期刊
BMC CANCER
卷 13, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1471-2407-13-193
关键词
Randomized clinical trials; Gold standard; Phase II trials; Drug combinations; Biomarkers
类别
资金
- Align2Action
- Amgen
- Transport Canada
- SAIC
- Trinity Partners LLC
- Coleman Research Group
- Frankel Group
- Roche Canada
- AstraZeneca
- Pfizer Canada
- NIH
- US Department of Defense
- University of Michigan/SWOG
- Ventana
- IASLC
- University of Texas San Antonio
- American Radium Society
- AstraZeneca Taiwan
- 5th International Pulmonary Congress
- Aronex
- Centocor
- Concordia
- Exelixis
- GlaxoSmithKline
- Hoffman LaRoche
- Janssen
- Merck
- Novartis
Background: Randomized controlled trials with a survival endpoint are the gold standard for clinical research, but have failed to achieve cures for most advanced malignancies. The high costs of randomized clinical trials slow progress (thereby causing avoidable loss of life) and increase health care costs. Discussion: A malignancy may be caused by several different mutations. Therapies effective vs one mutation may be discarded due to lack of statistical significance across the entire population. Conversely, expensive large randomized trials may have sufficient statistical power to demonstrate benefit despite the therapy only working in subgroups. Non-cost-effective therapy is then applied to all patients (including subgroups it cannot help). Randomized trials comparing therapies with different mechanisms of action are misleading since they may conclude the therapies are equivalent despite benefitting different subpopulations, or may erroneously conclude that one therapy is superior simply because it targets a larger subpopulation. Furthermore, minor variances in patient selection may determine study outcome, a therapy may be discarded as ineffective despite substantial benefit in one subpopulation if harmful in another, randomized trials may more effectively detect therapies with minor benefit in most patients vs marked benefit in subpopulations, and randomized trials in unselected patients may erroneously conclude that shot-gun combinations are superior to single agents when sequential administration of personalized single agents might work better and spare patients treatment with drugs that cannot help them. We must identify predictive biomarkers early by comparing responding to progressing patients in phase I-II trials. Enriching randomized trials for biomarker-positive patients can markedly reduce required patient numbers and costs despite expensive screening for biomarker-positive patients. Available data support approval of new drugs without randomized trials if they yield single-agent sustained responses in patients refractory to standard therapies. Conversely, new approaches are needed to guide development of drug combinations since both standard phase II approaches and phase II-III randomized trials have a high risk of misleading. Summary: Traditional randomized clinical trials approaches are often inefficient, wasteful, and unreliable. New clinical research paradigms are needed. The primary outcome of clinical research should be Who (if anyone) benefits? rather than Does the overall group benefit?
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据