Sipuleucel-T (Provenge(®))-Autopsy of an Innovative Paradigm Change in Cancer Treatment: Why a Single-Product Biotech Company Failed to Capitalize on its Breakthrough Invention.

Approved by the US Food and Drug Administration (FDA) in 2010, sipuleucel-T (Provenge(®)) was the first 'personalized' cancer vaccine for the treatment of prostate cancer in a metastatic, non-symptomatic population of 30,000 men in the USA. Sipuleucel-T is prepared individually for each patient and infused in three sessions over a period of 1 month. However, in 2015, Dendreon, the owner of sipuleucel-T, filed for bankruptcy. This opinion paper reviews the probable reasons this innovative product failed to achieve commercial success. PubMed and internet searches were performed focused on pricing, reimbursement, and market access. We found that sipuleucel-T's FDA approval was delayed by 3 years, reportedly because of the vaccine's new mechanism of action. Sipuleucel-T was cleared by the European Medicines Agency 2 years later, but other national agencies were not approached. It was priced at $US93,000 for a course of treatment, and this high price combined with the company's late securement of reimbursement for the vaccine by the US Centers for Medicare and Medicaid Services (CMS) resulted in another year's delay in accessing the market. Despite a positive recommendation by the National Comprehensive Cancer Network, sipuleucel-T's complex administration, high price, and uncertainty about the reimbursement status deterred doctors from prescribing the product. Furthermore, the vaccine's supply was limited during the first year of launch due to limited manufacturing capacity. In addition, two oral metastatic prostate cancer drugs with similar survival benefits reached the US market 1 and 2 years after sipuleucel-T. Also, even though Dendreon's market capitalization topped $US7.5 billion following the FDA's approval of sipuleucel-T, this value degraded gradually until the firm's bankruptcy 5 years later. We conclude that the bankruptcy of Dendreon was largely due to the delay in securing FDA approval and CMS coverage, as well as the high cost that had to be incurred by providers up-front. Licensing sipuleucel-T to a pharmaceutical company more experienced in the market access pathway may have saved the company and the product.

Sipuleucel-T for the Treatment of Metastatic Hormone-Relapsed Prostate Cancer: A NICE Single Technology Appraisal; An Evidence Review Group Perspective.

The National Institute for Health and Care Excellence (NICE) invited Dendreon, the company manufacturing sipuleucel-T, to submit evidence for the clinical and cost effectiveness of sipuleucel-T for asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer patients in whom chemotherapy is not yet clinically indicated, as part of NICE's single technology appraisal process. The comparator was abiraterone acetate (AA) or best supportive care (BSC). The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper describes the company submission (CS), ERG review, and subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost-effectiveness evidence of sipuleucel-T based upon the CS. Clinical-effectiveness data relevant to the decision problem were taken from three randomised controlled trials (RCTs) of sipuleucel-T and a placebo (PBO) comparator of antigen-presenting cells (APC) being re-infused (APC-PBO) (D9901, D9902A and D9902B), and one RCT (COU-AA-302) of AA plus prednisone vs. PBO plus prednisone. Two trials reported a significant advantage for sipuleucel-T in median overall survival compared with APC-PBO: for trial D9901, an adjusted hazard ratio (HR) 0.47; (95 % confidence interval [CI] 0.29, 0.76) p < 0.002; for D9902B, adjusted HR 0.78 (95 % CI 0.61, 0.98) p = 0.03. There was no significant difference between groups in D9902A, unadjusted HR 0.79 (95 % CI 0.48, 1.28) p = 0.331. Sipuleucel-T and APC-PBO groups did not differ significantly in time to disease progression, in any of the three RCTs. Most adverse events developed within 1 day of the infusion, and resolved within 2 days. The CS included an indirect comparison of sipuleucel-T (D9902B) and AA plus prednisone (COU-AA-302). As trials differed in prior use of chemotherapy, an analysis of only chemotherapy-naïve patients was included, in which the overall survival for sipuleucel-T and AA was not significantly different, HR 0.94 (95 % CI 0.69, 1.28) p = 0.699. The ERG had several concerns regarding the data and assumptions incorporated within the company's cost-effectiveness analyses and conducted exploratory analyses to quantify the impact of making alternative assumptions or using alternative data inputs. The deterministic incremental cost-effectiveness ratio (ICER) for sipuleucel-T vs. BSC when using the ERG's preferred data and assumptions was £ 108,585 per quality-adjusted life-year (QALY) in the whole licensed population and £ 61,204/QALY in the subgroup with low prostate-specific antigen at baseline. The ERG also conducted an incremental analysis comparing sipuleucel-T with both AA and BSC in the chemotherapy-naïve subgroup. Sipuleucel-T had a deterministic ICER of £ 111,682/QALY in this subgroup, when using the ERG's preferred assumptions, and AA was extendedly dominated. The ERG also concluded that estimates of costs and benefits for AA should be interpreted with caution given the limitations of the indirect comparison. The AC noted that the ICER for sipuleucel-T was well above the range usually considered cost effective, and did not recommend sipuleucel-T for the treatment of asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer.