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Optimizing the doses of cancer drugs after usual dose finding
Garth W Strohbehn1,2,3,4, Walter M Stadler5, Philip S Boonstra3,6
1Veterans Affairs Center for Clinical Management Research, Ann Arbor, MI, USA.
Abstract:
Since the middle of the 20th century, oncology's dose-finding paradigm has been oriented toward identifying a drug's maximum tolerated dose, which is then carried forward into phase 2 and 3 trials and clinical practice. For most modern precision medicines, however, maximum tolerated dose is far greater than the minimum dose needed to achieve maximal benefit, leading to unnecessary side effects. Regulatory change may decrease maximum tolerated dose's predominance by enforcing dose optimization of new drugs. Dozens of already approved cancer drugs require re-evaluation, however, introducing a new methodologic and ethical challenge in cancer clinical trials. In this article, we assess the history and current landscape of cancer drug dose finding. We provide a set of strategic priorities for postapproval dose optimization trials of the future. We discuss ethical considerations for postapproval dose optimization trial design and review three major design strategies for these unique trials that would both adhere to ethical standards and benefit patients and funders. We close with a discussion of financial and reporting considerations in the realm of dose optimization. Taken together, we provide a comprehensive, bird's eye view of the postapproval dose optimization trial landscape and offer our thoughts on the next steps required of methodologies and regulatory and funding regimes.
Insights
The traditional oncology maximum tolerated dose (MTD) approach for cancer drugs often leads to excessive side effects. Post-approval dose optimization trials are crucial for refining cancer drug efficacy and patient safety.
Area of Science:
- Oncology
- Clinical Trial Design
- Pharmacology
Background:
- The established oncology paradigm focuses on maximum tolerated dose (MTD), which frequently exceeds the optimal therapeutic dose for precision medicines.
- This MTD approach can result in unnecessary patient toxicity and suboptimal treatment outcomes.
Purpose of the Study:
- To evaluate the historical and current practices in cancer drug dose finding.
- To propose strategic priorities and ethical considerations for post-approval dose optimization trials.
- To outline key design strategies, financial, and reporting aspects for future dose optimization studies.
Main Methods:
- Review of historical and current dose-finding paradigms in oncology.
- Analysis of existing and proposed methodologies for post-approval dose optimization trials.
- Discussion of ethical frameworks and strategic priorities for trial design.
Main Results:
- The current MTD paradigm is often misaligned with the effective dose for modern precision cancer medicines.
- Post-approval dose optimization presents significant methodological and ethical challenges.
- Several design strategies can balance ethical standards with patient and funder benefits.
Conclusions:
- Re-evaluating approved cancer drugs through dose optimization trials is essential.
- Future trials require novel methodologies, regulatory adaptations, and funding structures.
- Optimizing cancer drug doses post-approval can enhance efficacy and minimize toxicity.
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