External control arms in oncology: current use and future directions.

Although randomized control trials allow for a comparison of treatment arms with minimal concern for confounding by known and unknown factors, a randomized study is not feasible in certain disease settings. When a randomized design is not possible, incorporating external control data into the study design can be an effective way to expand the interpretability of the results of an experimental arm by introducing the ability to carry out a formal or an informal comparative analysis. This paper provides an introduction to the concepts of external controls in oncology trials, followed by a review of relevant and current research on this topic. The paper also focuses on general considerations for designing a trial that may incorporate external control data, followed by case studies of the marketing applications submitted to the Food and Drug Administration that included external control data.

Concomitant botanical medicine use among patients participating in commercial prostate cancer trials.

OBJECTIVES: Patients with cancer frequently use botanical medications. The concomitant use of such medications by patients on commercial trials has not been well-described, despite the importance of these trials for evaluating the safety and efficacy of new agents. We sought to describe the use of botanical medications taken by patients with prostate cancer enrolled on global commercial trials. DESIGN: Retrospective study. SETTING: Regulatory repository of commercial clinical trial data. INTERVENTIONS: Anti-cancer therapy. MAIN OUTCOME MEASURES: Botanical and medication use data were pooled across six international commercial randomized trials for metastatic prostate cancer with detailed information on medication and indications. Botanical products were considered to have potential for drug interaction if they led to a change in drug exposure in human trials. Potential for interaction was ascertained by PubMed review. Descriptive statistics were used for analysis. RESULTS: Of 7318 enrolled patients, 700 (10 %) reported botanical use at any time and 653 (9%) reported use of botanical products while on trial. Nearly half of botanical product types were not classified by plant (43 %). The highest proportion of botanical use was among patients in Asian countries (32 %), followed by patients in North America (13 %). Eighty-six different types of botanical products were used; of these, nineteen had a patient-reported anti-cancer indication. CONCLUSIONS: Botanical medicine use among patients with prostate cancer in commercial trials is moderate, although it varies by region. Practitioners should be aware of the use of botanical interventions in a clinical trial context.

A Food and Drug Administration analysis of survival outcomes comparing the Adjuvant Paclitaxel and Trastuzumab trial with an external control from historical clinical trials.

BACKGROUND: Although the Adjuvant Paclitaxel and Trastuzumab (APT) trial has been adopted clinically, single-arm trials have limitations, and interest remains whether these patients with small node-negative human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) would benefit from more intensive chemotherapy. This analysis explored whether external controls can contextualize single-arm studies to add to clinical decision making in the use of de-escalated therapy in patients with low-risk HER2-positive EBC. PATIENTS AND METHODS: Patient-level data from five randomized trials supporting drug approval in adjuvant HER2-positive EBC were pooled, and patients with low-risk EBC were selected (n = 1770). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane/trastuzumab (ACTH) or taxane/carboplatin/trastuzumab (TCH; n = 1366) were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n = 406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT; n = 374) were also matched (1:1) to those treated with TH. Propensity scores were estimated using covariates of age, tumor stage, estrogen receptor status, progesterone receptor status, and histological grade. RESULTS: After matching, the estimated probabilities of invasive disease-free survival (iDFS) at 3 and 5 years were 98.6% and 96.5% in the TH arm, and 96.6% and 92.9% in the ACTH/TCH arm, respectively. The estimated probabilities of overall survival (OS) at 3 and 5 years were 99.7% and 99.3% in the TH arm, and 99.0% and 97.4% in the ACTH/TCH arm, respectively. Comparing the TH arm with the ACT arm in the matched sample, the estimated difference in iDFS was 7.5% (TH 98.8% and ACT 91.3%) at 3 years and 12.6% (TH 96.1% and ACT 83.5%) at 5 years. The estimated difference in OS was 2.6% (TH 100% and ACT 97.4%) at 3 years, and 5.3% (TH 99.3% and ACT 94.0%) at 5 years. CONCLUSIONS: Our analyses suggest that patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy.

Isozyme diversity in sour, sweet, and ground cherry.

Thirty-six sour (Prunus cerasus L.), sweet (P. avium L.), and ground cherry (P. fruticosa Pall.) selections were evaluated for seven enzyme systems and principal coordinate analysis was used to examine isozyme divergence among these cherry species. The enzyme systems studied were phosphoglucose isomerase (PGI), isocitrate dehydrogenase (IDH), phosphoglucomutase (PGM), 6-phosphogluconate dehydrogenase (6-PGD), leucine aminopeptidase (LAP), shikimate dehydrogenase (SKDH), and malate dehydrogenase (MDH). The first principal coordinate, which accounted for 41% of the total variation, separated the diploid sweet cherry selections from the sour, ground, and sour x ground cherry tetraploids. An additional 86 selections were evaluated for up to six of the enzyme systems to determine the polymorphisms at the enzyme loci and the level of heterozygosity between the diploid sweet cherry and the tetraploid species and interspecific hybrids. 6-PGD was the most polymorphic enzyme exhibiting 16 patterns. The tetraploid cherry species were more heterozygous than the diploid sweet cherry with an average heterozygosity of 78% compared to 19% for the diploids.

Haemoglobin inhibition of fibrin polymerization and clotting.

Clotting of human plasma by human alpha-thrombin was prolonged in the presence of haemoglobin as was human and bovine fibrinogen. Specifically, the clot time doubled for human plasma, human fibrinogen and bovine fibrinogen at 483, 233, and 116 microM haemoglobin, respectively. Fibrinopeptide A release was not inhibited at concentrations in approximately 16,000 molar excess compared with alpha-thrombin. Turbidometric analysis of fibrin polymerization showed a lengthening of the lag phase as well as the fibrin assembly process in the presence of haemoglobin. These findings suggested that neither fibrinogen recognition nor catalytic efficiency of thrombin was affected, implying that haemoglobin interferes with fibrin polymerization. Since human blood contains sufficient haemoglobin in erythrocytes to generate concentrations of up to 2.3 mM upon cell lysis, and haemoglobin concentrations of 0.16-0.48 mM caused 1.25 to two times longer clotting times in fresh human plasma, respectively, haemoglobin may act to modulate clot formation under conditions of haemolysis.