Setting clinical performance specifications to develop and evaluate biomarkers for clinical use

Background: Biomarker discovery studies often claim ‘promising’ findings, motivating further studies and marketing as medical tests. Unfortunately, the patient benefits promised are often inadequately explained to guide further evaluation, and few biomarkers have translated to improved patient care. We present a practical guide for setting minimum clinical performance specifications to strengthen clinical performance study design and interpretation. Methods: We developed a step-by-step approach using test evaluation and decision-analytic frameworks and present with illustrative examples. Results: We define clinical performance specifications as a set of criteria that quantify the clinical performance a new test must attain to allow better health outcomes than current practice. We classify the proposed patient benefits of a new test into three broad groups and describe how to set minimum clinical performance at the level where the potential harm of false-positive and false-negative results does not outweigh the benefits. (1) For add-on tests proposed to improve disease outcomes by improving detection, define an acceptable trade-off for false-positive versus true-positive results; (2) for triage tests proposed to reduce unnecessary tests and treatment by ruling out disease, define an acceptable risk of false-negatives as a safety threshold; (3) for replacement tests proposed to provide other benefits, or reduce costs, without compromising accuracy, use existing tests to benchmark minimum accuracy levels. Conclusions: Researchers can follow these guidelines to focus their study objectives and to define statistical hypotheses and sample size requirements. This way, clinical performance studies will allow conclusions about whether test performance is sufficient for intended use

Neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with systemic chemotherapy in patients with breast cancer

BACKGROUND AND PURPOSE: This is the first study investigating neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with chemotherapy in patients with breast cancer. The goal was to evaluate the type of surgical treatment, histopathologic response, side effects, local control, and survival. PATIENTS AND METHODS: 53 patients, who could not be treated with breast-conserving surgery due to initial tumor size (36/53) or due to an unfavorable breast-tumor ratio (17/53), were analyzed retrospectively. All but one were in an intermediate/high-risk group (St. Gallen criteria). The patients received a neoadjuvant protocol consisting of systemic chemotherapy combined with fractionated HDR brachytherapy (2 x 5 Gy/day, total dose 30 Gy). In cases, where breast-conserving surgery was performed, patients received additional external-beam radiotherapy (EBRT, 1.8 Gy/day, total dose 50.4 Gy). In patients, who underwent mastectomy but showed an initial tumor size of T3/T4 and/or more than three infiltrated lymph nodes, EBRT was also performed. RESULTS: In 30/53 patients (56.6%) breast-conserving surgery could be performed. The overall histopathologic response rate was 96.2% with a complete remission in 28.3% of patients. 49/53 patients were evaluable for follow-up. After a median of 58 months (45-72 months), one patient showed a mild fibrosis of the breast tissue, three patients had mild to moderate lymphatic edema of the arm. 6/49 (12.2%) patients died of distant metastases, 4/49 (8.2%) were alive with disease, and 39/49 (79.6%) were free from disease. Local recurrence was observed in only one case (2%) 40 months after primary therapy. After mastectomy, this patient is currently free from disease. CONCLUSION: The combination of interstitial HDR brachytherapy and chemotherapy is a well-tolerated and effective neoadjuvant treatment in patients with breast cancer. Compared to EBRT, treatment time is short. Postoperative EBRT of the whole breast -- if necessary -- is still possible after neoadjuvant brachytherapy. Even though the number of patients does not permit definite conclusions, the results are promising regarding survival and the very low rate of local recurrences

Practical guide for identifying unmet clinical needs for biomarkers

The development and evaluation of novel biomarkers and testing strategies requires a close examination of existing clinical pathways, including mapping of current pathways and identifying areas of unmet need. This approach enables early recognition of analytical and clinical performance criteria to guide evaluation studies, in a cyclical and iterative manner, all the time keeping the clinical pathway and patient health outcomes as the key drivers in the process. The Test Evaluation Working Group of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM TE-WG) https://www.eflm.eu/site/ page/a/1158 has published a conceptual framework of the test evaluation cycle which is driven by the clinical pathway, inherent to which is the test purpose and role within the pathway that are defined by clinical need. To supplement this framework, the EFLM TE-WG has also published an interactive checklist for identifying unmet clinical needs for new biomarkers; a practical tool that laboratories, clinicians, researchers and industry can equally use in a consistent manner when new tests are developed and before they are released to the market. It is hoped that these practical tools will provide consistent and appropriate terminology in this diverse field and offer a platform that facilitates greater consultation and collaboration between all stakeholders. The checklist should assist the work of all colleagues involved in the discovery of novel biomarkers and implementation of new medical tests. The tool is aligned with the IOM recommendations and the FDA and CE regulating body’s requirements