Costing 'the' MTD: what is the economic and human cost of 1-size-fits-all dose finding in oncology?
Creators: name: Norris, David C.
Publisher: name: F1000Research
Year: 2017

description: BACKGROUND: <br><br>Even after a decade of great advances for Bayesian adaptive design and model-based dose-finding, oncology dose-finding studies continue to pursue the mirage of ‘the’ maximum tolerated dose (MTD). This fallacious, anti-precision concept maintains a pretext for one-size-fits-all dosing that ignores the long-recognized heterogeneity of cancer patients’ pharmacokinetics and pharmacodynamics (PK/PD), as well as the equally important  diversity of their individual <i>values</i> and <i>goals of care</i>. Under this conceptual yoke, these dose-finding studies constitute a significant choke-point in drug development, where a severe discount may be applied to the potential value in new molecules through the hobbling of subsequent efficacy trials by inadequate individual-level dosing.<br><br>DOSE TITRATION ALGORITHM TUNING:<br><br>Dose Titration Algorithm Tuning (DTAT), a new methodologic advance [1], shows we can reconceive the aim of early-phase drug studies, not as ‘dose-finding’, but now as <i>dose titration algorithm (DTA)</i>-finding. This new conception lets us see through the mirage of <i>‘the’ MTD</i>, to a properly individualized notion of <i>MTD<sub>i</sub></i>.<br><br>IMPACT ON PATIENTS &amp; INNOVATION:<br><br>A large body of literature stretching back 2 decades ([2–4], <i>inter alia</i>) shows that patients who have adverse effects (such as neutropenia) from their chemotherapy also have better outcomes from treatment. DTAT allows safe titration to <i>each individual patient’s</i> maximum tolerated dose, so that each patient gets his or her best chance of achieving a remission. This, in turn, gives each investigational new drug (IND) the best chance to succeed in Phase 2 and 3 efficacy trials.<br><br>BEYOND THE CYTOTOXICS:<br><br>In the important area of immuno-oncology, common dose-limiting toxicities (DLTs) admit monitoring on time-scales comparable to the chemotherapy induced neutropenia (CIN) simulated in [1]. The cytokine release syndrome (CRS) that accompanies CAR-T therapies, for example, typically arises within 1 week of administration (even earlier with concomitant high-dose IL-2) and constitutes a clinical syndrome that admits multivariate monitoring on numerous quantitative clinical and laboratory measures. Even molecularly targeted agents (MTAs), for which late toxicities have attracted the lion’s share of attention, remain accessible to the DTAT principle—with DTA learning simply occurring on a longer time scale.<br><br>WHAT DTAT MEANS TO YOU:<br><br>DTAT presents a <i>prima facie</i> case for discarding the outmoded concept of ‘the’ maximum tolerated dose (MTD) of cancer therapeutics. The DTAT principle should be of interest to a wide range of stakeholders, from cancer patients with a stake in receiving optimal individualized ‘MTD<sub>i</sub>’ dosing, to shareholders in pharmaceutical innovation with a stake in efficient dose-finding before Phase III trials.<br><br>REFERENCES:

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