Abstract

Background: Most newly-approved drugs – especially precision medicines – are administered at excessively high dosages. The 21st Century Cures Act and 2023 FDA Appropriations Act attempts to address this by recom- mending post-marketing studies that test lower drug dosages. These trials are rarely conducted due to perverse incentives (less drug reduces industry revenue), patient reluctance (risk that lower doses may be worse), and perception of limited demand for them (given optimal dosing regimens’ slow adoption). Overcoming these issues requires (1) deeper understanding of prescribers’ evidence requirements for using optimal dosing regimens, (2) development of new trial designs that test optimal dosing regimens, and (3) making the trial design paradigm more accessible and accountable to patients and payers. Response-adaptive randomized trials use interim re- sults to change the probabilities with which participants are assigned to a study’s different treatment arms. These designs are ideal for post-marketing dose optimization studies because they reduce the risk of Veterans receiv- ing doses that are too low, yet we know very little about how these trial designs would be accepted or adopted. Significance: Optimizing high-risk precision medicine dosages will reduce harms to Veterans, increase Veter- ans’ access to care, and improve VHA care’s value – helping to address major HSR&D priorities. This CDA engages Veterans in research design to ensure ORD-funded research aligns with Veterans’ values, increase Vet- erans’ access to innovative studies, and build community among Veterans with cancer – all ORD strategic priorities. Innovation & Impact: This CDA reverses canonical drug development. It builds qualitative methods by using role play-enhanced focus groups (Aim 1) and simulated clinical trials to inform deliberative democracy (Aim 3). It uses a novel quantitative method (response-adaptive randomized optimization) to optimize drug dose (Aim 2). Specific Aims: Aim 1: Assess prescribers’ barriers to accepting the results of different dose optimization study designs using role-play-enhanced focus groups of oncologists. Aim 1 identifies (1) prescriber knowledge gaps and preferences and (2) barriers to be addressed in a subsequent implementation intervention (Year 3 IIR). Aim 2: Develop and evaluate in simulated clinical trials response-adaptive randomized trial designs that address stakeholders’ optimal dosing regimen preferences. Aim 2 enables these new trial designs to be evaluated by Veterans. Aim 3: Engage Veteran stakeholders in clinical trial co-creation by conducting (3A) an informed con- sent discussion of a hypothetical trial and (3B) democratic deliberation (DD) of dose optimization trials’ tradeoffs. Methodology: Aim 1: Role-play-enhanced focus groups of a nationally representative sample of VHA and non- VHA oncologists. Groups will role-play an advisory panel tasked with evaluating an optimal dosing regimen, which will uncover oncologists’ authentic evidence requirements for dose optimization trials and their barriers to implementing optimized regimens. Evidence requirements will inform the trials developed and evaluated in Aim 2. Aim 2: Simulations, conducted in R, of ~1000 distinct trials (combinations of study design, sample size, and efficacy), with the intent of identifying trial designs that identify optimal dosage while minimizing risks to subjects (i.e., receiving too low a dose) and society (i.e., by falsely declaring a suboptimal dose to be efficacious). Aim 3: In 3A, we conduct individual interviews with Veterans with cancer and their caregiver(s) discussing a hypothetical dose optimization study, conducted through the lens of informed consent. Participants in 3A will be invited to join 3B, which will consist of a Citizen Jury DD sessions seeking Veteran consensus on 1) how optimization trial designs can best align with Veterans’ values and 2) how best to approach informed consent for these studies. Next Steps/Implementation: (1) Enhance optimal dosing regimen adoption in VHA through targeted implemen- tation intervention (Year 3 IIR; Aim 1 as preliminary data) and (2) enhance Veteran access and safety and VHA value by proposing the CDA’s end trial product as a VA-based dose optimization platform (Year 5 IIR). PI’s presentations to standing regulatory, administrative, and research collaborators will enhance VA’s global impact.

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DRA: Cancer

DRE: Research Infrastructure, TRL - Applied/Translational

Keywords: None at this time.

MeSH Terms: None at this time.