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Pharmaceuticals as a market for "lemons": Theory and practice

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Abstract

Drawing on economic theory and institutional analysis, this paper reframes Akerlof's theory of how a market for lemons operates and argues that each of the many markets for lemons must be studied empirically to document how different stakeholders cope with the problems of information asymmetry, secrecy, and power. Such markets are a new field for sociological analysis. To illustrate, the paper characterizes pharmaceuticals as a multi-tier market of information asymmetry in which actors in each tier have substantial control over how much they disclose about hidden risks of harm. Such a market rewards the production and sale of "lemons." Current incentives and institutional practices reward developing a large number of barely therapeutically innovative drugs and ignoring their often hidden or understated harmful side effects. They reward designing and executing substandard, biased trials that mislead the FDA and regulators abroad to approve new drugs without clear evidence of their degree of harm. Approved drugs are likely to be "lemons" but promoted as "safe and effective." The result is substantial hospitalizations and deaths from adverse drug reactions. A "risk proliferation syndrome" of institutional practices maximizes sales, profits, and exposure to toxic side effects. An "inverse benefit law" of marketing operates as companies try to maximize sales. The probability of benefits decreases but the chances of lemons adverse events do not. The details presented here deepen understanding of how markets for lemons thrive on information asymmetry, secrecy, and power. Lessons can be applied to other markets.

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... The conclusions of Prescrire's assessments sometimes differ from those reached by regulatory authorities such as the European Medicines Agency due to Prescrire's focus on clinical benefits and harms. Concerns have been raised that a significant proportion of medicines are introduced to the market in the absence of any proof of tangible clinical benefit for patients [8][9][10][11]. Current regulatory evidence standards allow the use of unvalidated surrogate markers for efficacy in marketing applications. Regulatory approvals may be based on biased or non-comparative clinical trials and speedier approval processes that do not provide sufficient time to assess medicines rigorously [12]. ...
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Background: In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies. Methods and findings: We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway. Conclusions: The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.
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Background In November 2017, the Food and Drug Administration (FDA) approved a version of a second-generation antipsychotic, aripiprazole, embedded with a sensor (Abilify MyCite). Objective To systematically review the evidence supporting the FDA’s approval of digital aripiprazole and how that evidence was disseminated in the scientific literature and news reports. Study selection Prospective, double-blind, randomised controlled trials (RCTs), non-randomised and non-comparative studies were included if they focused on the use of digital aripiprazole. All scientific publications citing the trials were included if written in English. For the news reports, all languages were included if an English translation was available, and all records that were published after FDA approval were included. Findings In the primary evidence search, no RCT comparing digital aripiprazole with a non-digital formulation, other active comparators or placebo was found. Only three non-comparative uncontrolled cohorts were found. No study provided data on remission, quality of life or any efficacy outcome. Fourteen scientific papers were identified that cited the trials and 70 news stories met the inclusion criteria. Almost 80% (11/14) of the scientific papers and three-fourths (52/70) of the news stories conveyed an unsupported impression of benefit. Conclusions Regulatory approval for this first-ever digital drug was based on weak evidence, and there was no evidence of better adherence with the digital version of aripiprazole compared with the non-digital version. The possibilities afforded by this technology make room for a new type of evergreening (ie, patenting of older drugs with a sensor as a ‘new invention’). Both the scientific literature and news reports conveyed an unsupported impression of benefit. Trial registration number CRD42018089515.
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Objectives This study examines the use of expedited approval pathways by Health Canada over the period 1995 to 2016 inclusive and the relationship between the use of these pathways and the therapeutic gain offered by new products. Design Cross-sectional study. Data sources Therapeutic Products Directorate, Biologics and Genetic Therapies Directorate, Notice of Compliance database, Notice of Compliance with conditions web site, Patented Medicine Prices Review Board, La revue Prescrire, WHO Anatomical Therapeutic Chemical classification system. Primary and secondary outcomes Percent of new drugs evaluated by Health Canada that went through an expedited pathway between 1995 and 2016 inclusive. Kappa values comparing the review status with assessments of therapeutic value for individual drugs. Results Of 623 drugs approved by Health Canada between 1995 and 2016, 438 (70.3%) drugs went through the standard pathway and 185 (29.7%) an expedited pathway. Therapeutic evaluations were available for 509 drugs. Health Canada used an expedited approval pathway for 159 of the 509 drugs, whereas only 55 were judged to be therapeutically innovative. Forty-two of the 55 therapeutically innovative drugs received an expedited review and 13 received a standard review. The Kappa value for the entire period for all 509 drugs was 0.276 (95% CI 0.194 to 0.359) indicating ‘fair’ agreement between Health Canada’s use of expedited pathways and independent evaluations of therapeutic innovation. Conclusion Health Canada’s use of expedited approvals was stable over the entire time period. It was unable to reliably predict which drugs will offer major therapeutic gains. The findings in this study should provoke a discussion about whether Health Canada should continue to use these pathways and if so how their use can be improved.
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Background Surrogate outcomes are not intrinsically beneficial to patients, but are designed to be easier and faster to measure than clinically meaningful outcomes. The use of surrogates as an endpoint in clinical trials and basis for regulatory approval is common, and frequently exceeds the guidance given by regulatory bodies. Discussion In this article, we demonstrate that the use of surrogates in oncology is widespread and increasing. At the same time, the strength of association between the surrogates used and clinically meaningful outcomes is often unknown or weak. Attempts to validate surrogates are rarely undertaken. When this is done, validation relies on only a fraction of available data, and often concludes that the surrogate is poor. Post-marketing studies, designed to ensure drugs have meaningful benefits, are often not performed. Alternatively, if a drug fails to improve quality of life or overall survival, market authorization is rarely revoked. We suggest this reliance on surrogates, and the imprecision surrounding their acceptable use, means that numerous drugs are now approved based on small yet statistically significant increases in surrogates of questionable reliability. In turn, this means the benefits of many approved drugs are uncertain. This is an unacceptable situation for patients and professionals, as prior experience has shown that such uncertainty can be associated with significant harm. Conclusion The use of surrogate outcomes should be limited to situations where a surrogate has demonstrated robust ability to predict meaningful benefits, or where cases are dire, rare or with few treatment options. In both cases, surrogates must be used only when continuing studies examining hard endpoints have been fully recruited.
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Reports of clinical trials usually emphasize efficacy results, especially when results are statistically significant. Poor safety reporting can lead to misinterpretation and inadequate conclusions about the interventions assessed. Our aim was to describe the reporting of harm-related results from randomized controlled trials (RCTs). We searched the MEDLINE database for reports of RCTs published from January 1, 2006, through January 1, 2007, in 6 general medical journals with a high impact factor. Data were extracted by use of a standardized form to appraise the presentation of safety results in text and tables. Adverse events were mentioned in 88.7% of the 133 reports. No information on severe adverse events and withdrawal of patients owing to an adverse event was given in 27.1% and 47.4% of articles, respectively. Restrictions in the reporting of harm-related data were noted in 43 articles (32.3%) with a description of the most common adverse events only (n = 17), severe adverse events only (n = 16), statistically significant events only (n = 5), and a combination of restrictions (n = 5). The population considered for safety analysis was clearly reported in 65.6% of articles. Our review reveals important heterogeneity and variability in the reporting of harm-related results in publications of RCTs.
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A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus, but it is unclear how these agents compare with respect to long-term cardiovascular risk. Our objective was to systematically examine the peer-reviewed literature on the cardiovascular risk associated with oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides) for treating adults with type 2 diabetes. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception through January 19, 2006. Forty publications of controlled trials that reported information on cardiovascular events (primarily myocardial infarction and stroke) met our inclusion criteria. Using standardized protocols, 2 reviewers serially abstracted data from each article. Trials were first described qualitatively. For comparisons with 4 or more independent trials, results were pooled quantitatively using the Mantel-Haenszel method. Results are presented as odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular mortality (pooled OR, 0.74; 95% CI, 0.62-0.89) compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity and all-cause mortality were similar but not statistically significant. No other significant associations of oral diabetes agents with fatal or nonfatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity or mortality, but this result was not statistically significant (OR, 1.68; 95% CI, 0.92-3.06). Meta-analysis suggested that, compared with other oral diabetes agents and placebo, metformin was moderately protective and rosiglitazone possibly harmful, but lack of power prohibited firmer conclusions. Larger, long-term studies taken to hard end points and better reporting of cardiovascular events in short-term studies will be required to draw firm conclusions about major clinical benefits and risks related to oral diabetes agents.
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Seeding trials, clinical studies conducted by pharmaceutical companies that are designed to seem as if they answer a scientific question but primarily fulfill marketing objectives, have not been described in detail. To describe a known seeding trial, ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness), through documents of the trial sponsor, Merck & Co. (Whitehouse Station, New Jersey). Merck internal and external correspondence, reports, and presentations elicited to inform legal proceedings of Cona v Merck and Co., Inc., and McDarby v Merck and Co., Inc. The documents were created between 1998 and 2006. An iterative case-study process of review, discussion, and re-review of documents to identify themes relevant to the design and conduct of ADVANTAGE. To supplement the case-study review, the authors did a systematic review of the literature to identify published manuscripts focused on seeding trials and their conduct. Review of the documents revealed 3 key themes: The trial was designed by Merck's marketing division to fulfill a marketing objective; Merck's marketing division handled both the scientific and the marketing data, including collection, analysis, and dissemination; and Merck hid the marketing nature of the trial from participants, physician investigators, and institutional review board members. Although the systematic review of the literature identified 6 articles that focused on the practice of seeding trials, none provided documentary evidence of their existence or conduct. The legal documents in these cases provide useful, but limited, information about the practices of the pharmaceutical industry. This description of 1 company's actions is incomplete and may have limited generalizability. Documentary evidence shows that ADVANTAGE is an example of marketing framed as science. The documents indicate that ADVANTAGE was a seeding trial developed by Merck's marketing division to promote prescription of Vioxx (rofecoxib) when it became available on the market in 1999.
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Ghost-Managed Medicine by Sergio Sismondo explores a spectral side of medical knowledge, based in pharmaceutical industry tactics and practices. Hidden from the public view, the many invisible hands of the pharmaceutical industry and its agents channel streams of drug information and knowledge from contract research organizations (that extract data from experimental bodies) to publication planners (who produce ghostwritten medical journal articles) to key opinion leaders (who are sent out to educate physicians about drugs) to patient advocacy organizations (who ventriloquize views on diseases, treatments and regulations), and onward. The goal of this ‘assemblage marketing’ is to establish conditions that make specific diagnoses, prescriptions and purchases as obvious and frequent as possible. While staying in the shadows, companies create powerful markets in which increasing numbers of people become sick and the drugs largely sell themselves. Most agents for drug companies aim to tell the truth, but the truths they tell are drawn from streams of knowledge that have been fed, channeled and maintained by the companies at every possible opportunity. Especially because those companies have concentrated influence and narrow interests, consumers and others should be concerned about how epistemic power is distributed – or ‘political economies of knowledge’ – and not just about truth and falsity of medical knowledge. In pharmaceutical companies’ ideal worlds, medical research, education and marketing would be tightly fused. Doctors trying to educate themselves would turn to companies’ agents, such as researchers and educators sponsored to spread particular messages, local sales reps hired to change doctors’ behaviour, or journalists supplied with news stories. Ghost-Managed Medicine shows that the real world of medicine is not very far from the worlds that the companies want to create. Big Pharma’s many invisible hands are busy throughout medicine, and medicine changes as a result.
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Pharmaceutical companies have moved beyond just producing medicines to also controlling the knowledge about the products that they make and the diseases they are designed to treat. One of the tools that they employ in this pursuit is the use of experts or people known as Key Opinion Leaders (KOLs). Although KOLs are paid by pharmaceutical companies and their messages are crafted by these companies, they are presented to doctors and the public as independent experts. Some KOLs are “bought” by the companies they work for, but most are sincere in their beliefs about the products that they are speaking about and deny that their role places them in a conflict-of-interest position. One-third of the marketing budget for pharmaceutical companies is spent on KOLs and this spending is justified by the return that companies get. KOLs are intensively trained by firms contracted to drug companies to present the “correct” message. Pharmaceutical companies need to maintain the fiction that KOLs are independent sources of information. However, when KOLs deviate from the message, they are no longer of any use to the company that they are working for. The content of the talks given by KOLs can be scientifically valid, but deceptive at the same time, through a variety of techniques. The message from pharmaceutical companies overwhelms that coming from any other source and KOLs are part of the way that companies control knowledge.
Book
As a master's student in history at the University of Illinois, I found that my research in the early newspapers of that state was often halted by my inability to keep my gaze fixed purposefully on the news columns. My eyes inevitably sought out the patent medicine advertising, and this interest worked its way into a chapter of my master's thesis. Some years later, I yielded completely to the impulse, persuaded that medical quackery has been -and is-an important theme in American social and intellectual history. Quackery is important because through it vast numbers of our people have sought to bolster or restore their health and because it affords insight into an anti-rational approach to one of the key problems of life. This book is a history of proprietary medicines in America, from the early 18th-century appearance of patented brands imported from the mother country to the early 20th-century enactment of national legislation intended, in part, to restrain abuses in the packaged medicine industry. Native nostrum production began during the cultural nationalism of the Revolutionary generation, expanded rapidly during the age of the common man, received a new impetus from the Civil War, and reached floodtide in the late 19th century. The critique of patent medicine quackery first became significant as part of the humanitarian crusade accompanying Jacksonian democracy. As medicine became more scientific, the anti-nostrum movement developed a sounder base. During the Progressive period, journalists and civil servants added their support to physicians and pharmacists and created an articulate public opinion in behalf of a regulatory law.
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Background: Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical-industry sponsored studies are more often favorable to the sponsor's product compared with studies with other sources of sponsorship. A similar association between sponsorship and outcomes have been found for device studies, but the body of evidence is not as strong as for sponsorship of drug studies. This review is an update of a previous Cochrane review and includes empirical studies on the association between sponsorship and research outcome. Objectives: To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship. Search methods: In this update we searched MEDLINE (2010 to February 2015), Embase (2010 to February 2015), the Cochrane Methodology Register (2015, Issue 2) and Web of Science (June 2015). In addition, we searched reference lists of included papers, previous systematic reviews and author files. Selection criteria: Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions. Data collection and analysis: Two assessors screened abstracts and identified and included relevant papers. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals (CIs)). Main results: Twenty-seven new papers were included in this update and in total the review contains 75 included papers. Industry sponsored studies more often had favorable efficacy results, RR: 1.27 (95% CI: 1.17 to 1.37) (25 papers) (moderate quality evidence), similar harms results RR: 1.37 (95% CI: 0.64 to 2.93) (four papers) (very low quality evidence) and more often favorable conclusions RR: 1.34 (95% CI: 1.19 to 1.51) (29 papers) (low quality evidence) compared with non-industry sponsored studies. Nineteen papers reported on sponsorship and efficacy effect size, but could not be pooled due to differences in their reporting of data and the results were heterogeneous. We did not find a difference between drug and device studies in the association between sponsorship and conclusions (test for interaction, P = 0.98) (four papers). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment, follow-up and selective outcome reporting. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.25 (95% CI: 1.05 to 1.50) (13 papers), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.83 (95% CI: 0.70 to 0.98) (six papers). Authors' conclusions: Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.
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Background: Internal documents from the pharmaceutical industry provide a unique window for understanding the structure and methods of pharmaceutical promotion. Such documents have become available through litigation concerning the promotion of gabapentin (Neurontin, Pfizer, Inc., New York, New York) for off-label uses. Purpose: To describe how gabapentin was promoted, focusing on the use of medical education, research, and publication. Data Sources: Court documents available to the public from United States ex. rel David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company, mostly from 1994-1998. Data Extraction: All documents were reviewed by 1 author, with selected review by coauthors. Marketing strategies and tactics were identified by using an iterative process of review, discussion, and re-review of selected documents. Data Synthesis: The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging "key customers" to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results. Limitations: Most available documents were submitted by the plaintiff and may not represent a complete picture of marketing practices. Conclusion: Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. New strategies are needed to ensure a clear separation between scientific and commercial activity.
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This paper relates quality and uncertainty. The existence of goods of many grades poses interesting and important problems for the theory of markets. On the one hand, the interaction of quality differences and uncertainty may explain important institutions of the labor market. On the other hand, this paper presents a struggling attempt to give structure to the statement: “Business in under-developed countries is difficult”; in particular, a structure is given for determining the economic costs of dishonesty. Additional applications of the theory include comments on the structure of money markets, on the notion of “insurability,” on the liquidity of durables, and on brand-name goods.
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This paper provides a field level analysis of the process by which management knowledge is produced. Two linked dynamics are identified as important components of this process. The first is the commodification of management knowledge, or the tendency to reduce knowledge to a routinized and codified product. We argue that the commodification of management knowledge is a cyclical process that has been institutionalized by the interests of distinct categories of social actors. The second dynamic, termed colonization, refers to the migration of Big Five professional service firms into adjacent professional jurisdictions. Colonization is the result of intensification of commodification and has produced intense conflict and change in the organizational field of management knowledge production.
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When assessing the risks and beneé ts of medical drugs, the approach may be precaution- ary or permissive. If these different approaches actually inè uence the analysis and interpretation of technical medical data, then they are not merely a matter for discussion among philosophers, but should be debated by those concerned about medical risks and public health. To examine the interaction between expert risk-beneé t assessments of drugs, on the one hand, and permissive/precau- tionary approaches, on the other, the triazolam (Halcion) case is scrutinised. Specié cally, the assessments of triazolam by the FDA's 1992 Psychopharmacological Drugs Advisory Committee (PDAC) and the National Academy of Sciences' 1997 Institute of Medicine (IoM) are analysed. Both the PDAC and the IoM exhibited permissiveness towards triazolam. The PDAC gave priority to anecdotal evidence about triazolam in use, when assessing efé cacy, but to controlled clinical trial data, when assessing safety. In each instance the types of data which favoured triazolam were given priority. While a lack of compelling evidence of efé cacy from clinical trials was regarded as insufé cient to negate the drug's beneé ts, compelling evidence from clinical trials was required to coné rm signals of lack of safety. The IoM and the PDAC avoided the problem of patient safety in 'the real world' by limiting their conclusions to the safety of the drug under the conditions of use recommended on the label. Whether or not a society adopts a precautionary or permissive approach to the risk assessments of new technologies is not merely a matter for technical experts and science, it is also a social and political matter. A precautionary approach to drug safety could yield different expert assessments. It might require compelling evidence of drug efé cacy where good alternative therapies exist; integrate how a drug can be used safely into evaluation of controlled clinical trial data; and put more emphasis on the correlation between disaggregated clinical trial data and spontaneous reports of adverse drug reactions.
Book
The U.S. Food and Drug Administration is the most powerful regulatory agency in the world. How did the FDA become so influential? And how exactly does it wield its extraordinary power? Reputation and Power traces the history of FDA regulation of pharmaceuticals, revealing how the agency's organizational reputation has been the primary source of its power, yet also one of its ultimate constraints. Daniel Carpenter describes how the FDA cultivated a reputation for competence and vigilance throughout the last century, and how this organizational image has enabled the agency to regulate an industry as powerful as American pharmaceuticals while resisting efforts to curb its own authority. Carpenter explains how the FDA's reputation and power have played out among committees in Congress, and with drug companies, advocacy groups, the media, research hospitals and universities, and governments in Europe and India. He shows how FDA regulatory power has influenced the way that business, medicine, and science are conducted in the United States and worldwide. Along the way, Carpenter offers new insights into the therapeutic revolution of the 1940s and 1950s; the 1980s AIDS crisis; the advent of oral contraceptives and cancer chemotherapy; the rise of antiregulatory conservatism; and the FDA's waning influence in drug regulation today. Reputation and Power demonstrates how reputation shapes the power and behavior of government agencies, and sheds new light on how that power is used and contested.
Article
Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical industry sponsored studies are more often favorable to the sponsor's product compared with studies with other sources of sponsorship. This review is an update using more stringent methodology and also investigating sponsorship of device studies. To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship. We searched MEDLINE (1948 to September 2010), EMBASE (1980 to September 2010), the Cochrane Methodology Register (Issue 4, 2010) and Web of Science (August 2011). In addition, we searched reference lists of included papers, previous systematic reviews and author files. Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions. Two assessors identified potentially relevant papers, and a decision about final inclusion was made by all authors. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals). Forty-eight papers were included. Industry sponsored studies more often had favorable efficacy results, risk ratio (RR): 1.24 (95% confidence interval (CI): 1.14 to 1.35), harms results RR: 1.87 (95% CI: 1.54 to 2.27) and conclusions RR: 1.31 (95% CI: 1.20 to 1.44) compared with non-industry sponsored studies. Ten papers reported on sponsorship and effect size, but could not be pooled due to differences in their reporting of data. The results were heterogeneous; five papers found larger effect sizes in industry sponsored studies compared with non-industry sponsored studies and five papers did not find a difference in effect size. Only two papers (including 120 device studies) reported separate data for devices and we did not find a difference between drug and device studies on the association between sponsorship and conclusions (test for interaction, P = 0.23). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment and follow-up. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.32 (95% CI: 1.05 to 1.65), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.84 (95% CI: 0.70 to 1.01). Sponsorship of drug and device studies by the manufacturing company leads to more favorable results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.
Article
Policy reforms in the Food and Drug Administration (FDA) have led to substantial increases in the speed of new-drug review. While data show that FDA review times for new drugs have fallen as much as 50 percent, other data show that several new drugs have been withdrawn from the market for safety reasons. This flurry of new-drug withdrawals raises a question. Have increases in the speed of new-drug review had an adverse effect on new-drug safety? This analysis uses adverse drug reaction (ADR) data from the FDA's Spontaneous Reporting System to examine this question. Specifically, ADR counts for newly approved drugs are estimated as a function of drug characteristics, patient characteristics, and regulatory factors (such as the speed of new-drug review) using negative binomial regression analysis. The primary result is that reductions in new-drug review times are associated with increases in both ADRs requiring hospitalization and ADRs resulting in death.
Article
The Orphan Drug Act incentivizes medication development for rare diseases, offering substantial financial benefits to the manufacturer. Orphan products constitute most new drug approvals in oncology, but safety and efficacy questions have emerged about some of these agents. To define characteristics of orphan cancer drugs and their pivotal clinical trials and to compare these with nonorphan drugs. We identified all new orphan and nonorphan drugs approved between 2004 and 2010 to treat cancer. We then collected data on key development variables from publicly available information on the US Food and Drug Administration's Web site and in the Code of Federal Regulations. We assessed clinical testing dates, approved indications, and regulatory characteristics (regular vs accelerated review, advisory committee review, postmarketing commitments). We then compared design features (randomization, blinding, primary end point) of pivotal trials supporting approval of orphan and nonorphan drugs and rates of adverse safety outcomes (deaths not attributed to disease progression, serious adverse events, dropouts) in pivotal trials. Fifteen orphan and 12 nonorphan drugs were approved between January 1, 2004, and December 31, 2010. Pivotal trials of orphan drugs had smaller participant numbers (median, 96 [interquartile range {IQR}, 66-152] vs 290 [IQR, 185-394] patients exposed to the drug; P < .001) and were less likely to be randomized (30% vs 80%; P = .007). Orphan and nonorphan pivotal trials varied in their blinding (P = .04), with orphan trials less likely to be double-blind (4% vs 33%). Primary study outcomes also varied (P = .04), with orphan trials more likely to assess disease response (68% vs 27%) rather than overall survival (8% vs 27%). More treated patients had serious adverse events in trials of orphan drugs vs trials of nonorphan drugs (48% vs 36%; odds ratio, 1.72; 95% confidence interval, 1.02-2.92; P = .04). Compared with pivotal trials used to approve nonorphan cancer drugs, pivotal trials for recently approved orphan drugs for cancer were more likely to be smaller and to use nonrandomized, unblinded trial designs and surrogate end points to assess efficacy.
Article
Coinciding with sixty years of the U.K. National Health Service (NHS), this article reviews the neglected area of the governance of the pharmaceutical industry and the NHS. It traces the relationships between the pharmaceutical industry, the state, and the NHS from the creation of the health service to the present, as they have grappled with the overlapping challenges of pharmaceutical safety, efficacy, cost-effectiveness, pricing, promotion, and advertising. The article draws on the concepts of "corporate bias" and "regulatory capture" from political theory, and "counter-vailing powers" and "clinical autonomy" in medical sociology, while also introducing the new concepts of "assimilated allies" and "pharmaceuticalization" in order to synthesize a theoretical framework capable of longitudinal empirical analysis of pharmaceutical governance. The analysis identifies areas in which the governance of pharmaceuticals and the NHS has contributed to progress in health care since 1948. However, it is argued that that progress has been slow, restricted, and vulnerable to misdirection due to the enormous and unrivaled influence afforded to the pharmaceutical industry in policy developments. Countervailing influences against such corporate bias have often been limited and subject to destabilization by the industry's assimilated allies either within the state or in the embrace of pharmaceuticalization and consumerism.
Article
Clinical trials are the most credible and powerful form of marketing in the prelaunch period. Two alarming trends have surfaced in the pharmaceutical industry these past two decades. The first is a surge in ethics violations. Despite journalists, researchers, bloggers, and lately lawmakers who have been working to shame the industry into self-reform, the pace at which new scandals are born appears, if anything, to be accelerating.2 There is wrongdoing in every stage of drug development and promotion. The list includes campaigns to "ghost manage" the conduct of basic science, to rig clinical trials, to run trials in poor countries where ethical oversight is weak, to market medical conditions far beyond their natural incidence ("condition branding," as the marketers term it), to sway public health criteria for the threshold of disease risk, and to lure some of the nation's most respected doctors into risky off-label promotion schemes.3 All of these problems can be traced back to marketing-inspired ruses. The second, less apparent trend is a decline in new drug applications marking breakthrough discoveries. In the words of a 2006 Government Accountability Office report to Congress, "Innovation in the pharmaceutical industry has become stagnant."4 Merrill Goozner, head of the Center for Science in the Public Interest, explains, "Three out of every four drug applications involve drugs that either replicated the action of medicines already on the market or were new formulations that at best added minor conveniences for patients and doctors."5 Some have had the intuition that these two trends are connected, but the dots have not been empirically or even notionally linked in a way that would light a path to reform. The two appear to be effects of a different order. I will argue that they are joined because they reflect the ascendancy of marketing throughout the pharmaceutical industry and in particular because they result from the integration of pharmaceutical firms' marketing efforts with their formerly semiautonomous research and development (R&D) divisions. My goal in this essay is to connect some of the dots—to show that the decline of innovation is also linked to the rise of marketing. Discovery of medical cures relies on honestly pursued scientific outcomes and a clear separation of influence over scientific practices and goals. I specify the rise in the early 1990s of blockbuster drugs—the handful of brands that account for nearly half the industry's profit—as the catalyst for yoking R&D to marketing, a development that would have been unfamiliar and unnatural to most pharmaceutical executives of prior generations. I draw on industry sources to depict managerial principles at work in defining the relationship, the most telling of which is referred to as "precommercial planning and marketing." Precommercial planning and marketing demonstrates how the marketing-driven outlook in pharmaceutical companies today pushes these enterprises toward an escalation in the adoption of marketing rationales at the expense of public health. What emerges is a system in which the scientific search for cures and the marketing-led pursuit of meeting unmet medical needs stand not in cooperative tandem, one with the other, but in direct competition. Precommercial planning and marketing, in short, is a legal but unethical practice when applied to humanly vital industries such as the pursuit of medical cures. What is precommercial planning and marketing? A recent podcast at Pharmavoice, "a Website for life-sciences executives and other healthcare-service related professionals," was entitled "Pharmaceutical Marketing and Planning: Securing Future Success through Meaningful Differentiation." The guest speaker was Laurie Lucas, founder of L3 Healthcare Marketing, LLC, which explains its objective this way: "The pharmaceutical market is evolving rapidly, growing in complexity, and there is less time to maximize a product's potential. Medical communications are critical to understanding the target therapeutic area, and to communicating a product's unique attributes."6 The "less time" here refers to the length of time under patent during which a firm can sell and accrue profits for a drug. Since a patent is taken out upon the formulation of a molecule and several years elapse before the drug is developed, approved, and brought to market...
Article
I. Introduction, 488. — II. The model with automobiles as an example, 489. — III. Examples and applications, 492. — IV. Counteracting institutions, 499. — V. Conclusion, 500.
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Recently, lawsuits alleging damages from illegal marketing of gabapentin (Neurontin) have yielded remarkable discoveries about the structure and function of pharmaceutical marketing. Drs. Seth Landefeld and Michael Steinman write that Neurontin's most important legacy may be promoting our discussion of these issues and pushing us beyond the tipping point to action.
Article
The medicalisation of life problems has been occurring for well over a century and has increased over the past 30 years, with the engines of medicalisation shifting to biotechnology, managed care, and consumers. This paper examines one strand of medicalisation during the last century: direct-to-consumer advertising (DTCA) of pharmaceuticals. In particular, it examines the roles that physicians and the Food and Drug Administration (FDA) have played in regulating DTCA in the US. Two advertising exemplars, the late 19(th) century Lydia E. Pinkham's Vegetable Compound (for 'women's complaints') and contemporary Levitra (for erectile dysfunction) are used to examine the parallels between the patent medicine era and the DTCA era. DTCA re-establishes the direct and independent relationship between drug companies and consumers that existed in the late 19(th) century, encouraging self-diagnosis and requests for specific drugs. The extravagant claims of Lydia Pinkham's day are constrained by laws, but modern-day advertising is more subtle and sophisticated. DTCA has facilitated the impact of the pharmaceutical industry and consumers in becoming more important forces in medicalisation.