Blockbuster sepsis drug drotrecogin alfa (activated) receives FDA approval
Pharmacists share concerns about cost, appropriate use
The Food and Drug Administration (FDA) has approved the first biologic treatment for the most serious forms of sepsis, a life-threatening illness caused by severe infection. The price tag for drotrecogin alfa (activated) (Xigris) is high, however, and some pharmacists wonder if the risk factors are steep, too.
"[The drug] may hold some benefit in a certain subgroup of septic patients," says Daniel Albrant, PharmD, president of Pharmacy Dynamics, a health care consulting business based in Arlington, VA. "But it’s always going to have a significant downside with a bleeding risk and maybe some other things we don’t know about yet. It’s not going to cure sepsis."
Drotrecogin alfa (activated) is a genetically engineered version of naturally occurring human protein C, which interferes with some of the body’s harmful responses to severe infection. The drug is indicated for patients with severe sepsis (sepsis associated with severe organ dysfunction) who have a high risk of death.
FDA approval was based on results from the Phase III PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial. In the trial, researchers studied 1,690 sepsis patients, giving half of the participants the drug and the other half a placebo. Results showed a 6% reduction in the overall mortality rate, from 31% to 25%, during the 28-day study period. Among patients who had higher risks of dying, mortality was reduced by 13%. Drotrecogin alfa (activated) did not lower mortality rates in study patients who were less severely ill.
Following approval of the drug, Dept. of Health and Human Services Secretary Tommy Thompson issued an unusual statement praising the FDA’s decision. "Today’s approval of the new weapon against sepsis, called Xigris, is a hopeful milestone because this product is designed to actually interrupt the body’s harmful responses to severe infection." He went on to "congratulate the researchers whose long efforts have yielded Xigris," and he commended the FDA for its "careful work in reviewing the monitoring of this new product."
Approval of drotrecogin alfa (activated), however, was not a guarantee for Indianapolis-based drug manufacturer Eli Lilly. On Oct. 16, the FDA’s Anti-Infective Drugs Advisory Committee voted not to recommend the drug’s approval based on information that indicated the drug was not as safe or effective as previously thought. Some reports say that 10 of 20 panel members voted against the drug. The majority of the panel members suggested that Eli Lilly conduct additional tests on drotrecogin alfa (activated).
Possible side effect: Bleeding
Instead, the FDA voted to approve the drug for a subgroup of sepsis patients, while warning of the possible side effect of bleeding. During the time when the drug was infused in the trial (continuously over four days), serious bleeding episodes occurred in 2.4% of patients treated with drotrecogin alfa (activated) compared to 1% of patients in the placebo group. The drug is contraindicated for patients who have active internal bleeding, or who are more likely to bleed because of certain medical conditions, including recent strokes, recent head or spinal surgery, or severe head trauma.
Ten panel members said they didn’t think this drug has enough scientific evidence to be approved, Albrant says. "That has to be taken into account even though the FDA gave the go-ahead. There isn’t any other agent that we have for severe sepsis — each individual institution must decide whether it [the drug] is going to make a significant impact."
Albrant doesn’t believe that any single agent is going to make a big difference in the multifactorial problems associated with sepsis. "We don’t really understand a lot of what goes on in sepsis. Now we have a compound that we are going to throw at these folks. We don’t know if this is the right dose. We don’t know if this is the right duration."
One study — basically 850 patients — is not a lot to go on, he continues. "It’s hard to make a decision on this drug given the fact that we have so many unanswered questions."
It’s likely that Xigris will make some small benefit, he adds, but drugs coming out of research trials never perform as well as they do in clinical practice because of the vagaries of how they are used and patient idiosyncrasies. He also is concerned about the bleeding risk. "The bleeding was almost statistically significant in that small population. If you look at the contraindications of the drug, they are all bleeding issues."
If people start to bleed dramatically, there is no antidote, he says. "We start using precious resources like blood and blood products that carry their own risks." Plus, some patients may end up spending more days in the intensive care unit (ICU). "At $1,500 a day for the cost of an ICU bed, you eat up a lot of dollars."
Albrant is urging his clients to be cautious with the drug. Physicians, however, are telling him that it would be hard not to use it. If they wait, they might become vulnerable to lawyers who argue, "You had this drug available, why didn’t you use it?"
Albrant counters by saying that drotrecogin alfa (activated) isn’t a standard of care at this point. From a tort standpoint, lawyers usually look at what is the standard of care, he says. "In this case, it is still mechanical ventilation, fluids, antibiotics, and agents for blood pressure. I don’t think anyone can argue that it is a standard of care yet. There is no clinical experience with it."
The budget eater
Even if health systems are eager to use drotrecogin alfa (activated), they have to find a way to pay its hefty price tag. The average net wholesale price is $6,800 per 96-hour course of therapy.
An average-size hospital can see 100 septic patients a year. That is beyond a challenge to budget, Albrant says. "There is no way to budget for a drug that is going to cost somewhere between a half-million dollars to $1 million in the average pharmacy budget. As a percentage, a single drug that is going to eat up 20%-25% of an average pharmacy budget is unheard of."
He suggests treating the drug as a capital expenditure and not as a pharmacy addition. "People who are making financial decisions for the institution need to understand the impact of adding this drug to the formulary." These decision-makers also need to decide if they can afford to add the drug while they learn if any other morbidities are associated with it.
New cost of doing business
Although the drug is considered very expensive, at least one health system’s chief financial officer considers drotrecogin alfa (activated) a new cost of doing business. "Our guiding principal will be, Based on clinical criteria, does the patient need this drug?’ more than Look how expensive this drug is, can we [afford to] use it?’" says Steve Dedrick, MS, director of pharmacy at Duke Medical Center in Durham, NC. "We are going to keep it patient-focused and criteria-focused, and we are going to sensitize everyone to the cost, but [the cost] is not going to be the No. 1 knee-jerk reaction."
How can we learn more?
Dedrick wishes that some sort of central database existed where health care professionals could report their individual experiences with drotrecogin alfa (activated). "It would be nice to be able to report conditions and outcomes of patients who receive the drug. We’d get smarter sooner in aggregate rather than one hospital trying to figure it out for itself."
Albrant would like the drug to undergo more trials that examine some of the issues outstanding from the PROWESS trial. Eli Lilly already has agreed to do more research. As part of its Phase IV commitments, Lilly will work with the FDA to institute post-approval trials that will include a study of the efficacy of the drug in adult patients with severe sepsis who have a lower risk of death. Eli Lilly also plans to follow up on its PROWESS patients for up to one year.
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