Trodelvy, Orkambi, EU AI Diagnostics

MarcusAccess Brief. I'm Marcus, with Sara. Today we're looking at FDA's Trodelvy accelerated approval — the 48% risk reduction in ASCENT trial versus chemotherapy, but with mandatory RWE confirmation. CMS Part D reforms for 2027 — step therapy mandates and VBID incentives targeting $15 billion in savings. NICE's Orkambi reversal after RWE demonstrated 30% reduction in pulmonary exacerbations. And the EU JCA medical device expansion — first AI stroke algorithm assessment highlighting validation challenges. Sara, where do you want to start?

SaraThe Trodelvy accelerated approval is fascinating timing — right before the FDA's new RWE guidance.

MarcusThe ASCENT trial results are solid, but the accelerated pathway with RWE conditions creates a methodological quagmire. We've seen this pattern before—expedited approvals followed by evidence gaps. The FDA is essentially admitting they can't wait for confirmatory trials in rare oncology populations.

SaraBut that's the point of accelerated approval—getting therapies to patients who need them now. The 48% risk reduction is clinically meaningful, regardless of the pathway. And this RWE requirement isn't new—it's the FDA's standard approach to balancing access and evidence.

MarcusI don't think that's right. The RWE conditions here are particularly problematic because they're asking for real-world data that simply doesn't exist for this specific PIK3CA-mutated population. The ASCENT trial didn't collect the kind of granular RWE endpoints they're now demanding. This sets a dangerous precedent for circular evidence requirements.

SaraCircular? That's too generous to the FDA's position. They're being pragmatic about evidence generation in rare populations. The alternative would be another five years of waiting for confirmatory trials while patients progress on chemotherapy. The industry needs to step up with better RWE strategies, not complain about the requirements.

MarcusThe industry's RWE capabilities are precisely why this is problematic. Most companies can't generate the kind of robust real-world evidence the FDA is now expecting. This will create a two-tier system where only large pharma with substantial RWE infrastructure can meet these conditions.

SaraLet's move to the CMS Part D reforms—the step therapy mandates are more interesting than the accelerated approval debate. The 12% utilization reduction in pilot programs suggests these will have real impact, but the industry complaints about rare disease access are valid. Step therapy doesn't work for ultra-orphan drugs where there are no alternatives.

MarcusThe CMS claims $15 billion in savings over ten years, but that's based on preliminary data from 2026 pilot programs. We've seen these projections before—they consistently overestimate actual savings. The step therapy mandates will create significant administrative burdens without the promised cost reductions.

SaraYou're missing the point here. The administrative burden is secondary to the access issues. For rare disease patients, step therapy isn't just inconvenient—it's clinically inappropriate. CMS is applying a one-size-fits-all approach that doesn't account for the realities of ultra-orphan disease management.

MarcusThat's the obvious read but ignores the political context. CMS is responding to congressional pressure on drug spending. The step therapy mandates are as much about optics as actual savings. They needed to show they were doing something about high-cost drugs, regardless of the practical implications.

SaraThe NICE Orkambi reversal is more interesting than either of those. The 30% reduction in pulmonary exacerbations from RWE is exactly what the field has been advocating for—using real-world evidence to reassess rejected technologies. This could set a precedent for other rare disease therapies.

MarcusThe precedent is problematic. NICE applied a 50% discount for ultra-orphan drugs, which undermines their entire threshold framework. If they're willing to adjust thresholds based on disease rarity rather than pure cost-effectiveness, what's the point of having thresholds at all? This is arbitrary value assessment masquerading as evidence-based decision making.

SaraThat's too rigid. Ultra-orphan drugs have different value propositions—small populations with no alternatives. The threshold adjustment reflects that reality. This isn't about abandoning evidence; it's about applying evidence appropriately to different disease contexts.

MarcusThe evidence for Orkambi was available in 2023. The fact that NICE needed new RWE to reconsider their position suggests their initial assessment was flawed. If their process is that sensitive to new evidence, how reliable were their original conclusions?

SaraThe EU JCA medical device expansion is the most significant development here. The first AI stroke algorithm assessment highlights exactly why we need specialized HTA approaches for digital health technologies. Traditional clinical trial methodology simply doesn't capture the value of AI diagnostics.

MarcusThe EU's approach to AI validation is fundamentally flawed. They're requiring algorithm validation protocols and real-world performance data, but they haven't established clear standards for what constitutes adequate validation. This creates uncertainty for manufacturers and inconsistent assessments across devices.

SaraBut that's the point—they're starting to address the unique challenges of AI diagnostics. The traditional HTA framework was never designed for technologies that learn and evolve. The EU is at least attempting to create fit-for-purpose evaluation methods, unlike the FDA which still applies the same standards to AI as to traditional devices.

MarcusAttempting is not the same as succeeding. The lack of standardized validation metrics means the first JCA assessments will be inconsistent and potentially arbitrary. Manufacturers will waste resources trying to guess what evidence each HTA body wants rather than developing robust validation protocols.

SaraLet's agree to disagree on that. The convergence between FDA and NICE on RWE utilization is the real story here—both are recognizing that traditional clinical trials can't capture all aspects of value, especially for rare diseases and complex technologies. This represents a fundamental shift in how we generate and assess evidence.

MarcusThe shift is necessary but not sufficient. We need standardized RWE methodologies that can be consistently applied across different technologies and disease areas. Without that, we'll have more of the same—fragmented assessments based on whatever evidence happens to be available.

SaraThe future is in value-based contracting, not just evidence generation. The CMS VBID incentives and NICE's willingness to reconsider based on RWE both point toward a system that pays for outcomes rather than just inputs. That's where the real innovation is happening.

MarcusValue-based contracting is just rhetoric without robust outcome measurement. We need better endpoints that capture real-world benefits, not just surrogate markers that may not translate to meaningful patient outcomes.

SaraThe industry needs to adapt to these changes—faster evidence generation, better RWE capabilities, and more flexible value assessment approaches. Those who can navigate this new landscape will have a significant advantage.

MarcusWe're entering an era of evidence pluralism where traditional RCTs coexist with real-world data and digital endpoints. The challenge will be maintaining methodological rigor while accommodating these diverse evidence streams.

SaraThe regulatory divergence between FDA and EMA approaches to AI diagnostics will create global access challenges for manufacturers. Companies will need tailored evidence strategies for different markets.

MarcusTomorrow's evidence strategies must be agile and adaptive, ready to incorporate new data streams as they emerge.

SaraTomorrow's value assessments will increasingly focus on real-world outcomes rather than theoretical efficacy.

MarcusBack tomorrow on Access Brief. Show notes at outcomes-analytica.no.