As the moon traverses around the earth, its pathway or orbit is quite predictable. Because its pathway is around the earth and not around the sun, it is not a planet. The light from the moon is reflected from the sun, stars, and parts of the earth that are opposite us when the moon is cycling above us. To some of us, when we were growing up, the moon was a magical object. To others, it retains its magical powers in myths, mystical practices, and romantic songs. We can say for sure that the moon influences the tides, but there were only a few years during which we believed that a cow could jump over the moon.
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. This is an area of research that is currently intensifying because more drugs are being marketed after accelerated and sometimes incomplete reviews. The moon's movements through its second 180-degree cycling is the mirror opposite of the first 180 degrees—waning gibbous moon, half-moon, and waning crescent moon—and then the cycle begins again with another new moon. I think of the second half of the drug development cycle as composed of the numerous areas that remain to be studied. I have already mentioned comorbidities, drug interactions, and adverse effects. In addition, more work can be conducted on variables such as age, sex, pharmacogenetics, epidemiology, hormonal status, new indications, and product safety and stability. Postmarketing surveillance and pharmacovigilance are cornerstones of Phase 4.
The moon has its dark side. Some would say that there is also a dark side to drug development. For example, there are ethical issues that arise in the testing of new agents, questions about lack of product availability in the emerging world, and the ever present debates about profits and drug pricing.
I am not sure that sharing my thoughts on these matters has any heuristic value. Nor do I have any reason to believe that offering additional proof names (see Table 1) adds clarity to the drug development process. Believe it or not, the overlap between the phases of the moon and the phases of the drug development process occurred to me in a recent dream. It is my privilege as an editor to share my free and loose associations with the hope that readers may be able to find something useful in my whimsies.
AUTHOR DISCLOSURE INFORMATION
The author declares no conflicts of interest.