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The History of Drug Development

Jeffrey S. Barrett

Aridhia Digital Research Environment

Introduction

The history of drug development spans more than 10 centuries and is essentially coincident with the history of pharmacy although the modern era is much shorter. When we speak of drug development, we are typically referring to the development of small molecules as that constitutes a historical baseline for the most part but our scope in this text will also examine generic drugs, biologics, and therapeutic proteins as well as vaccines.

Most drug development milestones have occurred over the last hundred years consistent with the formal establishment of the pharmaceutical industry and the global regulatory community. However, we cannot consider drug development to have occurred from a completely undefined origin and there is indeed a prehistory to be defined and explained in order to appreciate the setting for modern drug development. There is an undeniable human behavior associated with the recognition of illness and the interest in aiding our fellow human being to improve our survival. We are very comfortable with the common cliché, "that's what separates us from the animals," but this may not be an entirely legitimate claim as we will see. A more poignant and relevant point of view is the appreciation for ethical drug development as we attempt to bring new medicines to market in an ever-competitive and complex healthcare environment.

The history of drug development also coincides with the history of regulatory oversight. Quite often the recognition of the need for regulation and oversight came on the heels of a tragedy in which a lack of understanding, negligence, or simple greed instigated an event that was ultimately dangerous for patients. In today's world, we are inundated with details regarding a new medicine's defendable attributes derived from years of research. In many cases, the prehistory of regulatory oversight also coincided with the marketing of non-pharmaceutical entities in which medical benefit was associated (see Figure 1.1 touting the presumed but unsubstantiated health benefits of malt whiskey by Whiskey distiller and manufacturer noted pharmaceutical manufacturer and reseller, Smith Kline and French - circa 1880s). It was commonplace during this time for alcohol distillers such as Duffy to make false claims like a tonic that "Makes the Weak Strong." Likewise, products promoted as patent medicines often contained alcohol, codeine, cocaine, and other opiates. The rapid expansion of glass bottle manufacturing via mechanical means helped fuel this expansion and promotion of medicines containing alcohol, a sign of the times in an era without regulation.

Figure 1.1 Advertisement from Duffy's Malt Whisky (circa 1880s) promoting alcohol for medicinal use.

While the modern pharmaceutical marketer tries to encourage potential patients that they might benefit from drug or therapy, there is also a staggering amount of detail shared regarding the safety of the drug and the potential for anticipated or unanticipated, though perhaps rare side effects. It should also be appreciated that given the nature of the data content, such information is not always properly interpreted or completely objective. We must again remind ourselves of the historical perspective, however, as this was certainly not the case prior to the late 1990s. Shown next are two ads from pharmaceutical products sold without evidence of safety or efficacy (see Figure 1.2).

Figure 1.2 Early pharmaceutical advertisements making unsubstantiated medical claims before regulated drug development and FDA oversight.

The objectives of this chapter are to describe the origins of pharmacy and humankind's quest to medicate. This necessity has roots in the natural world as we will describe and was the impetus behind traditional medicines and the evolution of scientific practices that sowed the seeds of drug development. With technological advances came the ability and necessity of manufacturing and distributing goods and services to a global economy. Some discussion of early pharmacies that in many cases became early pharmaceutical companies is provided along with the timeline and necessity of regulatory oversight in response to the tragedy in many cases. Finally, we will touch on the modern era and how the age of mergers and acquisition and the evolution of healthcare has affected the industry.

Wild Health and Nature's Pharmacy

A few years ago, I stumbled upon Cindy Engle's book, "Wild Health" (Engle 2003). It is the first book dedicated to the field of zoopharmacognosy, or animal self-medication. The parallels to clinical pharmacology are many and, while the field is still in its infancy, it will likely borrow concepts well established from more mature science focused on human and domesticated animal health. Engle's fundamental premise is "when wild animals are free to range over undisturbed habitat, not exposed to high levels of pollution and not exposed to extremes of environmental change, they are generally in good health. They live within an ecosystem to which their physiology and behavior are, by virtue of their very survival, well adapted (Wild Health, p. 13)." Perhaps not surprisingly, many wild animals when brought into captivity experience poor and declining health and often die within a short time period. Likewise, it can easily be shown that the health of their immune system is intimately linked with their behavior in a particular environment. If we draw a parallel to the human condition, we may conclude that the various epidemics that have plagued our species over time were largely influenced by migration, exploration, climate extremes, and perhaps exposure to various environmental toxins (see Jared Diamond's Gun, Germs, and Steel). Not to be excluded is the dynamic nature of the human, particularly the Western diet as our lifestyles have advanced and we struggle to feed an ever-growing and dispersed population. The healthcare industry, as we will see, has evolved primarily to help us cope with disease conditions born out of this developing human environment that is far away from where we began.

One of the more fascinating aspects of zoopharmacognosy is the evidence of self-medicating behavior of wild animals. As Engle is quick to point out, we don't need to overinterpret the knowledge regarding the behavior (i.e. assume that we can learn something about medical treatments from animals). The salient point is that these behaviors are associated with improved survival and consistent with attributes favoring natural selection (Costa-Neto 2012). Fundamentally, this is what we try to achieve with the development of new drugs. Table 1.1 provides some examples of self-medicating behaviors observed in the wild. The diversity, purpose, and species represented in this table highlight the fact that these behaviors are indeed a part of successful strategies to combat seasonal or other external intrusions to the environment. For example, as food supply changes with the seasons, animals and insects change their diet to maintain their nutritional needs (e.g. fallow deer change their grazing habits from grass to fruits and/or nuts to brambles, ivy, and holly). There is a constant adaption of diet and other behaviors based on changing circumstances. These behaviors are taught or otherwise passed on to future generations as part of such strategies and those that do not employ them are less likely to thrive.

Table 1.1 Examples of behaviors associated with self-medicating and health maintenance in nature.