PHARMA SINCE 1870
PRODUCTION This 1971 photo from a Pfizer plant in Groton, Conn.p shows one of the many stages between discovery of a medicinal compound and it's eventual introduction to the market.
A RISING DRUG INDUSTRY The pharmaceutical industry since 1870 has become gargantuan, but consumers cling to a love-hate relationship with drugs for health ARTHUR A. DAEMMRICH AND MARY ELLEN BOWDEN, CHEMICAL HERITAGE FOUNDATION
S
INCE THE MID-I9TH CENTURY, PHARMACEUTICALS
have moved from the periphery to the center of health care. In the course of that transition, a new industry sector expanded to global scope, the field of medicinal chemistry rose to its current prominence, and governments adopted dual roles of supporting basic research and regulating drug safety and efficacy For patients—and we are all patients at various points in life—drugs have taken on new medical roles and value. In recent 28
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years especially it has become common for people to take drugs for years, even decades, to reducerisksof disease and increase life span. Taking drugs for life has intensified a long-standing hybrid of scientific, emotional, and policy issues around side effects and widespread resentment ofcompanies that profit from drug invention and marketing. Combined with public health initiatives, newpharmaceuticals have contributed significandy to an improved quality oflife and helped increase human life span. In the U.S., for example, life span increased from an average of 47 years in 1850 to 78 years today. Advances in medicinal chemistry have marginalized or eliminated health WWW.CEN-0NLINE.ORG
France; and Abbott, Smith Kline, ParkeDavis, Eli Lilly, Squibb, and Upjohn in the U.S. all started as apothecaries and drug suppliers between the early 1830s and late 1890s. Other firms whose names carry recognition today began with the production of organic chemicals (especially dyestuffs) before moving into pharma ceuticals. These include Agfa, Bayer, and Hoechst in Germany; Ciba, Geigy, and Sandoz in Switzerland; Imperial Chemical In dustries in England; and Pfizer in the U.S. A merging of these two types of firms into an identifiable pharmaceutical indus try took place in conjunction with the emergence of pharmaceutical chemistry and pharmacology as scientificfieldsat the end of the 19th century Oriented to iden tifying and preparing synthetic drugs and studying their impacts on pathological con ditions, both disciplines were intimately linked with theriseof the industry Pharmaceuticalfirms,firstin Germany in the 1880s and more recently in the U.S. Emergence of pharmaceutical science and England, established cooperative rela and industry: 1870-1930. The modern tionships with academic labs. The result pharmaceutical industry traces its origin ing exchange ofresearch methods and find to two sources: apothecaries that moved in ings drove a focus on dyes, immune to wholesale production of drugs such as antibodies, and other physiologically active morphine, quinine, and strychnine in the agents that would react with disease-caus middle of the 19th century and dye and ing organisms. Postulated by Paul Ehrlich chemical companies that established re in 1906 following more than a decade of search labs and discovered medical appli research, the concept that synthetic chem icals could selectively kill or immobilize parasites, bacteria, and other invasive dis ease-causing microbes would eventually drive a massive industrial research program that continues to the present. Already in the early 19th-century, chemists were able to extract and concen trate traditional plant-based remedies, giv ingriseto treatments such as morphine and quinine. By the start ofthe 20th century ap plying similar methods to animal systems resulted in the isolation of epinephrine (adrenaline) as thefirsthormone that could be used as a medicine. Meanwhile, synthetic organic chemistry evolved as an industrial discipline, especially in the area of creating dyestuffs derived from coal tar. It was only a short step from staining cells to make them more visible under microscopes to dyeing cells to kill them. Chemists soon modified REMEDY Patent medicine recipes were not, in fact, patented, though the the raw dyestuffs and their by-products to formulas were usually a secret. make them more effective as medicines. however, and regulators are pilloried in the cations for their products starting in the Early products ofresearch continue to have press, asked to testify before Congress, and 1880s. Merck, for example, began as a small application today; for example, N-acetyi-ptold to tighten controls. apothecary shop in Darmstadt, Germany, aminophenol, the active ingredient in Industry faces its own set of difficult in 1668, only beginning wholesale pro Tylenol and Panadol, is a fast-acting me choices. Firms that commit too strongly duction of drugs in the 1840s. Likewise, tabolite of the analgesics acetanilide and to a small development portfolio face the Schering in Germany; Hoffmann-La phenacetin created in German laboratories possibility of failure in clinical trials and Roche in Switzerland; Burroughs Well in the 1880s. In 1897, a chemist at Bayer, disruption of their competitive standing. come in England; Etienne Poulenc in Felix Hoffmann, first synthesized aspirin,
scourges once prevalent around the world. This special issue of Chemical & EngmeeringNews contains 46 essays devoted to spe cific drugs or classes of drugs. Among the threads explored are the role of chemical professionals in inventing new therapies; the complex interplay of scientists, indus try, government regulators, physicians, and patients in converting laboratory molecules into medical therapies; and the changing professional roles of scientists and physi cians in the wake of increased government regulation and patient activism. Recently, drug safety issues have come to the fore in the wake of concerns about COX-2 inhibitors and antidepressant use among teens. Press attention and con gressional investigations have highlighted the complex choices faced by industry and regulators as new medicines come to mar ket. Government officials who act too slowly while reviewing mountains of doc uments—applications are typically 50,000 pages long or longer—face complaints from patients, disease-based organizations, physicians, and economists and politicians with antiregulatory sentiments. When reg ulators decide against approval, they may be accused of undermining a key sector that provides employment to thousands of skilled workers and serves the public in terest by producing medicines. Approve a drug that later causes adverse reactions, ζ υ α uu Σ u. Ο >•
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Those that push broad drug pipelines risk investor dissatisfaction with their failure to focus their research and develop block buster drugs. Market incentives drive com panies to invent medicines for ailments prevalent in the U.S., Europe, and Japan, while the absence of cures or affordable treatments for diseases prevalent in de veloping countries, especially HIV/AIDS and malaria, opens pharmaceutical firms to criticism. Another challenge in the past two decades has been theriseof a generic pharmaceutical industry ofincreasingglobal scope. Arecent Harris Poll thus recorded a 35% decline in consumers' approval of the in dustry, down from 79% in 1997 to 44% in 2004. For scientists involved in drug re search and for the industry more broadly, this shift reflects the quandary ofbalancing an ethos of research in the interest of the public good against the necessity of run ning pharmaceuticalfirmsas businesses.
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PHARMA SINCE 1870 another staple of our medicine cabinets. The end ofthe 19th century also saw the de velopment of several important vaccines, including those for tetanus and diphtheria. A theory relating chemical structure to pharmaceutical activity emerged from the interplay of experimental results from an imal and human tests using vaccines, an titoxins, and antibodies with chemical knowledge about dyes and their molecu lar structures. This structure-activity the ory inspired Ehrlich to pursue a long and systematic course of research that result ed in the antisyphilitic Salvarsan, often considered the first systematically invent ed therapy The progressively more important role of the chemist and chemical science in pharmaceuticals in the early-20th centu ry is mirrored in the history of the Amer ican Chemical Society's Division of Med icinal Chemistry It was founded in 1909 as the Division of Pharmaceutical Chem istry one year after ACS instituted a divi sional structure. Chemists in the U.S. had gained new stature and industrial employ ment due to the requirements for accurate analysis of medicines contained in the 1906 Food & Drugs Act. But U.S. chemists only rarely had the freedom to create new drugs, and relatively few companies man-
In 1920, the ACS division renamed itself the Division of Medicinal Products to re flect the wartime change in focus from analysis to synthesis. Edging ever closer to research functions, in 1927 the division took on its present name. While largely unregulated by govern ment bodies prior to the 20th century, the pharmaceutical industry faced challenges in differentiating its products from patent drugmakers whose secret recipes, in fact, were not patented. Professional bodies, in cluding national physicians' associations, pharmacists' groups, and national formu laries (which trace their origins to a 1498 pharmacopoeia for the apothecaries of Florence, Italy) set manufacturing stan dards and occasionally exposed fallacious claims made concerning medical ingredi ents. The development of diphtheria anti toxin in the 1890s and subsequent cases of inactive or contaminated doses led the health ministries in Germany and France to test and oversee biologicals; likewise, the U.S. Hygienic Laboratory was authorized to license manufacturers under the 1902 Biologies Control Act. Government regulators' authority to re move products from the market or constrain advertising claims, however, was limited in the U.S., Europe, and elsewhere. Larger com
ed locally by pharmacists. In many cases, physicians dispensed medicines directly to patients; companies often supplied physi cians with their favorite formulations. While the medical profession was well-es tablished in Europe and America, the phar maceutical industry was only beginning to develop medicines to treat pain, infectious diseases, heart conditions, and other ail ments. Direct application of chemical re search to medicine appeared promising, but only a few substances—newly isolated vitamins and insulin—were more effective than treatments available at the turn of the century. The industry's position at the crossroads of science, medicine, and grow ing health care markets nevertheless set the stage for explosive growth. The pharmaceutical "golden era": 193060. The middle third of the 20th century witnessed a blossoming of pharmaceutical invention, with breakthroughs in the de velopment of synthetic vitamins, sulfon amides, antibiotics, hormones (thyroxine, oxytocin, corticosteroids, and others), psy chotropics, antihistamines, and new vac cines. Several of these constituted entire ly new classes of medicines. Deaths in infancy were cut in half, while maternal deaths from infections arising during child-
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DYESTUFFS The press room (photo at left) of the Althouse Azo Dye Manufacturing Plant, Reading, Pa., in 1946. Dyes were among the first substances investigated for pharmaceutical activity. A Merck delivery truck in front of company headquarters in New York City, circa 1908. ufactured complex therapies. Those ac tivities were largely monopolized by Ger man chemists working in conjunction with the major German chemical companies. World War I blockades forced U.S. chemists to replicate German processes for producing drugs such as aspirin; Sal varsan; and Veronal, a powerful hypnotic useful in easing the pain of battle wounds.
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panies supported additional legislative in terventions, including the 1906 Food & Drugs Act in the U.S. and similar laws in sev eral European countries that prohibited adulteration and forced manufacturers to reveal ingredients on product labels. Nevertheless, at the start of the 1930s, most medicines were sold without a pre scription and nearly halfwere compound
birth declined by more than 90%. Illness es such as tuberculosis, diphtheria, and pneumonia could be treated and cured for the first time in human history As in other domains, wartime support for research accelerated the development of certain therapies. Programs sponsored by the U.S. government focused on anti malarials, cortisone (which was thought to
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PHARMA SINCE 1870 permit aviators to fly higher without blacking out), and, most especially, penicillin. The development of penicillin by 11 U.S. pharmaceutical companies under the oversight of the War Production Board gave U.S.firmsa leading position after WWII. In the late 1940s, they produced over half of the world's pharmaceuticals and accounted for one-third of international trade in medicines. Pharmaceutical firms in the U.S., Europe, and Japan expanded rapidly following the war with strong investments in research, development, and marketing. In this period ofrapid growth in pharmaceutical research, companies expanded in-house R&D while continuing collaborations and consulting relationships with academic researchers. At the same time, the primary methods used for drug invention shifted radically between 1930 and I960. During the advent of the antibiotic era, drug firms screened thousands of soil samples in a global search for antimicrobial agents. Antibiotics including streptomycin (Merck), chlortetracycline (Lederle), chloramphenicol (Parke-Davis), erythromycin (Abbott and Lilly), and tetracycline (Pfizer) gave companies the opportunity to extol the miracles of medical research to health professionals and consumers alike. Profitsfromthe sale of antibiotics enabled companies to build campuslike research parks from which further breakthroughs were expected.
used diethylene glycol, a sweet-tasting but toxic chemical, to prepare one of the thennew sulfa drugs in syrup form. Although chemists at thefirmexamined the appearance, flavor, and fragrance of their "elixir of sulfanilamide," they did not test it on animals or even review published literature on solvents. After more than 100 people—mostly children—died from the compound, a public uproar prompted rapid approval of the 1938 Food, Drug & Cosmetic Act. The law significantly expanded the Food & Drug Administration's authority over the marketing of new drugs. Officials were required to review preclinical and clinical test results and could block a drug's ap-
new medicines (Staffverordnung) was continued into the 1950s as a means for the health ministry to regulate pharmaceutical manufacturers. In England, the Therapeutic Substances Act was revised and consolidated in 1956, bringing more substances under government control and setting formal standards for their testing and manufacture. Similar laws in the U.S., European countries, and other nations around the world distinguished over-the-counter therapies from prescription drugs. This division, in turn, drove further specialization by the pharmaceutical industry into high-profit prescription-only medicines.
In the late 1940s, U.S. pharma firms produced over half of the world's pharmaceuticals and accounted for one-third of international trade in medicines.
As part oftheir regulatory oversight, govg ernment officials promoted the | double-blind, clinically controlled | trial as the gold standard for testing ? new medicines on patients. For reg< ulators, datafromformal clinical trië als narrowed the field of decisionJ2 making by characterizing drugs in 1 terms of their safety (and eventual° ly effectiveness) across large patient populations. In time, pharmaceutical companies found that testing helped target populations who would purchase a new drug, generWithin a short time, firms shiftated information useful in marketed their research focus from natural ing, and raised the entry costs for products to modified natural prodcompeting firms. Medical reformers ucts to synthetic chemistry Associand consumer protection advocates ated with this shift, new analytical expected morerigorouspremarket techniques and instrumentation entests to prevent harmful or useless tered the research laboratory to aid productsfromreaching consumers. in the determination of the molecInterestingly despite national variular structures of antibiotics, steation in regulations and clinical triroids, and other potential medicines. al methods, in all countries the pharX-ray crystallography, as well as ulmaceutical industry retained traviolet and infrared spectroscopy, responsibility for product testing. initiated a gradual shift from wet Thus, even as government regulachemistry of solutions in beakers tory agencies expanded their auand test tubes to dry chemistry of CHIEF Harvey Washington Wiley, head of the Division thority they remained reliant on the minute samples and molecular mod- of Chemistry of USDA, predecessor of FDA, is pictured industry to sponsor and oversee the els. As a result, chemists began to here around 1899 with his technical staff behind him. vast majority of clinical trials. develop a good working knowledge Wiley's formal attire perhaps suggested his activity Despite increasing regulation, of the relationships between mo- that day to stump for the latest in a long line of the industry operated largely out lecular structure and bioactivity, comprehensive federal food and drug bills. of the public eye, in part because making possible the first effective its marketing was oriented primarily to antipsychotics, tranquilizers, antidepresproval by requesting additional testing or by formally refusing to allow its marketing. physicians. In most countries, companies sants, and antihistamines. Less stringent regulations than in the advertised pharmaceuticals to physicians, This period also saw the institution of physicians prescribed them to patients, safety regulations in the U.S. in the wake of U.S. were put in place in other countries during the first half of the 20th century In and patients obtained the drugs from pharthe 1937 sulfanilamide incident. Tragedy Germany for example, a wartime ban on macies. Drug salesmanship was transstruck when a scientist at S. E. Massengill 34
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PHARMA SINCE 1870 formed into a professional service that educated physicians about new therapeutic options during the middle third of the 20th century At the same time, critics such as John Lear of the Saturday Review began exposing marketing practices in widely read articles such as "Taking the Miracle out of the Miracle Drugs" {Saturday Review Jan. 3,1959, page 35) and "Do We Need a Census ofWorthless Drugs?" (Saturday Review May 7, I960, page 53). Nevertheless, one consequence of the post-WWII growth of social democracies and socialized medicine in Europe and greater availability of private health insurance in the U.S. was that neither patients nor physicians paid close attention to drug prices in this time period.
Social reassessment, regulation, and
done among natural sources, including substances produced by microbes that might have the desired biochemical effect. Drawing on the store of molecular structure-activity relationships that chemists have built up over time, researchers modify the lead candidate from this process to turn it into a pill or injection tolerated by humans. While rational in intent, the process to this day often benefits from sheer chance and the tenacity of researchers who develop a passionate attachment to certain molecules, such as Miguel A. Ondetti and Emily Soba with the ACE inhibitor succinyl-L-proline, which was developed into captopril, or Albert Carr with a metabolite of terfenadine, which was marketed as an antihistamine. During the 1960s and 70s, new instruments were brought to bear on the process of drug discovery, including nuclear magnetic resonance and high-pressure liquid chromatography Rendering the pharmaceutical laboratory yet more dry comput-
growth: 1960-80. The pharmaceutical industry was buffeted by significant scientific, medical, political, and market forces between I960 and 1980. Approaches to drug discovery and early-stage testing changed as medical advances made it possible to identify compounds that block specific physiological processes. Major innovations were made in cardiovascular drugs (starting with antihypertensives and beta-blockers in the 1960s, followed by calcium-channel blockers, ACE inhibitors, and cholesterol-reducing drugs in the 1970s and 1980s); tranquilizers, antidepressants, and antihistamines with fewer side effects; nonsteroidal anti-inflammatory drugs; oral contraceptives; cancer therapies; and means of controlling the symptoms of Parkinson's disease and asthma attacks. Clinical testing achieved greater standardization under strict FDAoversight in the U.S., whereas many European and other countries maintained more flexible systems that allowed drugs on the market sooner, contingent on closer physician monitoring of side effects. As a result, a hotly contested "drug lag" motivated U.S.-based firms to diversify into fragrances, cos- SCALE-UP Sir Alexander Fleming (front) in metics, and other consumer products. 1945 at a pharmaceutical production facility. Though chemists at least from the ~~ days of Ehrlich had hoped to design medicines to fit molecular targets, so-called rational design became a real possibility in the 1970s. In rational design, substrates or receptors for enzymes, hormones, or neurotransmitters known to be involved in a particular disease are selected on the basis ofknowledge ofthe body's biochemical and physiological processes. Next, chemists investigate compounds that might block the function of the chosen target molecule. Alternatively, or simultaneously a search is 36
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ers were increasingly used to perform complex calculations such as Fourier transforms and to host databases used in comparing new compounds to established reference molecules and in analyzing results from large clinical trials. Among the factors driving adoption of new instruments and computers was a major new regulatory law Starting in the late 1950s, the pharmaceutical industry faced a lengthy investigation into pricing policies and marketing approaches spearheaded by
former Sen. Estes Kefauver (D-Tenn.). Kefauver brought to public attention huge markups between raw material costs and the final price of a drug; his congressional hearings also exposed a variety ofunsavory marketing practices. Nearly simultaneous with the Kefauver investigation in the U.S., the thalidomide tragedy— a case in which a sedative widely marketed in Europe, South America, and parts of Asia caused severe birth defects in approximately 10,000 children worldwide—drew attention to inadequate clinical testing and regulatory oversight prior to the marketing of new drugs. In Germany home to the manufacturer (Chemie Griinenthal) and the country hardest hit by the tragedy a 1961 statute ordering federal registration of new medicines was strengthened in 1964 to require prescription drug status for new drugs. Nevertheless, a more comprehensive drug law with formal premarket requirements for drug a safety and efficacy was not enacted in | Germany until 1976. !» In the U.K., the Ministry of Health | responded to the crisis by establishing è the Committee on Safety of Drugs I (CSD) in 1963. Although it worked £ closely with the government, CSD was 12 not a regulatory agency and did not poI lice physician or industry behavior be° fore or during clinical trials. A national licensing authority was established in the 1968 Medicines Act, which put the control of market access for new drugs under the Committee on Safety ofMedicines. Although thalidomide was not marketed in the U.S., publicity about birth defects in Europe led Congress to rapidly pass new legislation. Whereas Kefauver had proposed mandatory crosslicensing of drug patents, price limits, and restrictions on marketing in an effort to lower drug prices, the final legislation was oriented solely to drug safety and efficacy standards. Subsequent to passage of the Kefauver-Harris Amendments to the Food, Drug & ~~ Cosmetic Act in 1962, FDA promulgated guidelines detailing approved methods for clinical testing, enforced a strictly quantitative approach of evaluating drug applications, and began using its new authority to postpone or reject New Drug Applications. Pharmaceutical firms responded to the thalidomide tragedy and subsequent regulations by investing greater resources in preclinical and clinical testing. Trials that previously were carried out on populations of tens or hundreds of patients soon grew WWW.CEN-0NLINE.ORG
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[email protected] PHARMA SINCE 1870 to the thousands. Within a decade of enactment of the Kefauver-Harris Amendments in the U.S., however, even large companies with extensive research and testing programs began to complain of a decline in the number of new drugs approved for marketing. Drug companies then diversified into a range of other businesses including medical devices, diagnostics, optics, cosmetics, foodstuffs, and household goods. American firms increased sales overseas and also expanded international research with new labs in Europe, South America, and Asia. The period between 1960 and 1980 also saw challenges to the authority of the medical profession in the form of feminist criticisms of patriarchy, publication of the influential book "Our Bodies, Ourselves" (1973) by the Boston Women's Health
insulin that historically were extracted from animals can now be produced with greater purity by genetically modified organisms. Methods employed for drug invention have also changed as combinatorial chemistry and high-throughput screening have automated many features of laboratory work. As a result, companies have increasingly battled to develop proprietary molecule libraries. Despite predictions that high research costs and tight government regulation would prevent new firms from joining the pharmaceutical industry a wave of small biotech companies took center stage in the early 1980s. Their focus on molecular biology, genetics, and genomics soon drew the attention and involvement of established companies. By 2004, according to a survey conducted by the Biotechnology Industry Organization, some 50% of the
lations were made using computers to model the target. Databases also helped generate the structures of possible lead candidates. By the late 1980s, it appeared that a productive route to new therapies would be found in the automated mass production of compounds that are systematic variations of a particular molecular structure. So competitive advantage lay in the efficient design of syntheses to focus on the most likely candidates. New compounds generated by this approach were subjected to very fast screening, including a variety of physical tests as well as bioassays to determine how a compound would be metabolized in the human body whether it would bind to the chosen target, and whether it would prove toxic to human beings. Although pharmaceutical companies have invested millions
DRUG DISCOVERY Sir Alexander Fleming (photo at left) is holding a petri dish in this undated photo. Chemist Carl Djerassi is center left in this 1951 photo of the announcement, at Syntex in Mexico City, of cortisone synthesis from a plant source.
Book Collective, and expansion of diseasebased organizations for childhood disorders and cancer. This was also the era when "the pill"—the birth-control pill—became a common term as pharmaceutically based birth control connected to significant social changes. Market challenges, patients and activists, and industry consolidation: 1980present. During the past two decades, the pharmaceutical industry has brought a new wave of medicines to market that act on the central nervous system, offer treatment for viral and retroviral infections (including therapies for HIV/AIDS), and cure or delay the onslaught of cancer. At the same time, new biotech medicines such as interleukins and interferon have been able to mimic or support key features of the immune system. Likewise, compounds such as 38
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research projects under way at major drug companies were based on biotechnology. The U.S. emerged as a leading site for biotech innovation, and European firms established joint ventures with American companies; in some cases, they even moved their research operations to North America. Breakthrough medicines to treat cancer, such as angiogenesis inhibitors and drugs targeted to particular molecular features of cancer cells, and tofightHIV/AIDS, such as reverse transcriptase inhibitors and protease inhibitors, were made by a combination of rational design and fortuitous discovery Several means of speeding up the process beckoned: computational chemistry, combinatorial chemistry, and highthroughput screening. Where little was known about the conformation of the target molecule, electronic databases were searched and quantum mechanical calcu-
of dollars in these technologies, their worth in delivering new drugs recently has been called into question. Alongside computational and combinatorial chemistry genomics and biotechnology offered the possibility to revolutionize the discovery and manufacturing of therapeutics. The techniques and technologies employed in genetic and genomic drug research are oriented to the molecular structures of diseases, which represent knowledge gained over decades of biochemical research, and the molecular details ofthe genetic code, which represent knowledge gained through the relatively new science of molecular biology Starting in the late 1940s, pharmaceutical firms relied on microorganisms to manufacture antibiotics like penicillin in deep-tank fermentation processes. New techniques ofrecombinant DNAnow allow genetic engineers to make WWW.CEN-0NLINE.ORG
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PHARMA SINCE 1870 microbes that produce a far greater range of desired molecules. One future possibility in this field lies in gene repair by means of introducing engineered cells. In addition to its laboratory impacts, biotechnology emerged as a distinct entrepreneurial business sector. Three events in 1980 were ofparticular importance. First, in a pivotal Supreme Court decision, the justices decided that genetically manipulated organisms could be patented. Second, Congress passed the Bayh-Dole Act, allowing recipients of federal research funding to secure patents. Third, Genentech— the first publicly traded biotechnology company— set a record in its initial public offering, as its stock price soared from $35 to $89 per share in two minutes. Within a few years, several thousand biotech companies were founded in the U.S., raised funds from venture capitalists, and, in many cases, went public at early stages. Investors accepted surrogate markers for sales and income, including prominent scientists on boards of directors; patents on untested medicinal compounds; and ambitions to cure major diseases, including cancer, diabetes, and AIDS. The industry went through successive waves of
scientists and physicians, and had high-techbased medical treatment. Abiotechnology sector did not immediately arise across Europe; instead, established pharmaceutical firms set up newin-house research labs and invested in partnerships with biotech ventures and academic research centers in North America. Without investors eager to take the risk of supporting new ventures, and in the face of strict national and state laws on effluents from production facilities, comparatively few small biotech companies were created in Europe until the mid-1990s. At that point, a combination of government subsidies and reduced regulatory oversight helped stimulate the growth of a biotech sector. Simultaneous with the business challenge posed by new biotech firms, the pharmaceutical industry faced policy challenges from nongovernment organizations, led by disease-based activists. Patients with HIV/AIDS, breast cancer, and other dis-
By 2004, some 50% of the research projects under way at major drug companies were based on biotechnology.
LEGISLATION President Kennedy signing the 1962 Kefauver-Harris Amendments to the Food & Drug Act into law. He is handing the pen to former Sen. Estes Kefauver (D-Tenn.). boom and bust; yet by 2005, nearly 1,500 biotech companies were active in the U.S. The sequence from university spin-off to venture-capital-funded firm to publicly traded company—pioneered so successfully by Genentech—was not followed universally For example, by the early 1980s, European countries and the U.S. shared advanced capital markets, had well-educated 40
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the other hand, they promoted the Orphan Drug Act of 1983 and new regulations that sped regulatory approval ofmedicines in the 1990s, especially for potentially life-saving drugs. Intriguingly comparatively fewer activists pushed for changes to drug regulation in European countries, perhaps due to more comprehensive health care coverage. While their origins stretch back to the 1950s, generic pharmaceutical manufacturers became a significant industry only following the 1984 Drug Price Competition & Patent Term Restoration Act (Hatch-Waxman), which authorized FDA to approve generics without additional preclinical or clinical testing. As a result of the industry's growth, of the 10,357 approved drugs listed in the 2004 edition of FDAs Orange Book, 7,602 have generic counterparts. According to the Generic Pharmaceutical Association, drugs with annual sales of $35 billion will lose patent protection within three years. Large firms, including Eli Lilly and Merck, have experimented with owninggeneric companies; most recently Novartis purchased two generics firms for a total cost of $8.3 billion. As a result, the pharmaceutical industry has faced challenges on several fronts since 1980: from a new set of competitors in the biotech industry from generics manufacturers, and from the end users of their products. The primary strategy for large firms has been to focus intensively on inventing new drugs and marketing approved molecules. Companies thus sold off the chemical, cosmetics, and other consumer goods divisions they had built up during the 1960s and 70s. For a briefperiod in the late 1990s, some firms advocated a so-called life sciences concept intended to find synergies among medical, agricultural, and industrial biotechnology; within a few years, however, this model was largely discarded. Safety and efficacy regulations that were once perceived as proximate causes for diversification and reduced profitability in pharmaceuticals were now viewed as driving consolidation and a singular focus on inventing and marketing blockbuster drugs. Whereas it made sense to speak of an American, German, French, or British drug company as recently as a decade ago, mergers and greater cross-national R&D investments have since rendered such delineation largely irrelevant. Between 1985 and 2005, nearly 40 major mergers pro-
eases mobilized to focus research agendas on their illnesses, protest drug prices for life-saving therapies, and speed regulatory review On the one hand, activists attacked the benign public perception of the industry as they confronted firms about their pricing policies and their apparent focus on the diseases and vanities ofmiddle-aged and older citizens in developed countries. On
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PHARMA SINCE 1870 duced firms of an unprecedented size and scope in the pharmaceutical industry In 1994, American Home Products joined with Ayerst and Wyeth; in 1995, Glaxo merged with Wellcome, and Pharmacia with Upjohn; in 1996, Novartis was formed out of Ciba-Geigy and Sandoz; in 1999, Aventis was created out of Hoechst and Rhône-Poulenc, formerly venerable independent German and French firms; in 2000, Pfizer merged with Warner Lambert before purchasing Pharmacia in 2003; and in 2004, Aventis was purchased by Sanofi-Synthélabo, itself the product of a long string of mergers and acquisitions. Nevertheless, the simultaneous emergence of new biotech companies has prevented monopolistic concentration in the industry; the combined worldwide market share of the top 30 pharmaceutical and biotechnology firms is just over 50%, and Pfizer, the largest pharmaceutical firm, had less than 10% of global sales in 2003. Looking to the future. In the wake of recent cases of adverse drug reactions, FDA announced plans in February 2005 for a new Drug Safety Oversight Board that will monitor Phase IV (postmarket) pharmaceutical use. Questions about the status of drug research, especially widely circulated claims that pipelines are empty, may be more difficult to resolve than concerns about side effects, ^et some of these claims are exaggerated; in 2004, FDAapproved 34 new molecular entities and biologies, including innovative treatments for diabetes, Parkinson's disease, pain, macular degeneration, and several therapies for cancer. This is a drop in numbers of new approvals compared with the mid-1990s; however,
SUGGESTIONS FOR FURTHER READING Bowden, Mary Ellen. "Pharmaceutical Achievers: The Human Face of Pharmaceutical Research." Philadelphia: Chemical Heritage Press, 2003. Daemmrich, Arthur A. "Pharmacopolitics: Drug Regulation in the U.S. and Germany." Chapel Hill: University of North Carolina Press, 2004. Landau, Ralph, et al. "Pharmaceutical Innovation: Revolutionizing Human Health." Philadelphia: Chemical Heritage Press, 1999. Swann, John P. "Academic Scientists and the Pharmaceutical Industry: Cooperative Research in Twentieth-Century America." Baltimore: Johns Hopkins University Press, 1988.
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PROTEST In 1988, the AIDS Coalition to Unleash Power (ACT-UP) organized a demonstration at FDA headquarters in Rockville, Md., to protest for increased access to and accelerated approval of treatments for AIDS. contrary to some pundits' arguments, new drugs continue to offer improvements to medical care. Recent criticisms ofboth regulators and regulated create a dilemma for public policy. Are government interventions necessary, and if so, what unintended consequences will they inflict? Pharmaceutical manufacturers have long operated on the boundary between, on the one hand, acting as free-market inventors and sellers of drugs, and on the other, serving the public interest by providing an essential health service. Thanks to this unique market position, the industry has played a leading role in globalization, developed innovative scientific advances in a wide range of medical fields, and pioneered academic-industrial research collaborations. Balancing of private and public interests is unquestionably difficult; yet pharmaceutical invention and delivery to patients have relied on medicine being run as a business. Interestingly, new initiatives, including those for H I V and tuberculosis put forth by the Bill & Melinda Gates Foundation and the Drugs for Neglected Diseases Initiative launched by Doctors Without Borders, seek to challenge this model by sponsoring not-for-profit drug invention. Given the typical time frame of two to 10 years from promising chemical compound to an approved drug, their success will take some time to judge. Nevertheless, proponents suggest that nonprofit drug developers, either government or foundations, will serve the public interest better than the pharmaceutical industry Physicians, the pharmaceutical indus-
try, and government regulators are in an awkward dance around the molecules synthesized by medicinal chemists. Cases like the analgesic Vioxx are but the most recent incarnation ofwhat M. N . G. Dukes, author and editor of several books on the drug industry characterized in 1979 as "the love-hate relationship which exists between the public and its drugs—substances which are hailed one moment as the solution to every problem and castigated the next as the cause of every ill." Pharmaceutical policy today is in a trap: Stronger regulation may lead to fewer medicines, while weaker regulation may lead to more drug disasters, and strong enforcement of patent rights may lead to less affordable medicines, while weaker enforcement of intellectual property may eliminate incentives for innovation. Better policies for government regulation and incentives for the industry will only come from a less polarized debate, lowered expectations for miracle cures, and a renewal of chemists' passion for the molecules they discover. Arthur A. Daemmrich is the director ofthe Center for Contemporary History if Policy at the Chemical Heritage Foundation. Among other works, he is the author of'Pharmacopolitics. " He can be
[email protected]. Mary Ellen Bowden is a senior research historian at the Institute for Chemical History at the Chemical'Heritage Foundation. She is the author of "PharmaceuticalAchievers, "among other works intendedfor high school and college teachers of chemistry. She can be reached at mebowden@chemheritage. org. WWW.CEN-0NLINE.ORG
