Adjusting for patient crossover in clinical trials using external data: a case study of lenalidomide for advanced multiple myeloma.

OBJECTIVES: In some trials, particularly in oncology, patients whose disease progresses under the comparator treatment are crossed over into the experimental arm. This unplanned crossover can introduce bias in analyses because patients who crossover likely have a different prognosis than those who do not cross over; for instance, sicker patients not responding to standard therapy or those expected to benefit the most may be selectively chosen to receive the experimental treatment. Standard statistical methods cannot adequately correct for this bias. We describe an approach designed to minimize the impact of crossover, and illustrate this by using data from two randomized trials in multiple myeloma (MM). METHODS: The MM-009/010 trials compared lenalidomide and high-dose dexamethasone (Len+Dex) with dexamethasone alone (Dex). Nearly half (47%) of the patients randomized to Dex crossed over to Len with or without Dex (Len+/-Dex) at disease progression or study unblinding. Data from these trials was used to predict survival in an economic model evaluating the cost-effectiveness of lenalidomide. To adjust for crossover, the prediction equations were calibrated to match survival with Dex or Dex-equivalent therapies in trials conducted by the Medical Research Council (MRC) in the United Kingdom. To adjust for differences between the MM and MRC trial populations, a prediction equation was developed from the MRC data and used to predict survival by setting predictors to mean values for patients in the MM-009/010 trials. The expected survival with Dex without crossover was then predicted from the calibrated MM-009/010 equation (i.e., adjusted to match survival predicted from the MRC equation). RESULTS: The adjusted median overall survival predicted by the MRC equation was 19.5 months (95%CI, 16.6-22.9) for patients with one prior therapy, and 11.6 months (95% CI, 9.5-14.2) for patients with >1 prior therapy. These estimates are considerably shorter than was observed in the clinical trials: 33.6 months (27.1-NE) and 27.3 months (95% CI, 23.3-33.3) as of December 2005. CONCLUSION: The calibration method described here is simple to implement, provided that suitable data are available; it can be implemented with other types of endpoints in any therapeutic area.

Evaluating technology for acquisition.

Cancer care consumes approximately 8% to 9% of all healthcare spending. The use of technology plays a key role in cancer, with both diagnostic and treatment implications, and technology is a large driver of healthcare spending. Understanding the role of technology and its integration in care may contribute to appropriate selection and utilization of technology, better decision making as to priorities in acquisition, and clinical cost efficiency.

Uniform response criteria in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is a malignant disorder of lymphoplasmacytic cells that produce a monoclonal immunoglobulin M (IgM). Since the original description by Jan Waldenström of three patients with symptoms of hyperviscosity due to circulating monoclonal IgM, the definition of WM has been controversial. Standardized criteria for diagnosis have now been proposed, including the presence of any IgM monoclonal protein and marrow and/or nodal lymphoplasmacytic cells. Although previous response criteria have generally incorporated parameters for monoclonal protein reduction and/or improvement of marrow/nodal involvement, specific and uniform response criteria are needed to facilitate comparisons of response, remission duration, progression-free survival, and overall survival in clinical trials similar to those previously established for other diseases such as chronic lymphocytic leukemia, lymphoma, and myeloma. This is of particular importance as new agents are developed and evaluated. This presentation represents consensus recommendations for uniform response criteria for use in assessing responses to treatment for patients with WM, which were prepared in conjunction with the Second International Workshop held in Athens, Greece during September 2002.

Implementation of PET scan as a new service.

Positron emission tomography (PET) is a diagnostic test using injected radiopharmaceuticals (drugs or compounds tagged with radioactive isotopes) to obtain images of metabolic/physiologic processes. PET provides physiologic data rather than just anatomic data such as that provided by CT scan or MRI. Metabolic changes precede anatomic changes, hence the higher accuracy of PET. Scar tissue, necrosis and tumor mass may appear identical on CT and MRI, but markedly different on PET. PET may decrease unnecessary surgeries and improve treatment through greater specificity about the disease and may provide a better evaluation of recurrent disease.