Bayer Pharmaceutical Products
Bayer Pharmaceutical Products
Technology Allows for Medicines to Be Developed in Quantity
Source: Anonymous advertisement. Harper's Weekly, 1900. (Image also appears in A. S. Lyons and R. J. Petrucelli. Medicine: An Illustrated History. New York: Abrams, 1978.)
About the Author: Harper's Weekly was launched in 1857 by Fletcher Harper, one of the four brothers who owned Harper & Brothers, the largest book publisher in the United States at that time. It was Fletcher Harper's second successful foray into magazine publishing following Harper's Monthly, which he had created in 1850 and modeled on the London Illustrated News. By 1860 the circulation of Harper's Weekly had reached 200,000.
The Bayer company is one of the world's oldest drug manufacturing firms. It began as an industrial chemical company in the German city of Wuppertal in 1863 and became a pharmaceutical company, Farbenfabriken vorm. Friedr. Bayer & Co., in 1881. Bayer's development of industrial chemical processes and adaptation of these processes to the bulk manufacturing of pharmaceuticals laid the foundation for the modern pharmaceutical industry. The company established a scientific laboratory in the 1880s that was primarily focused on industrial research and development. These research efforts gave rise to numerous intermediates, dyes, and pharmaceuticals, including the "drug of the century"—aspirin—which was launched in 1899.
The promotional illustration reproduced here shows the portfolio of products manufactured by Bayer Pharmaceuticals and distributed in the United States around the turn of the century. It presents the company's entire product offering in a compact format. Prominent illustration panels are devoted to the four most widely used and heavily promoted products: Aspirin for pain and fever, Lycetol for gout, Heroin for cough suppression, and Salophen for arthritis. In addition to these "blockbuster" products, sixteen specialty or "niche" products share smaller panels in the illustration. These include Sycose, a homeopathic remedy, Europhen, an herbal medication, Somatose for providing nutrition to typhoid patients, Hemicranin for migraine headaches, Protargol for the staining of laboratory samples, and Phenacetin, formerly used to ease pain or fever, but now withdrawn from use because of its link to high blood pressure, heart attacks, cancer, and kidney disease.
While safety concerns soon emerged for several of these products, Bayer's production and promotion of heroin as a "non-addictive" substitute for morphine and codeine stands out as one of the most dramatic mistakes in the medical use of dangerous substances. The Bayer promotional illustration comes from an era when pharmaceutical products were not systematically tested for efficacy, side effects, and long-term safety. Discovery of the medical use of these products, and the discovery of the drawbacks to their use, was based largely on anecdotal evidence from physician case reports describing the results of treating small numbers of patients or even based simply on folk wisdom. Bayer's main concern in those days was that the products be chemically stable, pure, and standardized, since the company's industrial chemical production methods made possible their manufacture in quantities sufficient for worldwide distribution.
BAYER PHARMACEUTICAL PRODUCTS
See primary source image.
Bayer's application of industrial chemical methods to the manufacturing of pharmaceutical products gave rise to a business sector that now dominates scientific innovation in health care worldwide. From the late 1800s until very recently, the structure of the pharmaceutical sector was based on the model created by Bayer, consisting of vertically integrated medium-sized and large companies that discovered drugs, tested them in the laboratory and on patients, developed processes for their mass production, and commercialized them. (Only recently have small biotechnology firms taken the lead away from the large integrated firms in drug discovery and initial human testing.) This integration of discovery, research and development (R&D), and commercialization made the pharmaceutical industry one of the two large-scale forces in the health care industry. The other major player is the third-party medical payment system, largely a private industry in the United States and mainly a taxpayer-funded government function in other industrial nations. Despite attempts to achieve economies of scale through hospital systems and physician group practices, health care providers, including both hospitals and physician practices, have remained mostly locally focused and relatively small scale operations by comparison.
From its inception, however, suspicions about the purity, quality, safety and efficacy of the pharmaceutical industry's products led to its intensive regulation by government. One needs only to look at the Bayer product portfolio and its inclusion of heroin to realize the stakes involved. The history of the pharmaceutical industry is inextricably bound to the history of its regulation, and this regulation has shaped both the medical and financial direction of the industry over the past century. In 1902, the American Pharmaceutical Association set up a drug laboratory intended to assist with standardizing pharmaceuticals and analytical test results. An expert in the detection of drug adulteration was appointed director of the laboratory and started testing operations in 1903.
The drug laboratory spent its first years searching for ways to make pharmaceutical analyses more accurate. This work alerted the public to problems with the drug supply. Publicity over these findings led to journalist campaigns to pass the Pure Food and Drug Act of 1906.
The Pure Food and Drug Act prohibited interstate commerce of wrongly labeled and adulterated drugs and food, and placed responsibility for monitoring compliance with the drug laboratory. The law established units for drug inspection, essential oils, synthetic products, and pharmacology units, all of which focused on the investigation and analysis and efficacy claims for products sold as therapies. The drug inspection unit was given enforcement powers. After scrutinizing hundreds of domestic and imported drugs during the first year of enforcement, it recommended prosecution for manufacturers of about five percent of the samples.
Given the industrial and financial interests at stake, major challenges to drug regulation were soon mounted. In 1910, the investigation unit recommended prosecution of "Johnson's Mild Combination Treatment for Cancer" as "worthless." The government lost the case at trial when enforcement of the veracity of claims was ruled outside the scope of the Pure Food and Drug Act. Congress then issued the Sherley Amendment in 1912, which brought therapeutic claims under the jurisdiction of the act, but required that such claims would have to be proven "false and fraudulent" before they could be outlawed.
Although the regulation of drug efficacy claims was established under the Sherley Amendment, drug safety was still unregulated. Reports of deaths from the administration of anesthesia, the use of a weight loss drug (dinitrophenol), and, in 1937, the use of an anti-freeze analogue as an elixir, which killed many children, prompted the passing of the Federal Food, Drug and Cosmetic Act in 1938. This act required that new drugs be tested for safety and have adequate labeling before marketing to the public. It also established the Food and Drug Administration (FDA), now the world's foremost regulatory agency controlling safety, efficacy, and manufacturing standards for pharmaceutical products. It was not until 1951 that a clear line was established between prescription and non-prescription or over-the-counter drugs, adding another layer of safety and efficacy verification before a patient could use a product claiming to be therapeutic.
Despite the regulation of drug safety came decades after the regulation of efficacy claims, the rationale and standards for safety monitoring are significantly less controversial than those for drug efficacy. Few opinion leaders are willing to protest FDA's safety monitoring requirements because safety concerns are more clear-cut and immediate than concerns over inadequately supported efficacy claims. The latter depend on the interpretation of population-based, inferential statistical analysis, particularly clinical trials. Periodically the Wall Street Journal editorial page faults the FDA for bureaucratically delaying or frustrating the development of drugs that could save the lives of cancer and other terminally ill patients. Some physicians would reserve the decision to allow treatment with specific drugs to an agreement between doctor and patient, with no government (or third-party payer, for that matter) second-guessing.
Familiarity with the history of fraud and lack of concern for public health on the part of a small, but persistent, minority of manufacturers appears to justify regulatory oversight of the pharmaceutical industry. If regulators did not require very expensive and often lengthy thorough scientific efficacy and safety testing before marketing, it is difficult to imagine that pharmaceutical firms would have established impartial and effective oversight on their own, given the history briefly recounted here. This oversight and the clinical trial regimen that it has spawned have provided the basic statistical evidence—admittedly just a "starting point" for deciding on therapy—on which physicians and patients rely in choosing products. This regulation-generated evidence standard is certainly not adequate for deciding treatment for every idiosyncratic patient case, because the results of clinical trials represent the average of the population's (or major sub-groups') response to treatment. Thus, concerns over the fairness and accuracy of efficacy regulation for particular patient sub-groups or patients with rare conditions will continue to arise.
In recent years, the news media have carried many predictions of the manufacture of individually tailored medicines based on matching the diversity of the human genome. Under this scenario, specific medications will be targeted to specific patient genotypes for reliably safe and effective treatment. If these predictions prove true, the current population-based statistical methodology used by FDA would need to be changed to become more sensitive to potential individual responses to treatments. Already the agency is reaching out to pharmaceutical and biotechnology firms in an attempt to jointly fashion new evidentiary standards that would be more appropriate for genomic-based medicine development. While current standards of proof of safety and efficacy are imperfect and should be modified as pharmaceutical technology progresses, the relationship between regulation and industry has been symbiotic and beneficial both for industry prosperity and public health. Given the history of drug development and marketing, the burden of proof rests with those asserting that physicians and companies by themselves could and would adequately protect human life and stick to evidence-based efficacy claims without government regulation.
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