In the past year there have been several notable, and expensive, reconsiderations of drugs. Erythropoietin after years of use and billions spent was shown to worsen outcomes and Avastin in breast cancer, again after billions spent, was shown to do nothing to improve outcome.
It’s therefore a medicynical imperative to look at new drugs and their reported efficacy and cost.
Provenge (sipuleucel-T) has been greeted with great enthusiasm. It does offer “hope” for certain prostate cancer victims.
When one reads the small print of the studies that resulted in FDA approval (July 29, 2010 NEJM), it turns out that the drug has very limited benefit especially considering the cost ($93,000) for one month’s treatment.
The Kaplan-Meier survival curves tells the tale. (see the article for the shape of the curve) The following summarizes that data:
No. Patients at 0 12 24 36 48 60
Risk in months
Sipuleucel-T 341 274 129 49 14 1
Placebo 171 123 55 19 4 1
When comparing the surviving cohorts note that there was a 2:1 randomization.
From the small numbers in the study it’s apparent that a very small difference in the selection or disease biology in just a few patients could account for the survival “differences.” Consider at 1 year the difference taking into account the 2:1 randomization is just 28 patients, at two years 19 patients and at 36 months just 10. At 60 months one patient survived in each group. Another way of putting it is that for the $93,000/patient cost or 33 million dollars for the entire group treated, at one year there was a mere 28 patient differential in survival between the treated and placeobo. That’s a cost of over a million dollars a patient for the benefit at one year.
There are other problems with the study as noted in the accompanying editorial:
The median survival was 25.8 months in the sipuleucel-T group, as compared with 21.7 months in the placebo group (unadjusted hazard ratio for death in the sipuleucel-T group, 0.77; P=0.02). Study-group assignment had no significant effect on the time to tumor progression; 1 of 341 patients in the sipuleucel-T group had a partial tumor response, and 3% had a reduction of at least 50% in PSA level on two visits at least 4 weeks apart. Thus, the improvement in survival came without evidence of a measurable anti-tumor effect.
First, a better control group would have included patients receiving PBMCs incubated with GM-CSF alone so that the main variable between the two study groups would be the tumor antigen.
Second, the prolongation of survival without a measurable anti-tumor effect is surprising. It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor progression. This lack of tumor effect raises concern that the results could have been influenced by an unmeasured prognostic variable that was accidentally imbalanced in study-group assignments.
Another concern with sipuleucel-T treatment is the cost. The current cost of care for men with prostate cancer has been estimated to be about $1,800 per month.10 The manufacturer has set the cost of a 1-month course of sipuleucel-T at $93,000, or $23,000 per month of survival advantage. The high cost may affect use. It is also uncertain what role sipuleucel-T will ultimately play in the treatment of prostate cancer, given the other promising treatments in development.
Medicynical note: This is an exceptionally expensive drug with an exceptionally limited benefit. No evidence of tumor regression save a transient decrease in PSA in 3% of patients and just a 4 month median survival benefit. Worth the money? Thinks the results will be confirmed?
Carpe Diem would appear this drug company’s watchword.