- David Jones
- Apr 14
- 5 min read
Clinical trial failures in high-risk myelodysplastic syndrome (HR-MDS) are all too common, even as the need for innovative treatments grows. This blog distills operational and design insights from a live COG UK session with Joab Williamson, VP of Operations at Faron Pharmaceuticals, exploring “Predictable Pitfalls: Designing Clinical Trials to Avoid Historical Failures in HR-MDS.” The analysis is directly relevant for sponsors, CROs, and biotech leaders navigating clinical trial outsourcing, CRO selection, and the optimization of clinical study protocols, especially in oncology and severe rare diseases.
Why This Session Matters
Joab Williamson (Faron Pharmaceuticals), a biotech leader with direct experience in immunotherapy and combination strategies for blood cancers, shared a sponsor’s perspective on understanding and addressing clinical trial failures in HR-MDS. Moderated by Sverre Bengtsson at COG UK, the discussion focused on practical, sponsor-led approaches to study design, operational controls, and lessons from the “graveyard” of past phase 2 and 3 trials.
For clinical operations professionals, the case study reveals how deep analysis of historical trials, and cross-functional collaboration between sponsor, CRO, and sites, can reshape risk management, endpoint protection, and the overall outsourcing model.
Mapping the Landscape of HR-MDS Clinical Trial Failures
Joab emphasized that HR-MDS is a particularly challenging indication, both scientifically and operationally. The disease is severe and rare, with most patients facing a prognosis of 18 months or less after diagnosis. Clinical trials consistently show minimal survival increases (often capped at two years), and the majority of patients never receive curative treatment. As a result, the main endpoint is life extension and quality-of-life improvement.
Despite attempts by leading pharma companies, including Novartis, Takeda, Gilead, AbbVie, and Genentech, many phase 3 trials in HR-MDS have failed. Recent examples like the Verona trial and others struggled to establish new standards of care. Joab pointed out that several trials could have succeeded if their designs had targeted incremental gains, had more realistic effect sizes, or embedded operational best practices from the outset.
Operational insight:
The need to conduct “pre-mortem” analyses, examining past trial failures before finalizing protocols, is critical. Sponsors must document the failures, identify patterns in trial design and operational execution, and avoid overestimating treatment effects when planning phase 3.
Understanding Treatment Switching and Post-Trial Therapies
One major operational pitfall that surfaced is the impact of post-trial treatment and switching on observed outcomes. In HR-MDS and related oncology trial designs, it’s common for control-group patients to eventually receive the active drug, either during cross-over or as subsequent therapy. For example, in the venetoclax trial, 20% of placebo patients ultimately received venetoclax after the study, meaning survival metrics converge and the true effect becomes diluted.
Many protocols lack mechanisms for censoring or adjusting for treatment switching or don’t deploy endpoints like treatment-free survival that would isolate the effect of the investigational drug. This operational oversight can flatten overall survival signals, distort primary endpoint assessments, and undermine the data needed for regulatory approval.
Clinical study optimization:
Sponsors should consider adaptive endpoints, integrate sensitivity analyses for subsequent therapies, and proactively address the real-world implications of post-trial access and treatment switching.
The Impact of Geography and Standard of Care Differences
Geography profoundly shapes trial outcomes, particularly in indications like HR-MDS that involve complex infection risks and differing standard-of-care practices. Joab highlighted that infection management varies significantly between regions, for instance, Asia versus the US, leading to operational heterogeneity.
Sponsors often expand phase 3 trials globally to accelerate enrollment or reduce costs. However, this expansion can introduce non-comparable patient populations and dilute the treatment effect observed in earlier, more homogenous, regional phase 2 studies. For example, certain failed trials recruited a substantial proportion of patients from regions unsupported in prior studies, which contributed directly to disappointing outcomes.
Clinical outsourcing best practice:
Sponsors and CROs must carefully assess standard of care across regions, use harmonized protocols, and align trial regions between phase 1/2 and pivotal studies. Centralized assessments and tighter eligibility criteria help maintain endpoint integrity.
Realistic Effect Sizing, Adaptive Design, and Eligibility Criteria
A recurring theme: Many HR-MDS trials overestimated the treatment effect seen in phase 1 and 2 and failed to achieve statistical significance in phase 3. Joab underscored the importance of setting incremental, evidence-based effect sizes, planning adaptive designs to resize trials based on interim readouts, and selecting endpoints beyond overall survival, including event-free, progression-free, or treatment-free survival.
Eligibility criteria also dramatically affect outcomes. Including stem cell transplant-eligible patients in a venetoclax protocol, for instance, harmonized active and placebo arms for 20% of subjects, diluting the observed treatment effect and limiting endpoint sensitivity.
Sponsors should prioritize eligibility criteria that preserve signal detection and align with operational feasibility. Avoiding “all-comer” designs in favor of tighter patient selection can increase the chance of trial success and ultimately approval.
What This Means in Practice
Pre-mortem analysis: Systematically review and document all prior trial failures in the indication, extracting specific operational and design lessons.
Endpoint selection: Use endpoints that account for treatment switching (e.g. treatment-free survival), and plan for post-trial therapy effects.
Geographical strategy: Align trial regions with earlier phase studies and harmonize standard-of-care procedures across geographies.
Adaptive design: Build in interim analyses for effect size adjustment and re-sizing, optimizing patient numbers and funding allocation.
Eligibility criteria: Vet every inclusion/exclusion decision for its impact on signal detection and operational complexity.
Centralized reviews: Leverage independent or centralized data assessments to drive consistency and reduce regional bias.
Realistic effect sizing: Don’t extrapolate phase 1/2 results to phase 3 without rigorous validation; incremental gains can be meaningful if trial is sized appropriately.
Key Takeaways
Pre-mortem analyses and historical review are essential for minimizing repeat trial failures in challenging indications like HR-MDS.
Trial designs must explicitly account for treatment switching and subsequent therapies to protect endpoint integrity.
Geographical variation in standard of care can distort outcomes; harmonizing regions and procedures is a key operational priority.
Adaptive designs, incremental effect sizing, and carefully curated eligibility criteria increase the likelihood of achieving regulatory endpoints.
Cross-functional collaboration and centralized data review support clinical operations best practices and reduce risk across outsourced and sponsor-driven studies.
Selected Quotes
“Our goal here has really been to narrow down on why trials have failed and what we can do better. The situation we're in now, being a small biotech but leading for this disease, is because of all these past failures.”
“Post-trial treatment has a big effect. When you don’t allow for censoring or treatment switching, you’re not really identifying the effect of other treatments on those patients.”
“Geography is a really important one. Infection management given in Asia is probably extremely different to what's given in the US, and it's easy to expand phase 3 globally without understanding these differences.”
“A full label probably is not as valuable as a successful trial. Encapsulating three different indications in a trial increases heterogeneity and can dilute signal.”
Links & References
Through pragmatic clinical trial design, operational integrity, and deep engagement with outsourced partners, sponsors and CROs in high-risk oncology have the opportunity to move beyond historical setbacks, turning “predictable pitfalls” into best practices for the next generation of research.
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