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I N R E C E N T Y E A R S , P H A R M A C E U T I C A L D R U G S H AV Ebecome implicated in global politics as never before. Inequitabledrug prices, persisting di√erences in national regulatory approaches,and debates over how to deﬁne safety and e≈cacy for diverse patientpopulations around the globe now attract an unprecedented degreeof attention. The political, ﬁnancial, and human health stakes havenever been higher for patients, manufacturers, government agencies,or the medical profession.
Unlike the conventional terrain of macro-politics where states
collide over interests of national security, pharmaceutical politicsplay out at a level where citizens deal with illness and health andsmall organizations voice demands for greater representation. The‘‘high’’ politics that shape relations among countries and determinegovernance structures at the national and international level nowcan be found in the ‘‘low’’ arenas of drug regulation and health caredelivery. Power and politics are not just found at the level of nationsor international agreements, but are wrapped up in seemingly in-nocuous pharmaceutical drugs and supposedly standardized re-gimes for verifying their safety and e≈cacy. Debates over pharma-
ceutical drugs in this ‘‘low’’ arena ultimately shape the organization of states,industry, the medical profession, and non-governmental organizations (NGOs).
Recent events o√er some striking illustrations of these points. Seeking to
reduce the cost of medicines for their citizens, the governments of India, SouthAfrica, Brazil, and other countries have threatened to ignore drug patents andinstitute compulsory licensing initiatives. Pharmaceutical ﬁrms headquarteredin the United States and Europe defend drug prices by explaining the expensesaccrued during research and testing. Between 6,000 and 10,000 compounds aresynthesized in the laboratory for each drug that ultimately enters the mar-ketplace. During 2001, pharmaceutical companies spent an average of 17 per-cent of sales on research and development, an outlay of $30 billion in the UnitedStates and $12 billion in Europe. According to industry-sponsored surveys,getting a new drug from the laboratory to patients requires companies to invest$800 million over the course of ten to twelve years.∞ As evidence for currentpricing patterns and enforcing strict patent laws, these facts nevertheless fall ondeaf ears when government o≈cials and activists attack ﬁrms for failing tomeet the health care needs of patients in developing countries. In response, theindustry has slashed prices—most notably for AIDS drugs—and has increasede√orts to help poor nations improve their health care systems.≤
Drawing a link among disease, poverty, and terrorism, U.S. President Bush
recently proposed an ‘‘Emergency Plan for AIDS Relief ’’ to help an estimatedthirty million Africans su√ering from the illness. In his 2003 State of the Unionaddress, Bush asked for $10 billion in new funds so that ‘‘this nation can lead theworld in sparing innocent people from a plague of nature.’’ Much of this newsupport would underwrite the purchase and delivery of anti-retroviral drugs,which Bush noted had declined in price from $12,000 to under $300 per year oftreatment. A $15 billion initiative took shape during spring 2003; among othergoals, the Bush administration plans to use these funds to make therapeuticdrugs available to two million Africans with HIV. Not coincidentally, Bush’sspeech turned next to national security: ‘‘And this nation is leading the world inconfronting and defeating the man-made evil of international terrorism.’’≥
In the context of security concerns, Bayer was forced to renegotiate the
price and availability of its antibiotic Ciproﬂaxin following anthrax attacks inthe fall of 2001.∂ An uproar concerning bioterrorist threats brought shifts in therelationship among government, industry, and the public to the fore. WhenTom Brokaw of NBC Nightly News held up a container of the pills and stated,‘‘In Cipro we trust,’’ he drew attention to the signiﬁcance of modern bio-medicine for national security and the public’s trust in governing authorities.∑Fearing shortages, government o≈cials in Canada and the United States threat-ened to ignore Bayer’s patent rights by licensing generic manufacturers to
produce the drug. The company ultimately avoided this scenario by increasingstockpiles and cutting prices.
In both the case of AIDS medicines in developing countries and anthrax
treatments in industrialized nations, intellectual property rights and drug pricescame under ﬁre for threatening public health and national security. Policysolutions in both settings involved negotiated compromise rather than strictregulation. States that once governed industry sectors through command-and-control mechanisms now negotiate with global companies. Patients who onceinteracted with issues of drug prices, safety, and availability mediated onlythrough their physicians now are organized as autonomous inﬂuential politicalactors. These developments o√er an interesting and exciting vision for thefuture as power and authority are shared among national governments, multi-national companies, and NGOs.
O√ering a distinctly technocratic vision for this future, government o≈-
cials and representatives of the pharmaceutical industry from the United States,the European Union, and Japan have met regularly during the past decade in anattempt to develop uniform standards for clinical trials and regulatory review.
They intend to standardize all aspects of drug testing and reduce the costs andtime involved in bringing new medicines to the market. Participants in this‘‘International Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use’’ (ICH) hope to achieve thisgoal by rationalizing safety and e≈cacy testing. They expect test results, likethe pills themselves, will transfer easily from any one political and medicalcontext to another.
The standardization of medical policies along the spectrum from premarket
testing to patient surveillance once drugs are marketed will require the mobili-zation of multiple actors. It will also require changes in a variety of less visiblypolitical settings. Concerns about representation, drug costs, and access tomedical care are not just negotiated in the course of government regulatory de-cisions, but also during clinical trials and in the doctor-patient relationship. Asthe examples of AIDS and anthrax illustrate, the extremely contentious issue ofdrug prices is linked to regulatory demands for product safety, scientiﬁc debatesregarding testing methods, and moral concerns with patients’ rights. Thesefeatures of national medical politics are likely to resist global standardization.
Therapeutic Cultures in the United States and Germany
Advances in medicine, the emergence and persistence of intractable dis-
eases, high-proﬁle drug disasters, and even low-proﬁle medical errors all fueldebates among the principal actors in medical politics. Throughout this book, I
advance the concept of therapeutic cultures
as shorthand for relationships amongthe state (including legislatures and regulatory agencies), the pharmaceuticalindustry, the medical profession, and disease-based organizations. These actorsfrequently o√er rival visions for health care with profound implications for theorganization of modern societies. Competition over who can best speak for‘‘the patient’’ was fundamental to the assertion of authority in this arena. Whilethe direct claims made by patients regarding the impact of disease and theappropriateness of competing treatments have reached broader audiences inrecent years, for the bulk of the twentieth century, patients did not speakdirectly in health care policy. Instead, professional groups and governmentagencies competed for the authority to represent them. As we shall see, di√er-ences between therapeutic cultures in the United States and Germany, the twocountries on which this book focuses, resulted in very di√erent choices forregulatory structures and produced di√erent therapeutic orientations to theirnational polities.
Therapeutic cultures, as I employ the term, refers speciﬁcally to the histor-
ical evolution of a distinctive set of institutionalized relationships among thestate, industry, physicians, and disease-based organizations. I argue throughoutthis book that the United States and Germany have put into place two di√erentsets of these institutional relations through incremental historical processes.
Their therapeutic cultures share a close interface with broader political andcultural beliefs and practices that are intriguingly similar and di√erent betweenthe two countries. Since 1950, citizens of both West Germany and the UnitedStates have experienced stable forms of democratic governance, remarkableadvances in medical technologies, capitalist economies that support free trade,and government involvement in medicine through research support and reg-ulation of the pharmaceutical market.
These similarities are o√set by contrasts in their health insurance arrange-
ments, access of patients to the political process, the authority wielded byphysicians, and social insurance systems. For example, health care in the UnitedStates is generally seen as a private good associated with individual choice andthe availability of ‘‘menus’’ for insurance, thereby rationing care by price. InGermany, by contrast, health care is seen primarily as a right or entitlement. Itserves as an instrument of broader social justice, and rationing, if at all, iscontrolled by providers on a local and individual level.
This institutionalist perspective on politics and culture sheds light on the
relation between broader cultural beliefs and practices on the one hand andinstitutional relations and policy outcomes on the other. The case of phar-maceutical regulation and medical care shows that there is no simple causal re-lationship between these two domains: we cannot argue that because
Germanyhas cultural belief X, it has institutions x; or alternatively, because
States has institutions y, it has cultural belief Y. Yet in key instances, the culturalpatterns exhibited in medical care in Germany di√er from those of the UnitedStates in the same way
that their institutions di√er.∏ In action—not least in thedeﬁnition of ‘‘the patient,’’ care for the ill, and formal medical policy—there aretight reciprocal relationships between cultures and institutions.
The concept of therapeutic cultures helps to untangle some of these con-
nections and draws attention to important contrasts between the United Statesand Germany. Di√erences between the two countries are especially meaning-ful in light of similarities in their o≈cial requirements for drug safety ande≈cacy, as well as their overarching similarities in medical care. Therapeuticcultures are active in three primary arenas: legislative/regulatory mandates,scientiﬁc testing in clinical trials, and oversight of adverse drug reactions. Be-cause of their di√erent therapeutic cultures, the distribution of authorityamong the quartet of actors in medical policy has shifted frequently in theUnited States, but remained comparatively stable in Germany. In one keyfeature of medical policy, American regulators delineated a strict boundarybetween premarket testing and market approval, whereas their German coun-terparts adopted a more ﬂexible approach that blurred the line between pre-and postmarket oversight. More recently, di√erences between their therapeuticcultures promoted the emergence of disease-based interest groups targetingregulatory policy in the United States, while few such organizations sought tochange regulatory approaches in Germany.
This means of explaining di√erences between the two countries brings into
focus the shifting role of politics in medicine. Instead of viewing regulatorydi√erences as the outcome of variation in state structures, we see that the polit-ical challenges posed by medical risks are mediated by a more complex web ofrelationships among the state and the other major participants in health caredelivery—including, most signiﬁcantly, the medical profession. The UnitedStates and Germany have some similar and some di√erent ways of interrelatingpatient needs with pharmaceutical research and testing, medical care, andgovernment regulation. In both countries, knowledge production and decision-making authority are distributed across a network of key actors includingindustry, the medical profession, government agencies, and disease-based orga-nizations. Yet di√erences in the relationships among the actors account for thefact that drug testing and scientiﬁc procedures have become politicized in theUnited States, but not in Germany.
Comparing the United States and Germany
The primary purpose of this book is to compare drug regulation in the
United States and Germany between 1950 and the present. For the period
between 1950 and 1990, ‘‘Germany’’ refers explicitly to the Federal Republic ofGermany, or West Germany. The German Democratic Republic (DDR) had aunique set of political and structural constraints on medicine and a radicallydi√erent relationship between the state and civil society, making it inappropri-ate for this study. During the past decade, a reunited Germany has graduallyintegrated key features of its government with the European Union. For thatreason, the comparison is expanded in Chapter 4 to encompass European-levelregulations and clinical testing.
Throughout the book, I explore several puzzling di√erences between the
United States and Germany. First, government o≈cials in the United Statesclosely control the production of information about the safety and e≈cacy ofnew medicines, whereas the medical profession has retained greater autonomyto design and oversee clinical testing in Germany. Second, a strict divisionbetween testing and marketing prevails in the United States, while Germaninstitutions follow a more ﬂexible regime regarding pre- and postmarket reg-ulatory oversight. Third, patients in the United States increasingly challengeexpert risk assessments and demand access to drugs, even in early stages ofclinical trials. A comparable politics of patient identity and access to medicinesis strikingly absent in Germany, where professional associations continue tooperate as intermediaries between citizens and the state.
While important in their own right, these di√erences become even more
interesting in light of major similarities and often-subtle contrasts between theprincipal actors in medical policy and politics in the two countries. Multina-tional ﬁrms headquartered in each country develop most new pharmaceuti-cals, but frequently market di√erent drugs in each nation. Drugs intended forboth countries undergo distinctive tests in each of them. Physicians are ac-corded a high status and have well-organized political representation in bothcountries; however, their inﬂuence on the government and authority to speakfor patients di√er. Analogous networks in the two countries pass judgment onthe market status of a new drug, yet their decisions vary to a surprising degree.
These same networks of government o≈cials, physicians, company o≈cials,and patients monitor approved drugs in each country, but they employ dif-ferent mechanisms for market surveillance and react di√erently to side e√ects.
More generally, the United States and Germany developed di√erent regulatorysystems during the twentieth century, despite similar citizen pressure to ensureproduct safety and industry lobbying to reduce barriers to market entry.
Both the United States and Germany since 1950 have had stable, democrat-
ically elected governments, although they exhibit di√erent forms of representa-
tion, legislation, and regulation. Government authority in both countries iscircumscribed by a constitution (termed the Grundgesetz, or basic law, inGermany) that delineates federal and state powers. Even though the UnitedStates is a representative democracy and Germany a parliamentary democracy,both have a tripartite division of power among executive, legislative, and judi-cial branches. Of all liberal-democratic countries, citizens in the United Statesand Germany most closely share the belief that strict limits should be placed ongovernment authority, albeit for di√erent reasons. The United States has a longtradition of balancing individual freedom against state interests. Citizens holdpowers not expressly granted to the government, and vociferously defend theirrights through political protest and legal action. For Germany, the Nazi dic-tatorship sharply illustrated that the concentration of power within a singlepolitical party with a charismatic leader could lead to destructive and inhumanpolicies. Consequently, the Grundgesetz strengthened federalism and placed astrong emphasis on the rule of law.
The executive branch di√ers in important ways between these two coun-
tries. American presidents are chosen during an independent election everyfour years and play a signiﬁcant role in setting policy agendas, advancing legis-lative initiatives, and overseeing regulatory action. In Germany, the Bundes-kanzler is elected by parliament, generally as head of the majority party. TheBundeskanzler’s ability to shape policy agendas is constrained by party politicsand the need to enter political coalitions with other parties to establish aparliamentary majority. Most new laws are proposed by the ruling coalition,not by individual parliamentary representatives. This gives the Bundeskanzlera larger role in crafting legislation than typically is held by the Americanpresident.
The U.S. legislature is divided between the House of Representatives and
the Senate; both must ratify legislation in order for it to become law. Congressplays an important role as a watchdog over the execution of laws. Investigativecommittees and congressional hearings frequently examine issues of politicalconcern soon after they arise. Germany also has a bicameral parliament; theBundestag represents public interests, while the upper house, the Bundesrat,represents the states (Länder). The Bundesrat votes on legislation that wouldimpact the division of power between the federal government and the Länder.
It can delay, but not veto, other legislation. Whereas the public elects both theAmerican House and Senate, German citizens elect only representatives in theBundestag. Bundesrat membership is composed solely of representatives fromthe Länder. According to some analysts, the German parliament has been veryconstrained in its oversight of how laws are executed and in its responses tonew policy concerns.π
Each country makes provisions for judicial review of new laws and regula-
tions. The U.S. Supreme Court early on asserted its constitutional authority todeclare legislative acts invalid or unconstitutional. It nevertheless serves pri-marily as the country’s highest court of appeals, not as a specialized court. Inthe aftermath of the Nazi dictatorship, the German system was constructedwith a Federal Constitutional Court that resolves disputes among governmentauthorities and protects the basic rights of citizens. More generally, Germanyemploys a continental law system under which judges interpret codiﬁed laws.
The United States, by contrast, bases legal decisions on case law (precedent)and trial by peer juries.
Restrictive tort laws limit lawsuits in Germany and claims against manufac-
turers such as drug companies rarely produce large settlements. Scientiﬁc andmedical experts are generally called as court-appointed witnesses in these andother cases, not as experts for the prosecution or defense. In contrast, Americantort law intentionally sets a low barrier to legal access for citizens and di√erentexpert witnesses can testify for each side of a case. Despite claims that U.S. tortlaw impedes innovation and is extremely costly to manufacturers, liability isnot uniform across product categories. Contraceptives, vaccines, and drugstaken during pregnancy are especially subject to liability claims in the UnitedStates. Thus three products, the Dalkon Shield contraceptive, Bendectin (atreatment for pregnancy-related nausea), and silicon breast implants have com-posed the majority of liability litigation in the health care sector during the pastthree decades.∫
Since World War II, the United States and Germany have experienced a
similar growth in government bureaucracies. New and expanded agenciesfaced similar pressures to draw upon scientiﬁc and medical expertise whenmaking decisions.Ω Regulatory agencies overseeing the pharmaceutical indus-try in the two countries develop and maintain their authority in similar ways bydemanding premarket testing and formal application for market approval.
New drugs achieve marketable status only if the manufacturer complies withgovernment guidelines for testing and provides authorities with evidence oftheir safety and e≈cacy. In both countries, drug companies must pay for clini-cal trials, oversee the clinics that test drugs, and then submit formal results tothe government. Likewise, regulatory agencies in both countries assess ‘‘userfees’’ to companies that want to expedite the review process.
Both nations have seen matching growth in multinational drug ﬁrms and
industry investments in research, advertising, and lobbying. Serving as majoremployers and contributors to the economy, pharmaceutical companies also
provide a vital public service by marketing new therapies to treat disease. Thecombined R&D investment in the United States by pharmaceutical ﬁrms was$32 billion in 2002.∞≠ In the same year, drug companies invested $3 billion onR&D in Germany.∞∞ Worldwide, the United States receives 36 percent of phar-maceutical R&D investments, while Germany comes in third (after Japan) at10 percent. The pharmaceutical industry accounts for over 18 percent of allcorporate-sponsored research and employs nearly 5 percent of all researchscientists and engineers.∞≤
As a number of critics have recently noted, massive R&D investments are
coupled to aggressive advertising. For this and other reasons, both countrieshave undergone a blossoming in ‘‘drug culture’’ as their citizens expect and evendemand quick ﬁxes for a wide variety of diseases, disorders, and discomforts.
Speaking mostly about Americans, the commentator Andrew Sullivan recentlynoted, ‘‘We are taking advantage of living in the 21st century and medicatingourselves to the gills.’’∞≥ Germans have also noted and criticized extremelywidespread use of pharmaceuticals in their country. People in the two countriesspend roughly the same amount for prescription drugs each year. Thus in 1997,per capita spending on pharmaceuticals in the United States was $319, whileGermans spent the equivalent of $294 per person on medications.∞∂
In terms of the number of pharmaceutical products available, Germany is a
global leader with some 2,500 approved active substances (equating to 8,900drug products), compared to 1,200 (6,000 products) available in the UnitedStates.∞∑ Measured by sales, the United States has the world’s largest drugmarket, followed closely by the European Union. Together, they now accountfor over 65 percent of annual drug purchases worldwide. Although not alwaysreﬂected in drug prices, the pharmaceutical market is extremely competitiveand sales are distributed across a large number of companies. Over the lastdecade, the combined worldwide market share of the top thirty pharmaceuti-cal and biotechnology ﬁrms has held steady at just over 50 percent. Even thelargest of these companies holds patents on only 6.5 percent of the phar-maceutical drugs approved in the United States.∞∏ Sales are likewise distributedacross many ﬁrms; Pﬁzer, the current industry leader, captured just 7.3 percentof worldwide drug sales in 2002.∞π
While it made sense to speak of an ‘‘American’’ or ‘‘German’’ pharmaceuti-
cal company as recently as a decade ago, mergers and greater cross-nationalR&D investments have since rendered these categories less signiﬁcant. Thusreports of Abbott Laboratories’ performance now incorporate BASF’s drugbusiness. Likewise, the 1999 creation of Aventis signaled a merger of Hoechstand Rhône-Poulenc, formerly venerable independent German and Frenchﬁrms. These and other pharmaceutical companies all seek to market their
medicines across the globe and work with physicians in a variety of settings tomeet regulatory demands.
German medical practitioners tap into a long history as a guild-based
profession. During a period of intense political ferment in the 1840s, physiciansplayed a signiﬁcant role in an e√ort to establish a constitutional democracy forthe emerging German nation.∞∫ Following the failed 1848 revolution, physiciansavoided further confrontations with the Prussian-led government by adoptingself-regulatory initiatives and agreeing to govern key features of the health caresector in collaboration with government ministers. The profession’s retreatfrom overt political engagement therefore was coupled to its expanded author-ity over the medical domain. Physicians determined membership criteria forthe profession, gained a monopoly to speak for ‘‘the patient’’ in political set-tings, and had the authority to deﬁne drug safety and oversee the use ofpharmaceutical drugs. To this day, these features continue to make the medicalprofession a major actor in medical policy and politics. The fact that twentieth-century regulations governing pharmaceutical drug safety and e≈cacy as-signed a great deal of authority to physicians illustrates a continuation of thishistorical pattern.
Nineteenth-century American physicians exercised similar controls over
membership in the profession, spoke for their patients in political settings, andoversaw drugs on the market.∞Ω Unlike the German Federal Chamber of Physi-cians (Bundesärztekammer), the American Medical Association (AMA) pro-gressively lost membership, from a peak near 70 percent of physicians in themid-1930s to only roughly 35 percent today.≤≠ When the Food and Drug Admin-istration (FDA) expanded its authority through a sequence of legislative andregulatory initiatives, physicians’ authority to deﬁne drug safety and ability tocontrol the use of pharmaceuticals declined. Likewise, the emergence ofdisease-based interest groups as major social and political organizations hasundercut the medical profession’s mandate to speak for ‘‘the patient.’’ Whilethe principal actors in American medical politics appear identical to Ger-many’s, di√erent voices are heard and a di√erent set of concerns come to thefore. No one group can easily claim a monopoly to represent patients inpolitical settings. Pharmaceutical drug regulations in the United States thus areassociated with signiﬁcant renegotiation of authority among the key actors inmedical policy.
The methods employed to test new drugs and the procedures followed to
verify their safety and e≈cacy consequently di√er between the United States
and Germany in important ways. More subtly, but far more signiﬁcantly, thelocation of authority to deﬁne ‘‘safety’’ and ‘‘e≈cacy’’ varies. Whereas theGerman system relies heavily on the medical profession to deﬁne the pre- andpostmarket status of a drug and oversee standards for clinical testing, the UnitedStates has allocated greater authority to government regulators. While Ameri-can physicians serve as expert consultants to regulatory authorities, the Ger-man medical profession itself serves as an authoritative intermediary betweenpatients and the industry. As a result, the American Food and Drug Administra-tion plays a far greater role in all aspects of drug testing and market surveillancethan its contemporary counterpart, the Bundesinstitut für Arzneimittel- undMedizinprodukte, in Germany.
Networks in Science, Technology, and Medicine
Therapeutic cultures arise from networks of actors that produce regulatory
policy, determine testing standards, and ultimately decide on market access fornew drugs. The principal actors in medical policy (regulatory agencies, physi-cians, pharmaceutical companies, disease-based organizations) form a ratherﬂuid and ﬂexible network that sustains intense debates and very serious di√er-ences of opinion. Underpinning their positions, each of these actors drawsupon smaller and tighter networks to articulate policy positions concerningmedical issues. Like in other networks mapped by sociologists and historians,information ﬂows unevenly, certain points are connected to others morestrongly, the ‘‘most legitimate spokespersons’’ change over time, and links aremodiﬁed during controversies.≤∞ Stable networks and standardized proceduresmake it possible for information, ideas, and people to move from one place toanother without drawing attention to the social features and assumptions thatlink any two nodes together.≤≤ During moments of controversy, however, thestabilizing forces themselves become contentious and connections break downas actors try to extend their individual authority.≤≥ Each then seeks to becomean obligatory ‘‘point of passage’’ for decisions that, for example, certify a newdrug as safe and e≈cacious.
Scientiﬁc knowledge is established, assimilated, and transmitted through
networks of social trust and authority, rather than by radical skeptical testing asdepicted in its dominant public image. Likewise, medical knowledge accumu-lates less through aggressive falsiﬁcation than through the gradual widening ofnetworks of practice and dissemination. These social aspects rarely are visiblebecause once facts are accepted, the informal inferences, human judgments,and social, political, and ﬁnancial features of a network that are integral to theresearch process disappear from public view.≤∂
A dominant technological product, such as a blockbuster drug that outsells
its competitors, is not always chosen for its technical superiority alone. Instead,a variety of social factors and informal judgments help determine technological‘‘winners.’’≤∑ Similarly, proving drug safety and e≈cacy involves a body ofinformal practices and testing methods, no matter how hard regulators andpractitioners seek to follow a standardized testing regime. Clinical trials are locifor social, ethical, and even moral debates about appropriate therapies, just asthey serve to reinforce social roles for patients and physicians. As a result, thetesting methods and results are often very controversial.
Of course, scientiﬁc and medical debates mostly do reach closure. Contrary
to conventional belief, however, closure is rarely achieved through additionallaboratory or clinical testing alone. One reason for this relates to the di≈cultyof deciding what counts as a proper replication of a test during a controversy. Inclinical trials, for example, questions may arise over whether a new series oftrials were run in the same way as earlier tests. Did the organizers follow thesame approach in diagnosing participants? Did unsuccessful trials follow thesame dosage regimen as successful ones? Since an inﬁnite number of thesetechnical questions can be used to question the results of a trial, scientists andphysicians face serious challenges in achieving consensus on therapeutic ap-proaches. Debates over the results of clinical trials get tangled up with debatesover the adequacy of methods used in the tests. As a result, further testing andadditional evidence alone cannot resolve such debates.≤∏
Closure to debates appears to come through changes in wider social and
institutional commitments. In e√ect, it takes a network of credible colleaguesand institutional support to end a controversy. As we shall see, controversiesover drug safety and e≈cacy often turned into disputes over testing methodsthemselves. Closure was reached by di√erent mechanisms in the two coun-tries; in the United States, the FDA used its full regulatory authority to enddisputes, while in Germany, physicians invoked professional norms and thecredibility of their ﬁeld in order to reach consensus.
To a surprising degree, the networks involved in medical policy di√er
between countries. In the case of the United States and Germany, even thoughsimilar actors are represented in the networks, the distribution of authorityand control di√ers between them in important ways.≤π The primacy of anyone node in the network shifted frequently in the United States, allowingfor relatively rapid accommodation of new technologies and new social move-ments that represent patients. The German network instead encouraged con-tinuity over change, thereby limiting policy interventions while favoring com-mitted interests and political stability. The behavior of individual actors andthe network’s overall stability thus reﬂect each country’s unique therapeuticculture.
Science, Policy, and the State
Clinical trials, and the pharmaceutical sciences more generally, serve in-
strumental purposes in policy decisions. Societal demands for safe medicineshave promoted massive growth of scientiﬁc research and product testing dur-ing the past century. Despite national variation in research, including clinicaltrials, decision makers in all countries face a similar ‘‘risk’’ quandary concerningmedicinal drugs. If they grant market access to a pharmaceutical later shown tocause side e√ects, they are criticized for failing to protect the public. Con-versely, if they withhold approval of a medicine that cures disease or prolongslife, they are criticized for excessive precaution. To borrow a phrase from riskanalyst Jonathan Wiener, e√orts to protect patients from dangerous medicinesproduce ‘‘iatrogenic [care-induced] risks of risk management.’’≤∫ Likewise,other critics have asserted that regulations often run counter to the publicinterest by limiting competition among ﬁrms and orienting innovation to areasthat may not beneﬁt the majority of patients.≤Ω
Models from political science that seek to explain the role of science in
these sorts of policy decisions have often depicted a one-way relationship,summarized most easily as ‘‘speaking truth to power.’’≥≠ According to thisarchetype, experts can be placed on a spectrum ranging from scientists, whopossess pure knowledge, to politicians, who embody decision-making author-ity. Scientists provide clear answers to government o≈cials on military, en-vironmental, and medical policy questions.≥∞
Empirical research on medical, environmental, and other areas of science
and technology policy, however, do not support these archetypes. As it turnsout, successful real-world applications often require more than laboratory test-ing of scientiﬁc or medical theories. Sheila Jasano√, who introduced the term‘‘regulatory science’’ into widespread use, therefore suggests, ‘‘When knowl-edge is uncertain or ambiguous, as is often the case in science bearing on policy,facts alone are inadequate to compel a choice. Any selection inevitably blendsscientiﬁc with policy considerations, and policymakers accordingly are forcedto look beyond science to legitimate their preferred reading of the evidence.’’≥≤In clinical trials, for example, we ﬁnd that the science itself necessarily incorpo-rates political dimensions, including choices about representation, and stan-dards of accountability that can inﬂuence the outcomes.
Trial results often remain open to political and medical contestation; in the
course of a debate over the safety or e≈cacy of a speciﬁc treatment, partici-pants do not separate ‘‘political’’ arguments from ‘‘scientiﬁc’’ ones. Questionsabout the validity of science carried out for regulatory purposes become par-ticularly salient when decision makers seek to predict future outcomes. Thusregulators trying to evaluate whether or not a drug will produce side e√ects on
the open market have to consider the institutional contexts in which the trialswere conducted and weigh the likely public responses to their decisions.
Greater awareness of the decision-making dilemma between approving a
drug later shown to cause side e√ects and withholding a beneﬁcial and poten-tially life-saving therapy has weakened the assumption that scientiﬁc or medicalresearch alone can develop predictive tools for public policy.≥≥ In a number ofimportant areas, the lay public itself has reshaped what counts as scientiﬁcevidence, in addition to more predictable demands for greater representationand participation. E√orts spearheaded by AIDS patients to speed drug ap-provals, for example, also had the outcome of loosening state control overclinical trials and changing the power relationship between physicians andpatients. These activists mobilized their own experts to support alternativeviews of disease origins and dissemination. They also demanded changes intrial protocols and revisions to entry criteria.≥∂
More generally, patients, consumers, and social activists not supported by
traditional organizations have joined to articulate demands in local, regional,and national arenas. These interest groups employ a wide variety of strategiesto gain access to government decisions. In the United States, traditional profes-sional groups like the American Medical Association are structured to matchthe federal system, thereby gaining policy input at levels ranging from locallicensing boards to national politics.≥∑ New groups, such as AIDS activists, oftenconcentrate on a single issue, which they raise in forums ranging from publicprotests to congressional hearings. Public readiness to organize new politicalgroups and the openness of the political system to their demands promotesrapid policy response to emerging issues. At the same time, it can lead to veryvisible conﬂicts when competing interests clash.
In contrast, associations representing business, professions, churches, and
other interests share authority with the decentralized German state.≥∏ Formallydesignated interest associations are included within the process of governmentdecision making and help implement new policies. As such, they are o≈ciallyrecognized by the state not just as intermediaries between government o≈cialsand the public, but as associations on equal footing with state agencies. Asso-ciations do more than lobby the state on behalf of their membership; they alsoprovide expert advice and get involved in both the formulation and implemen-tation of public policy. Since peak associations work so closely with the state,radical changes and sudden policy innovations are relatively infrequent. Incre-mental changes result from stable compromises between business and thegovernment.≥π Public confrontations between associations and the state arerare in Germany, and decisions about pharmaceutical and environmental reg-ulations, changes to the health care system, and other potentially volatile issuesgenerally are negotiated in a quiet, seemingly apolitical manner.
National-level di√erences of this sort have gained particular saliency in light
of regulatory harmonization both within the European Union and among theUnited States, Europe, and other countries. Proponents of international re-gimes argue that abolishing trade barriers, standardizing premarket testingregimes, and harmonizing regulatory oversight will reduce di√erences amongnational institutions, promote greater industrial e≈ciency, and bring cures topatients sooner. As we shall see, the European Union and the emerging inter-national regime for drug regulation both must account for persisting nationaldi√erences in therapeutic cultures.
For Germany, European integration has taken place concurrently with
internal integration of East and West following the 1990 uniﬁcation. Germany’swillingness, even eagerness, to give up sovereign power at a time of nationalexpansion surprised those analysts who predicted a less harmonious outcome.
In many ways, Germans have adopted an international and collective identitythat promotes broader interest representation and new norms for power rela-tions.≥∫ Tensions nevertheless remain regarding the status of Germany withinEurope, especially since German trade unions and NGOs frequently raise con-cerns about employment and the environment.
For the United States, participation in international agreements is a highly
politicized two-edged sword. Many analysts, activists, and corporate strategistswelcome the potential for regulatory harmonization to reduce burdens onindustry and speed medicines to the market. On the other hand, critics warnthat agreements to date have decreased product safety, weakened regulatoryoversight, and led to a loss of jobs. In the environmental arena, the UnitedStates seems increasingly willing to forgo global accords and forge its own path.
Likewise, risk assessment policies for genetically modiﬁed foods, chemicals,and other industrial products more commonly exhibit ‘‘American exceptional-ism’’ than harmonization with other countries.≥Ω The United States neverthe-less is an active participant in e√orts to unify pre-clinical and clinical test-ing standards. Technical standardization and international harmonization hastherefore proceeded apace in this area. These accords will not automaticallyequate to global drug approvals or international health care policies. Yet theydo illustrate the emergence of a loosely coupled system at the global level inwhich the United States is a signiﬁcant participant.
Sites for Therapeutic Cultures
The principal actors in medical policy and politics—government regulatory
agencies, pharmaceutical companies, the medical profession, and disease-basedorganizations—interact in distinct political and medical settings. The chaptersthat follow describe the impact of American and German therapeutic cultures
/ SITES FOR THERAPEUTIC CULTURES
on legislative and regulatory controls on pharmaceuticals, during the clinicaltesting of speciﬁc drugs, and in the postmarket surveillance of approved medi-cines (Table 1). The concept of therapeutic cultures allows us to better under-stand the signiﬁcance of networks for medical governance formed amongphysicians, patients, the state, and industry during the production, testing, andmarketing of pharmaceutical drugs. Political interactions in the clinic that areoften later ‘‘naturalized’’ and made invisible play an important part in theidentities and social roles occupied by each of these groups.
The therapeutic cultures of the United States and Germany form the back-
bone of this study, and the rest of the chapters are organized around sites wherethey are active: legal and regulatory structures (Chapter 2), experimentalmethods and testing approaches (Chapters 3 and 4), and surveillance andpostmarket controls (Chapter 5). Each of these areas is presented chronologi-cally, thereby o√ering three di√erent passes through the same historical period.
The conclusion explores how ﬁndings from each of these arenas relate tocontemporary plans for international regulatory harmonization, and speak tothe future of relations among the state, physicians, industry, and patients.
Regulations governing drug approvals were instituted under di√erent polit-
ical conditions and promote distinctive methods for testing drugs in the UnitedStates and Germany. Chapter 2 describes the passage and implementation oflaws regulating pharmaceuticals in the two countries. In the United States, apolitical construction of patients as ‘‘guinea pigs’’ in the wake of highly visiblemedical tragedies led to the rapid approval of laws that strengthened the FDA’sauthority over both industry and the medical profession. After the agencyimplemented a strict division between test and market, patient activists pro-tested slow drug approvals and brought about important policy changes. Ger-
/ CASE STUDIES—MARKET AUTHORIZATION
1998—moderate to severe erythema nodosum leprosum (ENL) in leprosy
man drug laws, in contrast, were linked to broader concerns in the health caresystem regarding the distribution of authority across the network of physicians,industry, and the state. Since physicians had more control over constructions of‘‘the patient,’’ few groups articulated political demands for either greater reg-ulatory protections or speedier drug approvals.
From the macropolitics of legislation and regulation, we shift to the nar-
rower domain of clinical trials. Case studies of Terramycin, thalidomide, andpropranolol in Chapter 3 reveal that clinical trials served di√erent functions inthe therapeutic cultures of the United States and Germany (Table 2). The FDAenforced the use of quantitative testing methods and imposed methods forstatistical evaluation of test results between 1950 and 1980. Formal testingprocedures were a means to demonstrate objectivity and helped shield theagency from criticism and public controversy. In Germany, on the other hand,trials were integral to deﬁning physicians’ authority in relation to the state andkey to establishing new professional norms for medical care after World War II.
Clinical trials carried out in the period between 1950 and the mid-1970s weregenerally integrated into overall patient care in Germany, rather than formingdistinctive testing sites as in the United States.
Chapter 4 describes how clinical trials underwent important changes in
both countries between 1980 and 2000, as evidenced by the case studies ofinterleukin-2 and indinavir. The emergence of patient activists and disease-based interest groups in the United States led to a new politics of testing andcare. Meticulously designed clinical trials that excluded large domains of pa-tients’ lived experiences were challenged as irrelevant to ‘‘real world’’ drug use.
Methods used to generate knowledge about a given drug’s actions in humansconsequently changed to reﬂect arguments posed by patients, activists, anddisease-based interest groups. In Germany, there were fewer changes of thiskind. Instead, governance of the clinical setting by the medical professionremained comparatively intact throughout this period. No disease-based activ-ists challenged tested methods, and medical elites continued to determinesafety and e≈cacy in much the same way as in earlier eras. Even the establish-ment of a pan-European regulatory agency had little impact on the Germanclinical domain.
Since the mid-1950s, a growing emphasis on observing patient-drug interac-
tions for medicines on the market has extended the boundaries of testingbeyond clinical trials into routine drug therapy. Chapter 5 compares approachesto collecting, reviewing, and responding to side e√ects in the two countries. Inthe United States, the medical profession initially played an important role inthis area. By the late 1960s, however, the FDA increasingly took over this task asthe agency centralized and standardized mechanisms for dealing with adversereactions. In Germany, on the other hand, the medical profession maintained asigniﬁcant position in collecting and responding to adverse reaction reports,despite recent expansion of government involvement. Di√erences betweentheir therapeutic cultures explain why the United States adopted a state-centered approach, while Germany vested political and regulatory authority inthe medical profession.
The conclusion explores further the di√erent ways in which American and
German citizens mobilize around medical treatment and new drug approvalsas points of entry for policy change. Di√erent structures for interest groupactivity and di√erent interactions in the networks that make up therapeuticcultures are particularly salient in light of current e√orts to promote interna-tional regulatory harmonization. The complex interrelationships that havebeen built up over the past ﬁfty years among physicians, patients, industry, andgovernment agencies in each country will not be displaced by technical stan-dardization alone. Instead, greater accommodation of patients’ perspectivesmust be an integral part of the policies promoted by international agreements.
Segnalazioni di particolare interesse pediatrico dalle Agenzie Regolatorie A cura della Prof.ssa Adriana Ceci (Dipartimento di Farmacologia e Fisiologia Umana, Bari) • Infliximab (in Italia con il nome di Remicade) • Informazione pubblica sugli eventi avversi associati a "terapia genica" e "terapia cellulare" • Rischio di trasmissione vCJD attraverso emoderivati: mi
REPORT OF THE COMMITTEE ON PARASITIC DISEASES Vice Chair: J. Mathews Pound, Kerrville, TX Bob H. Bokma, MD; Corrie C. Brown, GA; Leroy M. Coffman, Fl; A. A. Cuthbertson, NV; J. Kieth Flanagan, FL; John E. George, TX; Chester A. Gipson, MD; Larry L. Hawkins, MO; Thomas J. Holt, FL; Lee C. Jan, TX; Ralph C. Knowles, FL; Ulysses J. Lane, NC; Linda L. Logan, APO; Terry F. McElwain, WA; Daniel G.