NCATS 4DM · small molecules

Small Molecule 4D Map

The Drug Discovery, Development and Deployment Map for small-molecule therapeutics. It lays out the modern therapeutic development process as eight connected neighborhoods rather than a straight line, so the dependencies that actually govern a program — and the bottlenecks between them — are visible in one view. Published by NCATS at the NIH and reproduced here under CC BY-SA 4.0.

What is specific to small molecules

Six of the eight neighborhoods are common to both 4D Maps. Two are not — and they are the two that decide what a program actually looks like day to day: C, lead identification, and D, lead optimization.

C · Lead identification is a screening problem

Compound libraries and chem-informatics feed assay development and a high-throughput screening system. The HTS run sorts into hits and misses, and the hits leave the neighborhood as unapproved compounds — new chemical or molecular entities (NCE/NME). No immune system is involved anywhere in this stretch, which is precisely what the biologics route spends the same stage on.

D · Lead optimization is a chemistry problem

In silico modeling and medicinal chemistry run alongside in vitro functional and safety screening; process chemistry and non-GMP supply carry early CMC. Candidate compounds go through non-GLP investigative safety and toxicology and in vitro / in vivo pharmacology, which together yield a predicted therapeutic dose and exposure and a short list of preclinical candidates. Early cGMP manufacturing and GLP preclinical studies follow — pharmacokinetics, pharmacology, toxicology — and then the long tail the biologics map has no equivalent for: long-term toxicology, reproductive toxicology and carcinogenesis, late CMC such as formulation, and sustained product availability.

The biologics map replaces both neighborhoods wholesale with immunization, library screening, binding maturation and protein engineering. Comparing the two side by side is the fastest way to see why a modality choice is a program-structure choice.

The six shared neighborhoods

Substantively the same on both maps:

A · Basic science research & target identification — informatics, data mining and biorepositories, through pathophysiology, molecular pathways, cell lines and animal models, out to a therapeutic target.
B · Target pharmacology & biomarker development — target engagement, prognostic, predictive and response biomarkers, qualification, companion diagnostics and surrogate endpoints.
E · Clinical research & development — IRB review, contractual and legal agreements, recruitment and informed consent, trial design, and preapproval trials through Phase I, II and III.
F · Regulatory review — IND, reporting, meetings and amendments, NDA, then the fork between marketing approval and a Complete Response Letter.
G · Postmarketing — postapproval data collection, spontaneous reporting, pragmatic safety and effectiveness trials, label changes, off-label use, and repurposing that feeds back into A.
H · Medical landscape — patient needs, standard of care, access to therapies, coverage and reimbursement, pricing, incorporation into practice.

Source and licence

The Drug Discovery, Development and Deployment Maps (4DM) are produced by the National Center for Advancing Translational Sciences at the National Institutes of Health, and are released under the Creative Commons Attribution-ShareAlike 4.0 International licence. This page reproduces the small-molecule map unchanged and is shared under the same licence. The current maps and the accompanying material are at ncats.nih.gov.

The maps are described in: Wagner JA, Dahlem AM, Hudson LD, Terry SF, Altman RB, Gilliland CL, DeFeo C, Austin CP. A dynamic map for learning, communicating, navigating and improving therapeutic development. Nature Reviews Drug Discovery 17, 150 (2017). doi:10.1038/nrd.2017.217

DISCLAIMER: Reference visualization for educational purposes only. Not legal, regulatory, or medical advice. Consult qualified professionals.