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Patient-Centered, Physician-Investigator Friendly Pragmatic Phase I/II Trial Designs—The 4P Model

      To the Editor:
      Traditional dose finding studies designed around safety and toxicity offer no flexibility for physician-investigators or patients. With the recent advent of targeted and immunotherapy, a few early-phase trials in oncology have started opening up physician-investigators’ flexibility to exercise their clinical judgment in the evaluation and care of their enrolled patients. For example, immunotherapy trials may allow treatment past progression for investigator-perceived clinical benefit. Yet still most trials mandate that patients come off trial based on RECIST measures, and only a few are flexible to continue beyond clinical progression for clinical benefit. With respect to the crucial question of drug dosing,
      • Daugherty C.K.
      • Siegler M.
      • Ratain M.J.
      • Zimmer G.
      Learning from our patients: one participant’s impact on clinical trial research and informed consent.
      early-phase trials still impose algorithmic rigidities or statistical formalities on us, hampering our clinical judgment. Even when dose reductions or intrapatient dose escalation are permitted, these occur neither by a clinically coherent
      • Norris D.C.
      Comment on Wages et al, Coherence principles in interval-based dose finding. Pharmaceutical Statistics 2019, doi:10.1002/pst.1974 [published online ahead of print March 29, 2020].
      design nor with adequate formal supports.
      The recent advent of pragmatic phase 1 dose-titration designs,
      • Norris D.C.
      Dose titration algorithm tuning (DTAT) should supersede ‘the’ maximum tolerated dose (MTD) in oncology dose-finding trials.
      ,
      • Norris D.C.
      Precautionary coherence unravels dose escalation designs.
      however, facilitates extending such support to clinical judgment in matters of dose individualization. By generalizing one such design
      • Norris D.C.
      Precautionary coherence unravels dose escalation designs.
      to incorporate measures of therapeutic response, we wish to exemplify a “4P” concept of patient-centered, physician-investigator friendly pragmatic phase I/II trial design.
      During on-trial follow-up, early-phase trial participants ask their oncologists several characteristic questions:
      • 1.
        Have you found signs my cancer is or isn’t responding to the study drug?
      • 2.
        How does my experience compare with other patients in this trial?
      • 3.
        Should I keep taking the drug at my current dose, or should we change the dose—or even stop it?
      Current phase I/II trial designs offer us no rational support for meeting these valid and urgent questions. To this end, we propose a synoptic graphical “trial dashboard” (Figure).
      Figure thumbnail gr1
      FigureThe dose-titration diagram (A) and “dose-survival curve” (B) introduced in reference 4 constitute the upper half of our 4P dashboard. The bottom half represents extensions motivated by our 3 use cases. A vertical “swimmer plot” (C) hangs downward from the dose-titration plot, depicting dose titration by color saturation, and key clinical events by markers. A “titration heuristic” plot (D) aligns likewise with the dose-survival curve above it, thereby scaling doses according to population level tolerability. Consequently, the trial population will tend toward uniform distribution horizontally when titration to final dosing is complete, rendering this plot more directly useful as a starting point for inference. CR = complete response; DLT = dose-limiting toxicity; PR = partial response.
      Building on a previously described phase 1 dose-titration graphic,
      • Norris D.C.
      Precautionary coherence unravels dose escalation designs.
      we see questions 1 and 2 as use cases for a swimmer plot
      • Phillips S.D.
      Swimmer plot: tell a graphical story of your time to response data using PROC SGPLOT. In: PharmaSUG 2014 Conference Proceedings; June 1-4, 2014; San Diego, CA. Paper DG07.
      linked to the dose-titration diagram. Question 3 underscores the imperative to maintain an up-to-date titration heuristic, incorporating emerging evidence that links drug-exposure measures (including on-target toxicities) with clinical response. This latter consideration prompts addition of response-vs-exposure plots in which both absolute dose and grade of on-target toxicity appear as covariates.
      This clinically realistic dashboard illuminates a 4P concept that bolsters patient-centered decision making in early-phase oncology trials. Moreover, by accentuating crucial decision problems faced by early-phase cancer trial participants and their oncologists, this model should help trial methodologists to propose useful adjunctive formal decision supports.

      References

        • Daugherty C.K.
        • Siegler M.
        • Ratain M.J.
        • Zimmer G.
        Learning from our patients: one participant’s impact on clinical trial research and informed consent.
        Ann Intern Med. 1997; 126: 892-897
        • Norris D.C.
        Comment on Wages et al, Coherence principles in interval-based dose finding. Pharmaceutical Statistics 2019, doi:10.1002/pst.1974 [published online ahead of print March 29, 2020].
        (Pharm Stat)
        • Norris D.C.
        Dose titration algorithm tuning (DTAT) should supersede ‘the’ maximum tolerated dose (MTD) in oncology dose-finding trials.
        F1000Res. 2017; 6: 112
        • Norris D.C.
        Precautionary coherence unravels dose escalation designs.
        (bioRxiv)
        • Phillips S.D.
        Swimmer plot: tell a graphical story of your time to response data using PROC SGPLOT. In: PharmaSUG 2014 Conference Proceedings; June 1-4, 2014; San Diego, CA. Paper DG07.