days that followed.
Before July 1, the Lehigh Township boy loved tearing through the house with his older brother Eli and watching "SpongeBob SquarePants." Since then, he has lost his hair and grown nauseous from his chemotherapy; it took weeks for his parents to adapt to their new reality.
His mother, Pauline Grady, said she feared a third time period for Sam: the dates after her son missed taking methotrexate, the medicine essential to his recovery.
Doctors at Lehigh Valley Hospital-Muhlenberg in Bethlehem administered the drug to him Monday via spinal tap, but national reserves of the drug were reduced to a two-week supply at the time.
"It's worth its weight in gold," Pauline Grady said of the drug. She took a photo of it Monday, not knowing if it was the last time her son would receive a dose of the medicine.
Dr. Leslie Simpson, one of Sam's physicians, described methotrexate as a miracle drug for battling leukemia in children.
Without it, children face a stronger risk of the cancer spreading to the brain, which would require radiation treatment. Children receiving radiation face strong risks of brain tumors, delayed growth and a drop in IQ, Simpson said.
Without drug, brain at risk
As supplies dwindled, the hospital began to reschedule cancer patients to receive care at the same time so they could use medicine from the same vial, Simpson said. Her clinic treats 20 children in the Lehigh Valley for leukemia, and she estimated another 10 to 15 families in the area travel to Hershey or Philadelphia for similar treatments.
"We really need this drug to keep the leukemia from going to the brain," she said.
Concerns of a shortage have dropped in the last week, and local hospital officials are hopeful rationing won't be needed. The Food and Drug Administration approved foreign imports of the drug Tuesday as a short-term solution.
The FDA also cleared two American companies to begin producing it. It could take weeks for production to meet the demand, however.
"We're cautiously optimistic that this will be a cork in the damn," Simpson said.
Patrick Ferguson, network director of pharmacy for St. Luke's hospitals throughout the region, said the drug fell into short supply after Ben Venue Laboratories, one of the nation's largest suppliers of methotrexate, shut down its production in November over quality concerns.
Without the company's supplies, stocks of the drug dropped to dangerous lows.
"This is one of the worst times I can think of in pharmacy of trying to get a hold of a drug," Ferguson said. He added that St. Luke's had an adequate supply of the drug, which is also used to treat rheumatoid arthritis, but St. Luke's treats fewer patients needing the drug than Lehigh Valley Hospital.
Seeking a production incentive
Simpson and Ferguson said the near shortage was created in part because of economics. Medicine for children with cancer is a niche market that doesn't receive much funding, so pharmaceutical companies move on to more profitable ventures.
Pauline Grady plans to head to Washington, D.C., to attend Childhood Cancer Action Day. On June 4 and 5, she and other advocates will meet with members of Congress in a push to get more funding for pediatric cancer research.
One of the measures supporters are pressing for is the Creating Hope Act, which would put profitable pharmaceuticals on the fast track for approval if the companies making them increase production of less profitable, but needed, medications. The scare families received last week proved the need for such a law, Grady said.
"Crisis averted for four weeks. But what's it going to be in May?" Grady said.
U.S. Sen. Bob Casey, D-Pa., is one of the bill's supporters. He and a group of bipartisan senators called on the president of Ben Venue Laboratories to explain what forced the company to shut down production of methotrexate.
In the meantime, Simpson said Sam Grady has responded fabulously to the treatment. Pauline Grady said there have been days she's felt like quitting. But then she sees Sam laughing and smiling with his brother, and it gives her the strength to continue.
"For a 3-year-old with leukemia, he's doing great. He's the definition of resilience," Grady said.
Missing Data Lead FDA Panel to Vote Against Rivaroxaban for ACS May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine. Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data. We Don't Know What We're Missing Based on the ATLAS ACS 2 results, FDA reviewer Dr Karen Hicks recommended approval of rivaroxaban for the requested indications except all-cause mortality. However, another FDA reviewer, Dr Thomas Marciniak, was adamant that the trial results are not interpretable because about 12% of the patients had incomplete follow-up, far higher than the 1% to 1.5% differences in the end-point rates between rivaroxaban and placebo. A total of 1294 subjects discontinued the trial prematurely, and the company was only able to contact 183, of which 177 were confirmed to be alive. Because of the patient dropouts, the company adopted a "modified intention-to-treat analysis," whereby patients were observed for 30 days after randomization or the global end date for the trial, instead of observing all the patients until the end of the trial as the FDA originally suggested. Marciniak criticized the sponsor's efforts to follow the patients and said that three patient deaths not counted in the modified intention-to-treat analysis may just be the "tip of the iceberg." Because the percentage of patients whose ultimate vital status remains unknown is much greater than the reported differences in mortality rates, the claimed mortality benefits are not reliable. The majority of the panel sided with Marciniak. For example, Dr Sanjay Kaul (University of California, Los Angeles) voted "no" because "there was enough uncertainty in the quality and robustness of the data that dissuaded me from voting yes. . . . The 'missingness' of the data doesn't invalidate it, but it certainly makes it hard to infer [the conclusion]." Dr Steven Nissen (Cleveland Clinic, OH) said that the decision to use the modified intention-to-treat analysis had a "profound impact" on the interpretability of the data. "It's saying we don't care what happens after 30 days, [and] that colored the trial in ways we couldn't recover from." Given the risk of major bleeding, "I want to see better evidence that this strategy of adding an Xa inhibitor or a direct thrombin inhibitor or something else to a good antiplatelet agent is robustly better for the patient," Nissen said. He recommends that the companies run a new trial of the 2.5 twice-daily dose of rivaroxaban using a strict intention-to-treat approach, but, he said, "I don't expect the death benefit to be too robust." Several panelists said they were concerned that the patients who dropped out of the trial were disproportionately likely to have a bleeding event, which led them to quit the trial, or a "protopathic" event, as statistician Dr Scott Emerson (University of Washington, Seattle) put it. "We're worried that an impending event is what is changing their behavior. We see that all the time in clinical trials--that regularly measured end points do not pick up [all of] the events," he said. He said that since the company was only able to contact 183 of the over 1200 patients who dropped out, it is possible that the dropouts skew the outcomes comparison of the trial. "Differential event rates after dropout are the number-one thing we're afraid of, so you have to explore it" in a statistical sensitivity analysis of the potential impact of these unknown outcomes. "It would not surprise me if, at the end of the day, these data did not hold up under a proper sensitivity analysis," he said. "What I want to know is, among the people who had events, how differential was the follow-up, but I can tell you by just looking at it, there was a very slightly different amount of follow-up of the people in the treatment arm. But I don't know whether everyone in the treatment arm was cured and they were trekking in the Himalayas and everyone in the placebo arm went home to die. I don't know that that's not the case." Dr Maury Krantz (University of Colorado, Denver) voted in favor of approval but said he does not know how rivaroxaban would perform in general clinical practice, especially when used with aspirin and clopidogrel. "I felt very much torn by this. This isn't a simple paradigm shift. It means going to triple therapy, which is really a three-headed monster in many ways. I think that what you're going to see in practice, if this is not done carefully with the proper labeling and secondary studies, is really dramatic magnification of bleeding and perhaps minimization of the efficacy benefit."
May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting , the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel , or ticlopidine . Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the ri...
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