FDA Draft Guidance on MRD Endpoints in Multiple Myeloma: What It Means for Drug Developers and IVD Innovators
Today, FDA released a draft guidance titled “Minimal Residual Disease and Complete Response in Multiple Myeloma: Use as Endpoints to Support Accelerated Approval.” While nonbinding, the document represents a significant regulatory signal: minimal residual disease (MRD) negativity is now explicitly recognized as an acceptable primary endpoint to support accelerated approval in multiple myeloma (MM).
Beyond its implications for oncology drug development, this guidance marks a pivotal inflection point for IVD and companion diagnostic (CDx) developers, particularly those working on NGS-based MRD assays and next-generation flow (NGF). At the same time, it surfaces unresolved challenges around assay harmonization, regulatory alignment, and global clinical trial execution, especially in the context of multiregional clinical trials (MRCTs).
1. Why MRD Matters More Than Ever for Drug Development and Approval
Historically, accelerated approval in MM relied on endpoints such as overall response rate (ORR). However, as therapeutic efficacy has improved with response rates exceeding 90% in some settings, traditional endpoints are becoming less discriminating and require increasingly large trials.
The FDA guidance acknowledges this reality and positions MRD negativity as a more sensitive, biologically meaningful measure of treatment effect. FDA explicitly recognizes MRD as:
A prognostic biomarker associated with improved progression-free and overall survival;
An endpoint capable of supporting accelerated approval in both single-arm and randomized trials;
A bridge that allows earlier regulatory decisions, while confirmatory trials continue to mature.
From a drug development standpoint, this creates a pathway to:
Shorter development timelines;
More efficient trial designs;
Earlier patient access to transformative therapies.
Critically, the guidance also reinforces FDA’s expectation that MRD-based accelerated approvals must be followed by timely confirmation of clinical benefit, underscoring that MRD is not a shortcut, but a scientifically grounded surrogate.
2. A Strategic Opportunity for IVD and CDx Developers
For IVD companies, this draft guidance is more than regulatory housekeeping, it is a market-shaping signal.
FDA clearly states that MRD assays used to support regulatory decisions must be appropriately validated, and it explicitly references both:
Sequencing-based methods (e.g., NGS), and
Flow cytometry–based approaches, including next-generation flow (NGF).
This creates several concrete opportunities:
Expansion of regulated MRD testing beyond exploratory or academic use into registrational drug trials;
Increased demand for fit-for-purpose, analytically validated assays with defined sensitivity (≥10⁻⁵) and robust performance;
Earlier and deeper drug–diagnostic co-development discussions, even when assays are not formally labeled as CDx at approval.
NGS developers can leverage strengths in sensitivity, clonotype tracking, and scalability, while flow/NGF providers can emphasize speed, cost efficiency, and broad clinical familiarity. Importantly, FDA does not mandate a single technology, which opens space for innovation, differentiation, and competition.
3. The Hard Part: Harmonization Across Technologies, Assays, and Regions
While FDA’s openness is welcome, it also exposes a major unresolved issue: harmonization.
The guidance allows multiple MRD technologies, thresholds, and analytical approaches, but in practice, this flexibility creates challenges:
NGS vs. Flow / NGF
Differences in analytical sensitivity, precision near cutoff, baseline calibration failures, and sample requirements complicate cross-trial and cross-platform comparisons.
FDA appropriately emphasizes assay validation and context of use, but stops short of defining equivalency or interchangeability standards.
LDTs vs. IVDs
Many MRD assays used today are laboratory-developed tests (LDTs).
When these assays are used as primary endpoints supporting drug approval, questions arise:
When does an LDT become an investigational device?
When is an IDE required under 21 CFR Part 812?
How should sponsors manage transitions from LDTs to commercial IVDs?
MRCT and Global Regulatory Friction
For global development programs, the complexity multiplies:
EU IVDR imposes stricter controls on IVD performance, clinical evidence, and intended use;
China’s HGRAC framework adds constraints on sample export and genetic data use;
Divergent expectations across regions risk fragmented assay strategies, duplicated validation efforts, and operational inefficiencies.
Without proactive alignment, MRD risks becoming a regulatory bottleneck rather than an enabler of global drug development.
4. This Is a Draft so Stakeholder Input Is Essential
FDA is explicit that this document is draft guidance, issued for comment only, and that the Agency expects ongoing dialogue with sponsors, diagnostic developers, and other stakeholders
This is a critical window for:
IVD and CDx companies to advocate for practical, globally harmonizable assay expectations;
Drug sponsors to highlight real-world operational challenges in MRCTs;
Regulators and standards bodies to move toward greater cross-platform and cross-region convergence.
Thoughtful public comments can meaningfully shape the final guidance, especially in areas such as assay comparability, validation expectations, and coordination between drug and device regulatory pathways.
Closing Thought
FDA’s draft guidance sends a clear message: MRD is no longer just a biomarker; it is becoming regulatory infrastructure. For drug developers, it offers a faster path to patients. For IVD innovators, it opens a new frontier of clinical and regulatory relevance. But realizing this promise will require coordination, harmonization, and engagement now; before the guidance is finalized.
Stakeholders across the ecosystem should take FDA up on its invitation to comment. The future of MRD-guided drug development is being written in real time.