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Potential underestimation of cerebrovascular events in the PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data

We read with interest the article by Higano et al, which reported the results of the PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED). The authors reported a cerebrovascular event (CVE) rate of 2.8%; a prior pooled analysis of phase 3 trials reported a CVE rate of 3.5% among patients treated with sipuleucel-T. We would like to request clarification of the PROCEED methodology and analysis to help the reader interpret the results. First, in the Supporting Information, the authors indicate that “men were enrolled before receiving sipuleucel-T or within 6 months after the first leukapheresis to manufacture sipuleucel-T.” Thus, enrollment occurred prospectively (before receipt of sipuleucel-T) and retrospectively (within 6 months after the first leukapheresis), assuming that infusions were administered at approximate 2-week intervals. In the 2009 study by Higano et al, the median time from the first sipuleucel-T infusion to a CVE was 167 days (range, 26-859 days) and approximately one-half of the CVEs occurred within 6 months after the first sipuleucel-T infusion. Similarly, the median interval from “most recent infusion” to a CVE, as reported by Kantoff et al, was 210 days, indicating that approximately one-half of the CVEs occurred within 7 months of an infusion of sipuleucel-T. However, a recent report from the US Food and Drug Administration Adverse Event Reporting System (a passive surveillance system subject to limitations) noted that >50% of deaths reported occurred within 30 days of the most recent sipuleucel-T infusion. Therefore, CVEs that occurred within 6 months of leukapheresis potentially could be underascertained if affected patients did not enroll in the registry of long-term follow-up due to debilitated health status or death. In sum, retrospective enrollment results in potential underascertainment of CVEs (and deaths) and introduces a participation bias wherein those individuals who enrolled retrospectively may have enjoyed better health (they had the opportunity to survive for up to 6 months) than those who enrolled prospectively (who did not yet have the opportunity to survive the exposure). Second, in PROCEED, “all CVE data were collected, regardless of causality, severity, or outcome” and cases then underwent adjudication by an independent neurologist to include “all strokes (ischemic and hemorrhagic), intracranial hemorrhage, and TIAs [transient ischemic attacks].” However, the case definition of CVE in the original PROCEED protocol, which was used by study investigators submitting cases, is not described in the article, and it is unclear whether this definition differed from the one used by the adjudicator. The number of CVEs submitted by study investigators and excluded by the adjudicator, if any, was not specified. Retrospective case reviews may be challenging if medical records are not available or testing is not undertaken due to patient condition, contraindications, or patient refusal. The adjudication process may have used more stringent diagnostic criteria for CVE than the PROCEED study protocol, thereby resulting in fewer outcomes being identified and a potential underestimation of CVE rates. Therefore, a sensitivity analysis should be undertaken, first including all cases submitted by study investigators (who determined that the case met the definition of CVE as specified in the protocol) and then limited to adjudicated cases (with the specified CVE definition) to better understand true CVE rates and the effect of adjudication. Third, comparison of CVE rates in PROCEED with those in the preceding phase 3 clinical trials was limited by potential differences in the CVE case definition. Two of the studies did not specifically refer to CVEs; 1 study did not define the entities included in (or excluded from) CVE; and only 1 specified that “all types of CVEs (eg, hemorrhagic, ischemic, embolic, TIA, and bleeding from a dural metastatic lesion)” were included in the analyses. Because embolic stroke and bleeding from a dural metastatic lesion are not specified to be included in the PROCEED adjudication process, it is uncertain whether such events, and possibly others, were included in the analysis. It would be important for the authors to clarify the study design methodology and potential impact on results, the definition of CVE provided to PROCEED investigators and that which was used by the adjudicator, and the impact of the adjudication process on the CVE rate (sensitivity analysis).