Many breakthrough therapies in the U.S. stumble in their first year on the market, despite strong clinical promise.

The reason isn’t usually safety or efficacy. It’s cost pressures, evidence maturity, and system readiness. This is where the MARA framework becomes a powerful predictor.

Which MARA variables matter most

From recent launches, three categories consistently aligned with sluggish early uptake in the U.S.:

• Cost-Effectiveness & Budget Impact
  Poor or uncertain ICERs and high resource burden → payers slowed coverage, imposed restrictions, or demanded rebates.
• Evidence Quality & Comparator Selection
  Single-arm trials, weak comparators, or immature data → payers delayed broad adoption until real-world evidence or head-to-heads appeared.
• Care Pathway Integration & Monitoring
  REMS programs, PET/MRI scans, or infusion logistics → uptake held back until clinics and hospitals had infrastructure in place.

By contrast, strong safety profiles or efficacy signals rarely guaranteed early adoption if these three categories were weak.

Examples of sluggish U.S. launches flagged by MARA

#Rybrevant (amivantamab, exon20 NSCLC)

MARA: Cost-Effectiveness = B (Substandard), Comparator = B++ (Marginal), Evidence Quality = B++ (Marginal), Resource Use & Cost = B++ (Marginal).

U.S. hurdle: Eligible population was very small (EGFR exon20 mutations ≈0.1–4% of NSCLC). Uptake required lengthy split-dose infusions with infusion-related reaction management, and approval was based on single-arm data.

#Yescarta (axicabtagene ciloleucel, FL ≥3L)

MARA: Cost-Effectiveness = B (Substandard), Evidence Quality = B++ (Marginal), Resource Use & Cost = B++ (Marginal).

U.S. hurdle: By December 2017, only ~5 patients had been treated. Hospitals faced major reimbursement uncertainty until Medicare issued a national coverage determination in 2019.

#Spravato (esketamine, TRD)

MARA: Cost-Effectiveness = B (Substandard), Care Pathway Integration = B+ (Very Weak), HRQoL = B++ (Marginal), Comparator = B++ (Marginal).

U.S. hurdle: Launch between 2019–2021 was sluggish. REMS required ≥2 hours of monitoring per dose, and payers commonly imposed prior authorization and step therapy. Certified clinic infrastructure took time to scale.

#Zeposia (ozanimod, RRMS)

MARA: Cost-Effectiveness = B (Substandard), Comparator = B++ (Marginal), Resource Use & Cost = B++ (Marginal).

U.S. hurdle: Approved March 26, 2020, but launch was delayed due to COVID-19. First-year sales were modest (~$10M), and adoption was constrained by payer step-therapy requirements.

#Monjuvi (tafasitamab + lenalidomide, R/R DLBCL)

MARA: Cost-Effectiveness = B (Substandard), Evidence Quality = B++ (Marginal), Uncertainty = B++ (Marginal), Resource Use & Cost = B++ (Marginal).

U.S. hurdle: FDA approved July 31, 2020, on single-arm L-MIND data. Coverage was broadly available but often restricted. Sales reached $79M in 2021, below guidance of $110–135M for 2022, and analysts cut forecasts repeatedly.

#Donanemab (Kisunla, early Alzheimer’s)

MARA: Cost-Effectiveness = B (Substandard), Care Pathway Integration = B++ (Marginal), Evidence Quality = A (Strong), Safety = A (Strong).

U.S. hurdle: FDA approved July 2, 2024. In Q1 2025, sales were ~$21M. Uptake was slowed by PET scans to confirm amyloid, MRI monitoring for ARIA, payer caution, and a list price of ~$32,000 per year.

The lesson for launch teams

If MARA shows:

• Cost-Effectiveness = B (Substandard)
• Evidence/Comparator = B++ (Marginal)
• Care Pathway or Monitoring = B+ (Very Weak) or B++ (Marginal)

→ you should expect a slow first 12–18 months in the U.S. unless countermeasures (rebates, coding, diagnostic funding, site enablement) are put in place before launch.

MARA is not just an HTA tool — it’s a practical early-warning system for U.S. launch friction.