Contract Pharma’s readers, advertisers, and contributors will want to examine two recent books that describe the efforts of a variety of researchers to develop new drugs. They may want to consider them as holiday presents for their friends and relatives who may not be very familiar with the difficulties of that undertaking. The public debate about the pricing of pharmaceuticals only grudgingly acknowledges the incredible contributions to human health made by dozens of prescription drugs developed and commercialized not by the world’s government agencies or non-profit groups, but by independent, for-profit pharmaceutical companies. The widespread circulation of accounts such as those recorded in these books may not lessen the pricing controversy; but spreading the word about the costs and challenges of drug development might just facilitate a more knowledgeable debate on the topic.

The Drug Hunters
In, The Drug Hunters: The Improbable Quest to Discover New Medicines, science writer Ogi Ogas aids long-time drug researcher Donald R. Kirsch in infusing the latter’s personal experiences throughout an accessible review of some important milestones in drug development. Adding these observations brings unusual perspective to this account of researchers who used the techniques of biology and chemistry to realize their goals. Importantly, the book also discusses many of the false hypotheses, managerial blunders, and clinical trial failures that have made the search for useful pharmaceutical products much more difficult than the general public appears to believe.

This history of drug development begins with the observation that many botanicals were somewhat randomly found to provide useful therapeutic products as far back as 3400 BC. It moves quickly, however, to the time of the Renaissance and the efforts of alchemists and apothecaries to identify and isolate the active ingredients in the world’s therapeutically useful botanicals. That work has indeed continued. In the first of the book’s striking personal reminiscences, Kirsch notes American Cyanamid’s fruitless quest in the 1990s to find a single useful compound after examining fifteen thousand species of plants.

The narrative moves on to relate several ground-breaking success stories in the nineteenth century, especially William T.G. Morton’s discovery of ether’s use as an anesthetic (1846), and Edward Robinson Squibb’s development of processes for making consistently pure quantities of that drug and many others. It notes how John Dalton’s theory allowed researchers to explore the active molecules in drugs extracted from plants, and how a group of them at Friedrich Bayer and Company used that technology to alter the well-known salicylic acid to produce acetylsalicylic acid—brand-named Aspirin in 1899. Along the way, Kirsch applauds the “medicine-first” culture of E.R. Squibb and Sons even as he critiques the “squeeze a few drops of profits” culture he says prevailed at both Cyanamid and American Home Products (AHP) when he worked for those firms. 

The authors identify an important advance in drug development that occurred at the turn of the nineteenth century when Paul Ehrlich used a new method not to improve the synthesis, formulation, or effectiveness of an existing drug, but to create an entirely new one. It took almost twenty years of research into his “magic bullet” thesis; but in 1910 Hoechst AG began marketing Salvarsan as a cure, not just a treatment but a cure, for syphilis—a contagious diseases that had plagued humankind for centuries. Unfortunately, Kirsch notes, Ehrlich had stumbled on one particular example of what would later be recognized as receptor theory. During the next twenty years, most efforts to find a similar antibiotic failed.

It’s not until page 100 that the authors first mention the role of the Food and Drug Administration (FDA) in policing the drug industry. Congress created that agency in 1906; but it was not until 1938 that it authorized the FDA to regulate the manufacture and distribution of drugs. It did so only after S.E. Massengill’s Elixir Sulfanilamide had caused the deaths of more than 100 people. In 1935, Bayer AG finally developed a successful broad-spectrum antibiotic. That drug (Prontosil) killed many pathogens in animals and humans; but it was curiously ineffective against the same pathogens when grown in test tubes. Kirsch tells how chemists at the Pasteur Institute identified sulfanilamide as one of many compounds produced when the drug was metabolized in the liver, and documented it as the source of the product’s bacteria-killing properties. In 1937, hundreds of chemical and drug companies began producing their own versions of this non-patented compound. S.E. Massengill’s exclusive formula included the use of diethylene glycol as a dissolving agent. FDA field inspectors recovered 234 of the 240 gallons of the product sold to the nation’s drug stores; but they were too late to help more than 100 people who died of the kidney failure caused by that toxic ingredient.

In another personal commentary, Kirsch details AHP’s failure in the mid-1990s to conduct clinical testing on the cocktail of the already-approved drugs fenfluramine and phentermine (fen-phen) when used in combination as a weight-loss product. It turned out that the interaction between the active agents of those drugs and a rare side effect of one of them caused severe cardiac problems.

The authors give plenty of ink to the searches for antibiotics that led to the development of penicillin and streptomycin. But Kirsch also notes the emergence of drug-resistant bacteria. And he injects yet another personal note by decrying the drug industry’s abandonment of the search for new antibiotics, allegedly because of the limited profitability of such products. Subsequent chapters tell the stories of such other twentieth century advancements as the development of purified insulin (1923), and the initial commercialization of an anti-psychotic (1952), an oral contraceptive (1961), and an anti-hypertensive (1964).

The book’s last chapter likens developing a new drug with producing an artistic work such as a movie or a play, not with designing and manufacturing a product such as a phone or an automobile. The uncertainties of biology that confront the drug researcher stand in sharp contrast to the scientific laws and engineering principles used by those developing products that rely on such physical sciences. As a result, even with the use of sophisticated equipment and advanced knowledge, today’s quest for effective pharmaceutical products depends just as much as yesteryear’s on the trial-and-error process.

Miracle Cure
Whereas The Drug Hunters is a personalized tour through decades of drug development, Miracle Cure: The Creation of Antibiotics and the Birth of Modern Medicine, covers only the story of twentieth century research efforts to develop antibiotic products. It too has a personal connection to the topic; the science writer and author William Rosen was suffering from a rare form of cancer while researching and writing this expansive story. He writes in a less breezy style than the Kirsch/Ogas team. But Miracle Cure still provides a descriptive narrative of both the successful and unsuccessful efforts of the men who developed most of the world’s armamentarium of antibiotics.

Rosen notes at the outset that the war between Homo sapiens and infectious disease had been dominated for “untold millennia” by the latter. He devotes only a handful of pages to a quick review of a couple centuries worth of largely fruitless efforts to understand the nature of those ailments. In the middle of the nineteenth century Louis Pasteur first connected the natural phenomenon of fermentation to the causation of infections. Robert Koch then advanced the idea by isolating the toxin that caused one particular disease (anthrax). Pasteur returned the favor by using Edward Jenner’s hundred-year-old idea to develop a vaccine against that deadly disease. Even while recounting more details of Pasteur’s and Koch’s subsequent work, Rosen suggests their most important contributions to science involved their establishment of dedicated research laboratories and rigorous investigational techniques.

Rosen presents extensive details of the day-day work done by Paul Ehrlich and his collaborators as they pursued his “magic bullet” theory of disease and discovered the antibiotic Salvarsan. He adds a bit of perspective on that work by also acknowledging the achievements of men such as Lavoisier, Dalton, Kekule, and Thomson. Indeed, at the turn of the nineteenth century, the combined efforts of researchers in many countries led to an explosion of knowledge in the relatively new science of chemistry. Rosen suggests that the earliest physicists, mathematicians, and biologists would be somewhat familiar with parts of a modern textbook on their subject. But a medieval alchemist or apothecary would find his knowledge to be quite out-of-date.

In yet another interesting perspective, Rosen notes how the exciting promise of advances in pharmaceutical chemistry that occurred right up until the introduction of an improved version of Salvarsan (called Neosalvarsan) in 1912 was short-circuited by the global conflagration that impeded such research beginning in August 1914. He picks up the story with the post-war achievements of German chemists who finally discovered that the combination of an azo dye and a sulfanilamide side chain was able to kill the family of Streptococci bacteria. As also noted in The Drug Hunters, this became Bayer’s Prontosil in 1935.

This version of that story provides more details about the discovery of sulfanilamide as the drug’s active ingredient and the implications of that fact for the economics of pharmaceutical sales and marketing. It also covers the tragedy of S.E. Massengil’s Elixer Sulfanimide and the passage of a new Federal Food, Drug, and Cosmetic Act in 1938. Rosen also notes yet another problem with the family of related sulfa drugs—the evolution of antibiotic-resistant bacteria that limited the utility of what had once seemed like a group of truly miracle products.

Miracle Cure provides a more thorough explanation than The Drug Hunters of the discovery of penicillin, starting with the Alexander Fleming’s initial encounter with Penicillium notatum in 1927 and ending with the identification of the seventeen companies chosen to manufacture commercial quantities of penicillin in 1943. Rosen uses that part of the story as a jumping-off point to describe the emergence in the post-World War II years of a more professional pharmaceutical industry. Companies such as Abbott Laboratories, Eli Lilly, Merck, and E.R. Squibb and Sons had long been making purified commercial quantities of various drugs and devoting some dollars to research on new products. They and others in the United Kingdom and Europe now began investing millions of dollars in state-of-the art research and production facilities.

Selman Waksman, Albert Schatz, Corwin Hinshaw, and Robert Woodward deserve to be just as well known as Alexander Fleming. In the late 1940s and early 1950s their efforts led to the development of Streptomycin, Aureomycin, Terramycin, Tetracycline, Erythromycin and other wonder drugs capable of attacking a range of bacteria-causing diseases. The story takes an unexpected twist, however, as Rosen notes how questionable patents, indistinct therapeutic effects, various cross-licensing agreements, and emerging drug-specific resistance dampened the financial prospects of many products. He tells how the efforts of Austin Bradford Hill and Arthur Sackler helped bring clarity to the use of these new drugs.
Hill was a researcher who recognized the value of randomized, controlled clinical trials long before the FDA began requiring them in 1962. Sackler was the first of a new army of advertising and marketing executives whose creative and persistent campaigns convinced physicians to prescribe their companies’ proprietary, branded products. Prior to the discovery of penicillin, 75% of all prescriptions were compounded by pharmacists using physician-supplied instructions; by 1955, 90% of all prescriptions were for branded products.
As had frequently happened before, the hubris of the drug industry was about to be challenged. One of the miracle antibiotics, Parke-Davis’ Chloromycetin, was found to cause more cases of aplastic anemia than occurred in the general population. The incidence was “only” 1 in 40,000 patients. But it was a side effect that was not particularly emphasized by the detail men selling this very profitable product to the physician community. Trusting those companies to provide complete information about their products seemed unwise. At the time, neither the FDA nor any other government agency had the power to force them to conduct rigorous studies to thoroughly validate each new product’s safety and efficacy before putting it on the market. But individual reviewers such as Dr. Frances Kelsey still had the authority to question companies about their potential new products before approving them for sale.

Rosen only provides the briefest comments on Dr. Kelsey’s success in limiting in the United States the number of birth defects associated with the use of Richardson-Merrell’s thalidomide. He does note, however, how that tragedy prompted Congress to expand the FDA’s power to require extensive documentation of any potential new product’s safety and effectiveness. He ends his history by commenting briefly on the decline of antibiotic research in the twenty-first century, while also acknowledging the recent initiation of the HWPAR and GAIN programs aimed at correcting that mistake. (Some 60% of all hospital-acquired infections are resistant to treatment with the current group of antibiotics.) Rosen’s plea for a renewed attack on the world’s species of bacteria came too late to save his own life; he passed away from gastrointestinal stromal cancer in April 2016, about a year before his book hit the shelves.

Reading The Drug Hunters and Miracle Cure will not help answer the key question of the actual cost of developing a successful new drug. Indeed, the former’s first chapter cites the $1.5 billion figure published in 2014 by the Tufts Center for the Study of Drug Development (CSDD); the latter’s Epilogue cites the figure of $43.4 million as reported in 2011 in the journal BioSocieties. Regardless, both works provide chapter and verse of the struggles encountered by drug researchers across time as they have sometimes succeeded but more often have failed to used their knowledge and skills to unlock the mysteries of human disease and treatment.