How to Build HTA-Ready Evidence Before Phase III Clinical Trials

Introduction

On January 12, 2025, a structural change in how pharmaceutical products access the European market took effect, one that fundamentally altered the evidence timeline for every oncology drug and advanced therapy medicinal product seeking marketing authorisation in the EU.

The EU Joint Clinical Assessment (JCA) regulation became mandatory for these product classes, creating a single EU-level clinical assessment that runs in parallel with the EMA regulatory review, not after it. For pharma teams accustomed to beginning HTA dossier preparation following regulatory approval, this is a strategic and operational discontinuity of the first order. JCA planning must now be underway before Phase III design is locked. Evidence that historically was assembled post-approval must now be built, structured, and continuously updated throughout clinical development itself.

The consequence is direct and unforgiving: market access teams that start HTA evidence preparation at EMA submission are already operating behind the JCA timeline. The 100-day window from consolidated PICO communication to dossier submission, covering the comparative clinical evidence requirements of all 27 EU member states simultaneously,  cannot be met by teams assembling evidence from scratch when the PICO list arrives.

AI Software for Healthcare is not an ancillary tool in this environment. It is the operational infrastructure that makes concurrent regulatory and HTA preparation possible. This blog examines what the JCA demands, why traditional sequential evidence preparation is structurally inadequate, and how pharma teams are using Pienomial's platform, KnolForge, KnolAI, KnolComposer, KnolPersona, and KnolModels, to build submission-ready HTA evidence packages before their Phase III trials end. 

What HTA Bodies Actually Demand — And Why the Bar Has Risen in 2026

Health technology assessment bodies across major markets have always applied rigorous evidence standards. What has changed fundamentally in 2026 is the structural requirement to meet the evidence needs of multiple HTA bodies simultaneously, through a single submission, under a compressed and non-negotiable timeline.

The JCA framework introduces demands that go well beyond what most pharma teams have previously designed their Phase III trials to address:

• Broader PICO scope than any single national HTA: The JCA consolidates PICO frameworks from all 27 EU member states. As confirmed by REMAP Consulting's analysis, the JCA scope includes many more comparators, subpopulations, and outcomes than a typical national HTA, because it must meet the evidentiary requirements of every member state simultaneously. Teams predicting PICOs only from their primary market will find significant evidence gaps when the consolidated PICO list arrives.
• 100-day dossier submission window: From the date the consolidated PICO list is communicated, there are just 100 days to submit the complete JCA dossier. This window is categorically too short to initiate evidence research, run feasibility assessments, or build comparative evidence packages from scratch. All substantive evidence work must be complete before the PICO communication arrives.
• Patient-relevant endpoints beyond regulatory primary endpoints: NICE in the UK requires overall survival and validated patient-reported outcomes. G-BA in Germany applies strict added-benefit standards. HAS in France and AIFA in Italy each have specific requirements that may not align with what satisfied the EMA. A JCA dossier must address all simultaneously, which means Phase III trial design must embed these endpoints before enrolment begins.
• Comparative effectiveness, not absolute efficacy: The JCA focuses on relative clinical effectiveness against each member state's relevant comparator. Where head-to-head trial evidence is unavailable, common in oncology and rare disease,  indirect treatment comparisons and network meta-analyses are required. The methodological feasibility of these analyses must be assessed before Phase III is designed, not after the data is locked.
• For US-focused pharma teams, the JCA represents a significant expansion of what AI for clinical evidence synthesis must deliver, and the timelines within which it must deliver it.

Why Traditional Sequential HTA Preparation Is No Longer Viable

The traditional model, complete the Phase III trial, obtain regulatory approval, then build the HTA dossier, was designed for an environment that no longer exists. The JCA has removed three conditions that made sequential preparation workable:

• Sequencing is structurally impossible: The JCA process begins at the time of EMA submission. The JCA report must be adopted within 30 days of EMA marketing authorisation. Dossier preparation cannot begin at approval, it must be substantially complete before submission is filed.
• The evidence scope exceeds what any manual team can cover in 100 days: Addressing all 27-member-state PICO requirements, with comparative evidence research, indirect treatment comparison preparation, patient-relevant outcome analyses, and real-world evidence sourcing, within 100 days is not achievable without AI-powered research infrastructure that has been building the evidence base throughout clinical development.
• Governance and traceability requirements have escalated: The FDA's January 2026 Good AI Practice guidance and the EMA's AI methodology qualification both require that AI-generated evidence outputs are fully traceable and auditable. This applies equally to JCA dossier preparation. Teams relying on manual evidence assembly cannot meet these traceability standards at the speed the JCA window demands.
• Evidence gaps in the JCA report become commercial liabilities: As confirmed by Global Legal Insights (2025), member states must give 'due consideration' to JCA findings in national reimbursement decisions. Evidence gaps flagged publicly in the JCA report will directly influence price negotiations across all 27 EU member states. A weak JCA dossier is not just a regulatory problem, it is a multi-market commercial problem that compounds across every national HTA that follows.

How KnolForge, KnolAI, KnolComposer, KnolPersona, and KnolModels Change the HTA Evidence Model

Pienomial's platform addresses the JCA evidence challenge through five interconnected products, each designed to handle a distinct component of the HTA preparation workflow — all connected through KnolForge's governed AI memory layer to ensure that every evidence output is traceable, current, and consistent across the entire dossier.

▸ KnolForge  —  Enterprise Knowledge & AI Memory Platform

KnolForge is the foundation that makes everything else possible. It ingests and structures your organisation's entire evidence base — published literature, regulatory databases, HTA body decisions, real-world data sources, internal clinical documents — into a governed knowledge graph. This is not a passive data repository. It is a continuously updated, expert-validated intelligence layer that every other product in the platform draws from.

For HTA preparation, KnolForge provides the structural answer to the traceability problem that haunts manual dossier workflows. Every evidence claim in a JCA dossier must be traceable to a primary source. Every analytical output must be auditable from input to conclusion. KnolForge embeds this traceability in the infrastructure itself — not as a documentation exercise added after the fact, but as a structural property of every data ingestion, every knowledge update, and every output generated on the platform.

▸ KnolAI  —  AI Research & Discovery

KnolAI is the research engine that builds and maintains the comparative evidence foundation that JCA dossiers require. For HEOR teams building HTA-ready evidence packages, KnolAI delivers three specific capabilities that manual research processes cannot replicate at JCA timelines:

• PICO prediction from historical HTA body decisions: KnolAI can scan the documented assessment history of NICE, G-BA, HAS, AIFA, and other EU member state HTA bodies across comparable therapeutic areas — identifying which comparators, subpopulations, and outcomes each body has historically prioritised. This enables HEOR teams to build predicted PICO frameworks months before the consolidated PICO list arrives, focusing evidence development on the most likely scope rather than waiting for confirmation.
• Continuous evidence base maintenance: Rather than a one-time literature review that ages immediately, KnolAI maintains a continuously updated evidence base on the KnolForge knowledge layer — capturing new publications, HTA decisions, and regulatory precedents as they emerge throughout Phase III conduct. The evidence package at EMA submission reflects the current state of the literature, not an 18-month-old snapshot.
• Rapid cross-domain evidence queries: HEOR teams developing JCA dossiers need to answer complex, cross-domain questions quickly: 'What ITCs have been accepted by G-BA for this mechanism class?' 'What PRO instruments have NICE validated for this tumour type?' KnolAI answers these queries across PubMed, Embase, regulatory databases, and HTA body publications simultaneously — in minutes, with full citation-level traceability.
• This is how AI tools speed up HTA dossier preparation in practice: not by automating a single workflow, but by maintaining a live, queryable evidence intelligence layer that the entire HEOR and market access team can access throughout clinical development.

▸ KnolComposer  —  AI Regulatory Writing Tool, Living Documents

KnolComposer transforms the evidence intelligence maintained in KnolForge and researched through KnolAI into structured, living regulatory documents. For JCA preparation, this capability is strategically decisive, because the JCA dossier is not a document that can be written once and submitted. It is an evidence package that must stay current throughout clinical development and be finalised rapidly when the 100-day window opens.

KnolComposer's living document architecture means that as the KnolForge knowledge layer is updated, as new comparator publications emerge, as HTA body decisions accumulate, as RWE data is incorporated, the dossier structure reflects these updates automatically. Teams are not reconciling a six-month-old document draft against twelve months of new evidence under time pressure. They are refining a document that has been evolving with the evidence throughout the trial.

For regulatory submissions pharma teams also managing EMA submission workloads simultaneously, KnolComposer's ability to maintain both the regulatory package and the JCA dossier on the same governed knowledge layer, with consistent evidence, consistent traceability, and no manual reconciliation between documents — is the operational breakthrough that makes parallel preparation feasible.

▸ KnolPersona  —  Expert Intelligence, Domain Expert Simulation

KnolPersona provides the expert validation layer that JCA dossier preparation requires but rarely has access to at the right stage. It simulates verified domain experts across medical, clinical, and regulatory specialties, enabling pharma teams to apply structured expert review to evidence claims, endpoint selections, and dossier arguments at points in the development timeline when consulting actual experts is expensive, slow, or logistically impossible.

For HTA readiness specifically, KnolPersona's most powerful application is HTA assessor simulation. By grounding simulations in the documented assessment history, published guidances, and precedent decisions of specific HTA bodies, KnolPersona enables pharma teams to evaluate how NICE, G-BA, HAS, or other key EU assessors are likely to respond to specific evidence claims before the dossier is submitted.

This turns what is traditionally a post-submission surprise, an HTA body identifying an evidence gap or challenging an endpoint choice after the JCA process is underway — into a pre-submission quality checkpoint. Teams that use KnolPersona to simulate assessor responses during dossier development arrive at the 100-day window with evidence packages that have already been stress-tested against the bodies that will review them.

▸ KnolModels  —  AI Clinical Modelling Platform

KnolModels provides the quantitative modelling layer that connects KnolAI's evidence research to the economic and clinical analyses that JCA dossiers and national HTA submissions require. For HEOR teams, this means building disease models, indirect treatment comparisons, cost-effectiveness analyses, and budget impact models on a foundation that is directly connected to the KnolForge evidence base, not on manually assembled assumption sets that are disconnected from the primary literature.

The JCA-specific value of KnolModels is in two areas. First, ITC and network meta-analysis preparation: KnolModels enables HEOR teams to build and validate NMA models from KnolAI-researched evidence, with all model assumptions traceable to the primary studies they are derived from. Second, country-specific economic modelling for post-JCA national submissions: KnolModels allows country-specific parameter adjustments and scenario analyses to be applied to the core model built during clinical development, enabling national HTA submissions to be generated efficiently from a common evidence foundation rather than rebuilt independently for each market.

The HTA Preparation Timeline — Mapped to Pienomial Products

The table below maps the key HTA evidence activities against clinical development stages, identifying both the critical timing constraints at each phase and the specific Pienomial products that address them:

Development Stage : Phase II Initiation (24–36 months pre-launch)
Pienomial Platform Activity : KnolAI performs landscape analysis including comparators, endpoints, and unmet need across key EU markets while predicting likely JCA PICOs from historical HTA decisions. KnolForge begins structuring the enterprise evidence knowledge base for the indication
Critical Timing Constraint : Evidence gaps must be identified before Phase III design is locked

Development Stage : Phase II Completion (18–24 months pre-launch)
Pienomial Platform Activity : KnolAI conducts ITC feasibility assessment and scans published evidence for NMA feasibility while continuously updating the evidence base. KnolPersona runs first expert simulation to validate predicted PICOs against regulatory and HTA precedent. KnolModels establishes the first HEOR model framework
Critical Timing Constraint : ITC evidence must be prepared early since the 100-day JCA timeline leaves no room for initiation after scope confirmation

Development Stage : Phase III Design Lock (12–18 months pre-launch)
Pienomial Platform Activity : KnolPersona simulates assessors from NICE, G-BA, and HAS to validate HTA-optimised endpoint selection and PRO instruments. KnolAI performs real-world data source scanning for comparative effectiveness
Critical Timing Constraint : JCA planning must begin before Phase III design is locked

Development Stage : Phase III Conduct (6–12 months pre-launch)
Pienomial Platform Activity : KnolAI enables quarterly evidence updates and continuous capture of new comparator publications. KnolComposer drafts JCA dossier structures and maintains living evidence documents updated via the KnolForge knowledge layer. KnolModels supports NMA preparation and scenario modelling
Critical Timing Constraint : High JCA volume and dossier quality directly influence secretariat assessment outcomes

Development Stage : EMA Submission (0 months pre-launch)
Pienomial Platform Activity : KnolComposer generates the final JCA dossier addressing all 27 member-state PICOs from the governed KnolForge evidence base with full audit trail. KnolPersona conducts final expert validation of evidence claims prior to submission
Critical Timing Constraint : JCA report must be adopted within 30 days of EMA marketing authorisation

Development Stage : Post-Approval (0–12 months post-launch)
Pienomial Platform Activity : KnolComposer enables national HTA submissions using the JCA report as a living document with country-specific updates. KnolModels develops country-specific economic models for Germany, France, UK, and additional markets
Critical Timing Constraint : Member states give due consideration to JCA findings, and identified evidence gaps will impact national pricing and reimbursement negotiations

Two timing constraints deserve specific emphasis because they are most frequently underestimated by teams preparing for JCA for the first time, and because the Pienomial platform addresses both in ways that manual processes cannot.

ITC Feasibility Must Be Confirmed Before Phase III Design Is Locked

Where head-to-head trial evidence is unavailable, indirect treatment comparisons are the JCA's required method for demonstrating comparative effectiveness. But conducting a rigorous NMA requires that sufficient published studies with compatible designs, endpoints, and populations exist. KnolAI's feasibility scan, run at Phase II completion across the published evidence base, confirms whether this methodological foundation exists, and identifies any evidence gaps that can still be addressed through Phase III design choices. This assessment done after Phase III completion is too late to change anything.

Assessor Simulation Must Run Before Dossier Finalisation

The single most preventable cause of JCA evidence gaps is endpoints and evidence claims that satisfy EMA requirements but do not meet HTA body standards, a misalignment that is entirely predictable and avoidable with KnolPersona assessor simulation run during Phase III design and dossier development. Teams that discover this misalignment during the 100-day window have no time to address it.

HTA Readiness Checklist — Built on the Knolens Platform

The following checklist maps each JCA evidence requirement to the Pienomial product that addresses it, providing both a readiness assessment framework and a practical guide to platform deployment sequencing:

HTA Readiness Requirement : Comparative Evidence Base
What the Pienomial’s Platform Builds : KnolAI delivers a governed evidence knowledge base covering all relevant comparators per JCA PICO, continuously updated and fully traceable
When to Start : Phase II completion
Product : KnolAI + KnolForge

HTA Readiness Requirement : ITC Feasibility
What the Pienomial’s Platform Builds : KnolAI performs NMA feasibility scans across published evidence to confirm ITC viability before Phase III design is locked
When to Start : Phase II to Phase III transition
Product : KnolAI

HTA Readiness Requirement : HTA Endpoint Validation
What the Pienomial’s Platform Builds : KnolPersona simulates NICE, G-BA, and HAS assessors to validate Phase III endpoint selection against each body’s requirements
When to Start : Phase III design lock
Product : KnolPersona

HTA Readiness Requirement : Patient-Reported Outcomes
What the Pienomial’s Platform Builds : KnolPersona validates PRO instrument selection through expert simulation aligned with HTA precedent for the indication
When to Start : Phase III design lock
Product : KnolPersona

HTA Readiness Requirement : Living Evidence Documents
What the Pienomial’s Platform Builds : KnolComposer creates JCA dossier structures as living documents that update automatically as the KnolForge evidence base evolves
When to Start : Phase III conduct
Product : KnolComposer + KnolForge

HTA Readiness Requirement : Rapid Evidence Query Access
What the Pienomial’s Platform Builds : KnolAI enables real-time evidence query access for HEOR teams, delivering answers in minutes during dossier development
When to Start : Phase III conduct onward
Product : KnolAI

HTA Readiness Requirement : HEOR Model Foundation
What the Pienomial’s Platform Builds : KnolModels builds economic and clinical models directly on the KnolForge evidence base with fully traceable assumptions
When to Start : Phase III conduct
Product : KnolModels + KnolForge

HTA Readiness Requirement : Full Audit Trail
What the Pienomial’s Platform Builds : KnolForge maintains a complete, timestamped evidence record from source to dossier across the entire JCA preparation workflow
When to Start : EMA submission
Product : KnolForge

HTA Readiness Requirement : National Supplementary Submissions
What the Pienomial’s Platform Builds : KnolComposer generates country-specific HTA submissions from the JCA dossier foundation without requiring full redrafting
When to Start : Post-JCA, pre-launch
Product : KnolComposer

Teams that can confirm all nine elements are in place before EMA submission have the evidence infrastructure for a credible JCA dossier. Teams with gaps, particularly in evidence base maintenance (KnolAI), assessor simulation (KnolPersona), and living document capability (KnolComposer), face the 100-day window without the tools to use it effectively.

Conclusion: HTA Readiness Is Built During the Trial, Not After It

The EU Joint Clinical Assessment has made one thing unambiguously clear: HTA evidence preparation is no longer a post-approval activity. For oncology and ATMP products, it is a clinical development activity that begins at Phase II, continues through Phase III conduct, and must be substantially complete before EMA submission is filed.

The pharma teams navigating the JCA most effectively in 2026 are not those with the largest HEOR teams or the most comprehensive manual processes. They are those with an integrated AI platform that connects research, document authoring, expert validation, and economic modelling into a single governed intelligence workflow, where evidence is continuously maintained, traceability is structural, and every output is defensible.

Pienomial's platform, KnolForge as the AI memory foundation, KnolAI for continuous evidence intelligence, KnolComposer for living regulatory documents, KnolPersona for assessor simulation and expert validation, and KnolModels for traceable economic and clinical modelling, is built to make this concurrent preparation operationally feasible. Not as a collection of point tools, but as an integrated system where every product draws from the same governed knowledge layer and every output is connected to the same evidence chain.

The teams building this infrastructure during clinical development will reach the market faster, negotiate from stronger evidence positions, and avoid the commercial consequences of evidence gaps identified publicly in JCA reports. The teams that wait until submission to start will find that the 100-day window is not a preparation window, it is a finalisation window, and it only works if the preparation is already done.

Ready to see how Knolens supports concurrent HTA and regulatory evidence preparation, from Phase II through the JCA 100-day window?

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