Appendix B: The Road to Drug Approval

Introduction

The U.S. Food and Drug Administration (FDA) drug approval process has nine stages (fda.gov). They are organic research; target identification and validation; determination of a lead compound; ADME/tox testing; compound optimization; preclinical testing; investigational new drug (IND) application; clinical trials (Phases 1, 2, and 3); new drug application (NDA); manufacture and scaling; and Phase 4 testing. Each step is described in detail in this appendix, with an eye to how it contributes to the ultimate expense of drug development (see fda.gov).

Organic Research

The initial step is a characterization of the disease or disorder that is in need of a new therapeutic approach. Academic medical centers (AMCs) such as Cleveland Clinic might seem to have an advantage in problem identification because of the volume and variety of the pathologies, but the understanding of disease processes isn’t limited to AMCs. Research universities, government laboratories, and industry-based scientists all are toiling to produce meaningful discovery science.

The understanding of basic chemistry, genetics, protein synthesis, and even potential chemical interactions informs initial paths. In addition to knowledge, there is also the need for insight; it takes a level of sagacity to understand a disease process and its relationship to a new drug treatment.

Target Identification and Validation

Understanding a disease needing treatment with a new drug therapy and selection of a molecular target is like looking at something with the naked eye versus an electron microscope. The target must be as focal as a single molecule, protein, or gene.

The target must also be “drugable,” meaning a new compound can influence its operation, block its synthesis, or alter its expression. Early studies that establish some form of cause and effect are crucial. If a specific molecule can be implicated in a disease and shown to be influenced or modified by a drug family, then it may be worthwhile to allocate resources to the process of drug discovery.

Determination of a Lead Compound

The processes thus far can be characterized as basic research and development. But once the search for a specific molecule commences, innovators are pursuing drug discovery. Whether it’s through observation of natural phenomena, creation at the bench or computer of molecules with certain structural characteristics, or high throughput screening, filters are necessary to identify the lead compound.

Lead compound designation is not equivalent to calling a newly identified molecule, whether discovered or synthesized, a new medicine. An extraordinary volume of lengthy, expensive testing awaits.

ADME/Tox Testing

Pharmacokinetics refers to how the body handles exogenous substances. The evaluation of lead compounds consists of a battery of tests to determine how the body will respond to and tolerate the substance. The acronym ADME/tox represents what innovators and scientists consider when sifting through ...