132: Strategic Selection of Clinical Trial Core Outcomes Customized to Disease & Drug Therapy: Examples Generated During coreVWD & coreHEM Initiatives

Statement of Purpose, Innovation or Hypothesis: Core outcome sets (COSs) developed with multistakeholder consensus facilitate alignment and consistency in outcomes recommended to be measured in every clinical trial for a given condition. We developed two COSs for rare bleeding disorders: coreHEM for gene therapy for hemophilia and coreVWD for prophylaxis and perioperative treatment for von Willebrand Disease (VWD).

Description of Methods & Materials: For both initiatives, a modified Delphi method was used to condense and prioritize a long list of candidate outcomes that was compiled from a literature/evidence review. International multistakeholder groups were invited to the Delphi panels (Table 1). Panelists rated each outcome on a scale from 1 (least important to include in a COS) to 9 (critical to include). Outcomes were retained or eliminated over three voting rounds based on pre-set criteria: if ≥70% of the panel rated the outcome 7-9, the outcome moved to the next round, otherwise it was dropped. We also incorporated patient-important criteria during Delphi Rounds 1 and 2 to elevate patient opinions. If the average rating by the patient group was ≥7, an outcome up for elimination could be retained. All outcomes had to reach full consensus in the final Delphi round, which was held after an in-person consensus meeting for each initiative.

Data & Results: Efficacy outcomes are listed in the final COSs (Figure 1); a special subset of outcomes for women, girls, and people with the potential to menstruate (WGPPM) are within the prophylaxis branch for coreVWD. The coreVWD COS focuses on multiple bleeding outcomes (frequency, severity, and duration of bleeds, as well as categorizing bleeds that need treatment and whether they are mucocutaneous or musculoskeletal) compared to coreHEM, which has just one (frequency of bleeds). This accounts for both the bleeding experiences of the two conditions and the current standards of access to treatment. Musculoskeletal bleeds account for 80-90% of bleeds in people with hemophilia (PWH) and the annualized bleeding rate (ABR), measured here by frequency of bleeds, is a commonly-used efficacy outcome. coreHEM voters added factor activity level and duration of (gene) expression, which are outcomes of high interest associated with gene therapy, a potential one-time durable treatment. As gene therapy is expected to be a transformational experience for PWH, quality of life outcomes beyond bleeding measures such as mental health outlook and chronic pain were prioritized in coreHEM. In contrast, people with VWD experience bleeding at many sites, including nose bleeds, oral cavity bleeds, joint bleeds, and heavy menstrual periods, and these bleeding experiences required several outcomes to be measured appropriately by the COS. coreVWD panelists chose to highlight WGPPM outcomes because of the burden of gynecologic and obstetric bleeding in VWD. The final list for the perioperative treatment branch of coreVWD included re-admission to the hospital and number of administrations of treatment needed to resolve a surgical bleeding episode, two outcomes measuring resource use, an important category for post-regulatory decision-making.

Interpretation, Conclusion or Significance: The outcomes in the final core sets reflect both the phenotypic experience of people living with the condition and the treatment modality.

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Additional Information/Authors: Acknowledgement of coreVWD Advisory Board Members: Nathan T. Connell, MD, MPH, FACP; Manon Degenaar-Dujardin; Veronica H. Flood, MD; Sarah Ford, Ben Kim, MD, MPhil; Michelle Lavin, MD Bch BAO, PhD, MRCPI, FRCPath; Dawn Rotellini; Maria E. Santaella, MSN, RN-BC, CPHON; Emily Ayoub, PhD