Reflections on the Phases of the Moon and the Phases of Drug Development
Quite a few countries have a crescent moon plus 1 or more stars on their national flags. Most of these are from countries where Islam is the predominant religion. The moon and stars are often said to symbolize faith. The Maldives, a South Asian island country, is the only country with only a moon and no stars on its flag.1 South Carolina is the only American state with a moon on its state flag.2 The current South Carolina flag is a direct descendent of the flag carried by Colonel William Moultrie's troops when they defeated the British on June 28, 1776.
When the earth is lined up between the moon and the sun, only limited light reflects off the moon. This is called a new moon. Before the moon is at 90 degrees in its trajectory, we call the moon a waxing crescent moon because of its shape. When it is beyond 90 degrees but not yet at 180 degrees, we call it a waxing gibbous moon. The illumination is more than half but less than full. Gibbous means convex, protruding, bulging, or humpbacked. When it reaches 180 degrees, the moon is full.
I like to think of the moon's phases as somewhat analogous to the phases in the drug discovery paradigm. Phase 0 is like the new moon. Like the limited light, tiny doses are used, and very few subjects are exposed. Most Phase 0 studies are a type of pilot study. I coined the term proof of feasibility to describe this phase.3 For example, Phase 0 studies can be used to explore nanotechnologies or to test recruitment practices, assessment tools, low exposure tolerability, and activity at biomarkers.
Phase 1 is like the waxing crescent moon. The moon is definitely visible. In Phase 1, the drug dosages administered should have clearly discernable effects. Phase 1 is called proof of principle because the pharmacology, pharmacokinetics, and aspects of the tolerability of the drug are now becoming known.
The half-moon at 90 degrees is both an end of the first quarter moon and a beginning of the second quarter moon. This duality is mirrored in Phase 2, which is often divided into Phases 2a and 2b. Phase 2a is understandable as the “proof of concept” step. The drug must benefit the patients for whom it is intended. In Phase 2b, optimal dosages are identified.
Next comes the waxing gibbous moon—with its growing convexity. In Phase 3, the patient groups are expanded, and the control group is better defined. If clinical efficacy can be established in this phase, the drug is most likely marketable. This is a pivotal trial. I have coined the term proof of marketability to describe this phase.
Phase 4 is like the full moon—fully developed and exposed. For Phase 4, I have coined the term proof of generalizability and sustainability. Comorbidities, drug interactions, and rarer unwanted effects are revealed.