Amol Akhade, Senior Consultant at Fortis Hospitals Mumbai, shared a post on LinkedIn about a paper by Vinay Prasad et al. published in NEJM:
“NEJM: FDA’s New ‘Plausible Mechanism Pathway‘ — A Major Shift for Bespoke Therapies
The NEJM Sounding Board by Vinay Prasad and Martin Makary introduces the Plausible Mechanism Pathway (PMP)—a new FDA framework created for individualized, N=1 therapies where RCTs are impossible. This is a regulatory response to what modern biology can now achieve with rapid sequencing, gene editing, and RNA-based platforms.
The Baby KJ Case (CPS1 deficiency):
A newborn with a single-gene metabolic defect received a customized adenine base–editing therapy within one week—designed, manufactured, infused, and clinically effective. This example defines the type of disease PMP is built for.
The 5 Requirements of the Pathway:
- A clear, single molecular abnormality
- Therapy that directly targets that pathway
- Well-understood natural history of the disease
- Evidence of target engagement (animal/cell models)
- Consistent and meaningful clinical improvement
If several such N=1 successes occur, the FDA may allow platform approvals using the same editing backbone with only the guide sequence changed.
Who benefits?
- Ultra-rare genetic diseases
- Fatal childhood-onset disorders
- Single-gene metabolic defects
- Rare pediatric cancers with a clear driver (future applications)
Who doesn’t?
- Multifactorial diseases
- Complex adult cancers
- Diseases with unclear biology
- Conditions with effective existing therapy
This pathway is not for broad or common diseases—it is meant for precisely defined biological targets.
FDA’s expectations
• Long-term safety & off-target monitoring
• Real-world evidence and registries
• Vigilance for developmental & immune effects
Given gene editing’s permanence, these safeguards are essential.
Key concerns raised by the authors
- Potential industry overreach
- Limited long-term safety data
- Need for strict mechanistic criteria
- Transparency in follow-up
Why this matters?
The Plausible Mechanism Pathway is a biology-first, logic-first regulatory shift that may accelerate therapies for ultra-rare diseases—and eventually influence precision oncology for small molecularly defined subsets.
A thoughtful evolution toward truly individualized medicine.”
Title: FDA’s New Plausible Mechanism Pathway
Authors: Vinay Prasad and Martin A. Makary
You can read the full article in NEJM.
More posts featuring Amol Akhade.