Kevin P. Hill

Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents From Rofecoxib Litigation

CONTEXT Authorship in biomedical publication provides recognition and establishes accountability and responsibility. Recent litigation related to rofecoxib provided a unique opportunity to examine guest authorship and ghostwriting, practices that have been suspected in biomedical publication but for which there is little documentation. OBJECTIVE To characterize different types and the extent of guest authorship and ghostwriting in 1 case study. DATA SOURCES Court documents originally obtained during litigation related to rofecoxib against Merck & Co Inc. Documents were created predominantly between 1996 and 2004. In addition, publicly available articles related to rofecoxib identified via MEDLINE. DATA EXTRACTION All documents were reviewed by one author, with selected review by coauthors, using an iterative process of review, discussion, and rereview of documents to identify information related to guest authorship or ghostwriting. DATA SYNTHESIS Approximately 250 documents were relevant to our review. For the publication of clinical trials, documents were found describing Merck employees working either independently or in collaboration with medical publishing companies to prepare manuscripts and subsequently recruiting external, academically affiliated investigators to be authors. Recruited authors were frequently placed in the first and second positions of the authorship list. For the publication of scientific review papers, documents were found describing Merck marketing employees developing plans for manuscripts, contracting with medical publishing companies to ghostwrite manuscripts, and recruiting external, academically affiliated investigators to be authors. Recruited authors were commonly the sole author on the manuscript and offered honoraria for their participation. Among 96 relevant published articles, we found that 92% (22 of 24) of clinical trial articles published a disclosure of Mercks financial support, but only 50% (36 of 72) of review articles published either a disclosure of Merck sponsorship or a disclosure of whether the author had received any financial compensation from the company. CONCLUSIONS This case-study review of industry documents demonstrates that clinical trial manuscripts related to rofecoxib were authored by sponsor employees but often attributed first authorship to academically affiliated investigators who did not always disclose industry financial support. Review manuscripts were often prepared by unacknowledged authors and subsequently attributed authorship to academically affiliated investigators who often did not disclose industry financial support.

Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review

IMPORTANCE As of March 2015, 23 states and the District of Columbia had medical marijuana laws in place. Physicians should know both the scientific rationale and the practical implications for medical marijuana laws. OBJECTIVE To review the pharmacology, indications, and laws related to medical marijuana use. EVIDENCE REVIEW The medical literature on medical marijuana was reviewed from 1948 to March 2015 via MEDLINE with an emphasis on 28 randomized clinical trials of cannabinoids as pharmacotherapy for indications other than those for which there are 2 US Food and Drug Administration-approved cannabinoids (dronabinol and nabilone), which include nausea and vomiting associated with chemotherapy and appetite stimulation in wasting illnesses. FINDINGS Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence. Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications. CONCLUSIONS AND RELEVANCE Medical marijuana is used to treat a host of indications, a few of which have evidence to support treatment with marijuana and many that do not. Physicians should educate patients about medical marijuana to ensure that it is used appropriately and that patients will benefit from its use.

The ADVANTAGE Seeding Trial: A Review of Internal Documents

Context People have long suspected that drug companies use seeding trials to promote a new drug by getting physicians to use it as they follow the protocol of a clinical trial. Strong documentary evidence has been lacking. Contribution The authors obtained court-ordered documents, some of which were e-mailed messages, that showed that the marketing division of Merck & Co. (Whitehouse Station, New Jersey) conducted the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness) randomized trial to promote the use of Vioxx (rofecoxib) by physiciansthe drug prescribed to patients assigned to the active intervention. The company did not tell institutional review boards, physicians, or patients the true purpose of the trial. Caution The documents lack many details about ADVANTAGE. Implication Seeding trials deceive trial participants and their protectors. The Editors Although much has been written about the marketing tactics of the pharmaceutical industry (1, 2), seeding trials have not been characterized in depth. Seeding trials are clinical trials designed by pharmaceutical companies to promote the use of pharmacotherapies that were recently approved or are under review by the U.S. Food and Drug Administration (FDA). Seeding trials are designed to appear as if they answer a scientific question but primarily fulfill marketing objectives. Kessler and colleagues (3) portrayed seeding trials as attempts to entice doctors to prescribe a new drug being marketed by the company while the company puts its product in the hands of practicing physicians, hoping that the experience of treating patients with the study drug and a pleasant, even profitable, interaction with the company will result in more loyal physicians who prescribe the drug (4). Despite attempts to call attention to seeding trials (5, 6), limited information about them is available in the public domain. Confidential internal communications made public as a result of recent litigation against Merck & Co. regarding the cardiovascular safety of Vioxx (rofecoxib; Merck & Co., Whitehouse Station, New Jersey) offer a view of the planning, implementation, and publication of a seeding trial from the pharmaceutical companys perspective. We examined the documents related to the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness) clinical trial, a seeding trial designed and conducted by Merck that was published in the peer-reviewed literature on 7 October 2003 (7). Methods Review of the Litigation Documents During Cona v Merck and Co., Inc., and McDarby v Merck and Co., Inc., documents produced by Merck in response to discovery requests were archived in an integrated database maintained by the plaintiffs attorneys. These documents were created between 1998 and 2006 and included Merck internal and external correspondence, reports, and presentations. As paid consultants to the attorneys representing the plaintiffs, we had access to all archived documents. We identified a subset of approximately 2000 relevant documents by using the following search terms: seeding, marketing, ADVANTAGE, and the names of Merck employees and academically affiliated authors known to be associated with the ADVANTAGE clinical trial. Document numbers are approximate because information within 1 document may overlap with another, making it difficult to determine the exact number of distinct documents. One investigator read the identified documents to determine relevance to seeding trials. We identified approximately 100 relevant documents from the search, most of which were Merck internal correspondence and marketing reports, memos, and presentations. Two investigators independently completed a line-by-line review of each identified document by using the constant comparative method, a systematic, verifiable technique (8, 9), to identify broad themes reflecting the design and conduct of a seeding trial. In this iterative process, segments of text are catalogued according to their essential concepts (8, 9). Similar methods have been used recently with court documents to examine tobacco marketing, pharmaceutical marketing, and ghostwriting for scientific papers (1013). Next, all investigators reviewed pertinent documents again to identify and develop core themes. Then, 2 investigators reviewed all of the documents for additional evidence to support or refute the core themes. Each investigator re-reviewed a subset of pertinent documents to compare the content with the 3 core themes that emerged from our review. The team communicated regularly to resolve discordant views through negotiated consensus. Finally, the investigators completed another iteration of the negotiated consensus process after the initial manuscript review by Annals. Systematic Review of the Literature To better understand ADVANTAGE in the context of seeding trials, we conducted a systematic review of the literature and identified published manuscripts about seeding trials. First, we searched MEDLINE (from 1950 to March 2008) for the exploded Medical Subject Heading term clinical trials as topic and identified 201557 publications. Second, we searched for the exploded Medical Subject Heading term drug industry and found 27210 publications. Third, we did a search that included the exploded Medical Subject Heading terms prescriptions, drug, advertising as topic, and conflict of interest and the keywords marketing and seeding and identified 58242 publications. Finally, we combined these 3 searches and identified 466 articles, 61 of which we excluded for not being published in English. Two investigators independently reviewed the titles and abstracts of retrieved publications and selected relevant articles for possible inclusion in our review. On the basis of this review, we excluded 400 publications that did not focus on seeding trials. We included the remaining 5 publications in our review and searched bibliographies of these articles for additional relevant publications; 1 was identified. Role of the Funding Source This research was exempt from review by the Yale University Human Investigation Committee. Neither the Hartford Foundation nor the Robert Wood Johnson Foundation had any role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or approval of the manuscript. All authors were compensated for their work as consultants to the plaintiffs counsel in connection with suits against Merck related to Vioxx. This independent research was not sponsored by the plaintiffs or in any way related to the trial work. Results In January 1999, before the launch of Vioxx, Mercks marketing division conceived the ADVANTAGE clinical trial (14). However, Merck did not reveal the key role of the marketing division and marketing objectives of the study. Instead, physician-investigators, participants, and institutional review board members were told that the purpose of the trial was to measure the gastrointestinal safety of Vioxx (15). Six hundred investigators enrolled and randomly assigned 2785 patients with osteoarthritis to Vioxx and 2772 patients to naproxen, with a target of 6 participants per site, for a 3-month trial starting on 27 March 1999, approximately 2 months before the drugs FDA approval on 22 May 1999 (16). A Merck marketing slide set used for the companys internal purposes stated that a goal of ADVANTAGE was for investigators to [g]ain experience with Vioxx prior to and during the critical launch phase (14). Review of the Vioxx documents revealed 3 key themes that were related to the design and marketing objectives of the ADVANTAGE trial: The trial emerged from the marketing division with a marketing objective; Mercks marketing division collected, analyzed, and disseminated both the scientific and the marketing data; and Merck did not reveal the marketing purposes of the trial to participants, physician-investigators, and institutional review board members. A Marketing Trial with a Marketing Objective The Merck marketing division designed and executed the ADVANTAGE trial. Figure 1 shows an internal award nomination memo from Charlotte McKines, Executive Director of Marketing Communications at Merck, and Louis Sherwood, Senior Vice President for Medical and Scientific Affairs, that describes the influence of the marketing division (17). Figure 1. Merck commends marketing divisions ADVANTAGE Trial. Merck executives nominate those responsible for the design and execution of ADVANTAGE for an internal marketing award. A&= arthritis and analgesia; CDP= clinical development program; NSAID= nonsteroidal anti-inflammatory drug; OA= osteoarthritis. USHS= United States Human Health. The memo outlines 4 key Merck marketing principles: target the trial to a select group of customersin this case, primary care physicians; use the trial to demonstrate the value of Vioxx to these physicians; integrate the marketing division and those responsible for trial-related operations in the field with the highest level of precision; and carefully track marketing-related results, that is, rates of Vioxx prescriptions written by study physicians. According to an internal presentation on 16 March 1999 by Jan Weiner, Executive Director of Public Affairs at Merck, the responsibilities of the marketing division were to [s]et objectives and [d]esign [the] protocol and oversee execution of [the] trial (18) (Figure 2). In a memo, Merck explained why the company targeted primary care physicians (17) (Figure 1): Figure 2. Merck slide defining the role of the marketing division in the ADVANTAGE Trial. CDP= Clinical Development Program; CRO= Clinical Research Organization. First, the trial was targeted to a select group of critical customers. The clinical trial program for VIOXX focused primarily on specialists. While they would be critical to the early

Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data Lessons for Postmarket Pharmaceutical Safety Surveillance

BACKGROUND In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts. METHODS We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event. RESULTS We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001). CONCLUSION Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3(1/2) years before the manufacturers voluntary market withdrawal.

d-Cycloserine attenuates reactivity to smoking cues in nicotine dependent smokers: A pilot investigation

Increasing evidence indicates that smoking cues contribute to nicotine self-administration and attenuating conditioned reactivity to smoking cues may aid abstinence of smoking and prevention of smoking relapse in individuals with nicotine dependence. Based on prior studies showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitates extinction of learned fear during behavioral exposure therapy in humans and facilitates extinction of cocaine-induced conditioned place preference in animals, we evaluated whether DCS would have potential for reducing reactivity to smoking cues when combined with cue exposure treatment in humans with nicotine dependence. In this double-blind placebo-controlled pilot laboratory study, 25 smokers were recruited from the general community and randomized to DCS or placebo, plus cue exposure therapy. DCS significantly attenuated smoking cue reactivity in response to in-vivo smoking cues based on physiological reactivity and subjective urge-to-smoke ratings and led to a significantly smaller expired carbon monoxide (CO) level at the one-week follow-up compared to placebo, although exploratory analyses indicated no effect on smoking behavior overall. These findings provide promising support for DCS combined with cue exposure therapy in attenuating conditioned reactivity to smoking cues.

Self-administration of intravenous nicotine in male and female cigarette smokers

Although nicotine is the main addictive chemical in tobacco, there have been few studies of pure nicotine self-administration in humans. The goal of this study was to test the parameters of an intravenous (IV) nicotine self-administration model using nicotine doses presumed to be within the range of those of average intake from cigarette smoking. Six male and four female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. In each experimental session, subjects were randomly assigned to one of the three doses of nicotine (0.1, 0.4, or 0.7 mg). The lowest nicotine dose, 0.1 mg, was chosen to be approximately half the amount of nicotine inhaled from one puff of a cigarette. During each experimental session, subjects first sampled the assigned nicotine dose and placebo and then had the opportunity to choose between nicotine and placebo for a total of six choices over a 90-min period. Out of six options, the average (SEM) number of nicotine choices were 3.0 (0.48) for 0.1 mg, 4.7 (0.48) for 0.4 mg and 4.5 (0.46) for 0.7 mg, indicating a significant effect of nicotine dose on nicotine choice. Both the 0.4 and 0.7, but not the 0.1 mg, nicotine doses were preferred to placebo. These higher doses also produced increases in heart rate, blood pressure, and ratings of drug liking and high. Overall, these findings indicate that smokers chose both the 0.4 and the 0.7 mg nicotine doses over placebo. Our model may be useful in the evaluation of the effects of both behavioral and pharmacological manipulations on nicotine self-administration in humans.

Serotonin transporter (5-HTT) gene polymorphisms and susceptibility to cocaine dependence among African-American individuals

Studies indicate that the serotonin system, particularly the serotonin transporter (5‐HTT), may modulate the central effects of cocaine. We investigated whether a polymorphism in the 5′ promotor region (5‐HTTLPR) of the 5‐HTT gene confers susceptibility to cocaine dependence. One hundred and ninety‐seven cocaine‐dependent African‐American subjects and 101 controls were studied. Polymerase chain reaction based genotyping of a biallelic repeat polymorphism in the 5′ promotor region yielded 2 alleles containing 484 (S) and 528 bp (L) repeats, respectively. There were no significant differences between controls of European background (n = 40) and African‐American controls (n = 61) in distribution of genotypes (European: LL = 32.5%, LS = 40.0%, SS = 27.5%; African‐American: LL = 27.9%, LS = 57.4%, SS = 14.7%) (χ2= 3.60, df = 2, p = 0.16) or allele frequencies (European: L = 52.5%, S = 47.5%; African‐American: L = 56.6%, S = 43.4%) (χ2= 2.21, df = 1, p = 0.13). When cocaine patients were compared to an ethnically diverse control group (n = 101), frequencies of the L variant (65.0%) were significantly higher while the S variant (35.0%) was less frequent among cocaine patients compared to controls (L = 53.9%, S = 46.1%) (χ2= 6.83, df = 1, p < 0.01). Similarly, there were more cocaine patients with the LL genotype (41.1%) and less with the SS genotype (11.2%) compared to controls (LL = 29.7%, SS = 21.8%) (χ2= 7.43, df = 2, p < 0.05). However, after restricting controls to African‐American individuals only (n = 61), cocaine subjects and controls did not differ significantly with respect to genotype distribution (χ2= 4.24, df = 2, p = 0.12) or allele frequencies (χ2= 2.83, df = 1, p = 0.10). In conclusion, although comparisons with a heterogeneous control group indicated a possible association between allelic variants of 5‐HTTLPR and cocaine dependence among African‐American cocaine subjects, this relationship was not observed when the control group was limited to African‐American people only. Our findings need to be confirmed on larger samples of ethnically matched individuals.

Bipolar disorder and alcohol use disorder: a review.

Bipolar disorder and alcohol use disorder represent a significant comorbid population, which is significantly worse than either diagnosis alone in presentation, duration, co-morbidity, cost, suicide rate, and poor response to treatment. They share some common characteristics in relation to genetic background, neuroimaging findings, and some biochemical findings. They can be treated with separate care, or ideally some form of integrated care. There are a number of pharmacotherapy trials, and psychotherapy trials that can aid program development. Post-treatment prognosis can be influenced by a number of factors including early abstinence, baseline low anxiety, engagement with an aftercare program and female gender. The future development of novel therapies relies upon increased psychiatric and medical awareness of the co-morbidity, and further research into novel therapies for the comorbid group.

Atomoxetine Attenuates Dextroamphetamine Effects in Humans

Background: Although preclinical studies support the contribution of the noradrenergic system activation in mediating the acute effects of amphetamines, these findings have not been followed up in clinical studies. Objectives: To examine the effects of atomoxetine, a norepinephrine transporter inhibitor, on subjective, physiological, and plasma cortisol responses to dextroamphetamine in 10 healthy volunteers. Methods: Subjects were randomly assigned to a sequence of atomoxetine (40 mg/day) or placebo treatments each lasting for 4 days. On Day 4 of each treatment period, responses to a single 20 mg/70 kg dose of dextroamphetamine were assessed. Results: Atomoxetine treatment attenuated dextroamphetamine-induced increases in systolic and diastolic blood pressure and plasma cortisol as well as the self-report ratings of “stimulated,” “high,” and “good drug effects.” Conclusions: These findings are consistent with previous preclinical studies supporting the role of the noradrenergic system in mediating acute amphetamine responses. Scientific significance: Atomoxetines capacity to attenuate some of the physiological and subjective responses to dextroamphetamine supports its potential use for stimulant addiction.

Comparison of Pretreatment Characteristics and Treatment Outcomes for Alcohol-, Cocaine-, and Multisubstance-Dependent Patients

Abstract We investigated whether pretreatment characteristics and measures of outcome differed for alcohol-, cocaine-, and multisubstance-dependent patients receiving outpatient substance abuse treatment. One hundred and forty substance dependent individuals (32 alcohol, 76 cocaine, and 32 multisubstance) enrolled in a 12-week outpatient treatment program were compared across measures of addiction severity, personality, and treatment-readiness at admission. In-treatment, end-of-treatment and 9-month follow-up assessments of treatment outcome were then compared across the three groups. Outcome measures included reduction in problem severity, abstinence, retention, number of sessions attended, dropout, and counselor and patient ratings of treatment benefit. At admission, the multisubstance group had a higher proportion of positive urines, reported more severe drug, alcohol and psychiatric problems, and displayed higher impulsivity and anxiety scores than one or both of the other groups. However, multisubstance patients were more treatment ready in terms of adopting a total abstinence orientation than alcohol or cocaine patients. While a significant reduction in symptoms occurred for the total sample during treatment as well as at follow-up, comparisons of outcomes did not consistently favor any particular group. The three groups had equivalent improvements in eleven of fourteen during-treatment and five of seven follow-up measures. Despite pre-treatment differences, in severity and treatment-readiness, outcomes were more similar than different for alcohol-, cocaine-, and multisubstance-dependent patients. Clinicians should be cautious about forecasting treatment-outcomes for addicted patients based on their primary substances of abuse.