Sponsor's Drug Research Articles

Seeding trials: Marketing gimmick or credible scientific research.

The pharmaceutical sector has become extensively competitive over the years across the world and India is no exception. While the World Health Organization (WHO) recommends 433 ‘essential medicines’ around 110,329 brands of registered pharmaceuticals, many of which are ‘me-too’ agents.[1,2] Competition in the industry fuels research and development, keeps prices of medicines in check and provides alternative therapeutic agents for the patients. However, in an overcrowded competitive market, enhancing or even sustaining sales volume and profit margins becomes increasingly difficult. Therefore, pharmaceutical companies often adopt aggressive and innovative marketing and positioning strategies aimed at influencing the prescribing habits of the physicians and try to usher them towards new medicines.[3,4] While prescribing new drugs, physicians often try to balance a range of factors, such as potential benefits and risk, long-term effects, cost and range of therapeutic indications. For quick assessment of these factors relatively little information is available in public domain and physicians have little or no prior experience with the use of the drug in a new indication. Under such circumstances, prescribing may be more ‘an act of faith’ than a rational process. In order to ‘educate’ and familiarise the prescriber with the new drug or a new indication of an old drug, manufacturer(s) often adopt various techniques.[3] Prominent among them are detailing by professional sales representative, distribution of promotional literature and physician's sample, conducting programmes such as continuing medical education (CME) activities, symposia and conferences, etc.[3,5] Another lesser-known method of drug promotion is ‘seeding trials’ or ‘marketing trials’.[6] What are seeding trials? Seeding trials are clinical studies designed by pharmaceutical companies with primary intention to promote the use of drugs that were recently approved or are under review by regulatory authorities.[6,7,8] Such trials have been described by Kesseler and colleagues as ‘company-sponsored trials of approved drugs that appear to serve little or no scientific purpose”. Many believe this as a marketing strategy in the guise of science. They are done to get physicians prescribe the new drug being marketed by the company rather than finding the safety and effectiveness of the drug.[6] The company promotes the new drug by sponsoring a clinical trial in which physicians participating as investigators are familiarised with the drug as they follow the trial protocol. It attempts to gratify the participating physicians by engaging them in the research team with the title of ‘investigator’. This honorable and supposedly academic involvement with the pharmaceutical industry for the cause of advancing science is often perceived as qualification for a physician to become ‘an opinion leader’ among their colleagues.[9] While the apparent purpose of such a study is to test a scientific hypothesis, the true purpose is to ‘seed’ the habit of prescribing the new drug into the trial investigators.[8] The company puts its new product in the hands of physicians, hoping that the experience of treating patients with the study drug and the pleasant interaction with the company will translate into increased prescription of the drug in their routine practice.[7] Early experience of using a new drug during its clinical development strongly influences its future use by the physician.[10] Andersen et al. had checked the association between physician participation in a clinical trial of fixed-dose combination of formoterol and budesonide, an asthma drug, and the prescribing patterns of their practices in the 2 years following the trial. The control group comprised general practitioners who did not participate as investigators in the clinical trial. They found that conducting the trial led to a significant increase in the use of the trial sponsor's drug by the investigators in their own daily practice as compared with the control group.[11] Seeding trials are also employed to trigger a ‘switch’ of brands from a competitor product to the new drug, thereby increasing volume of sales.[8] Another possible objective of conducting such trials is to convert the investigators into brand ambassadors of the new drug and use their research experience as testimonial for promoting the drug.[6]

Factors Associated with Results and Conclusions of Trials of Thiazolidinediones

BackgroundWhen a sponsor funds a study of two competing drugs in a head-to-head comparison, the results and conclusions are likely to favor the sponsor’s drug. Thiazolidinediones, oral medications used for the treatment of type 2 diabetes, are one of the most costly choices of oral anti-diabetic medications, yet they do not demonstrate clinically relevant differences in achieving lower glycosylated hemoglobin levels compared to other oral antidiabetic drugs. Our aim is to examine associations between research funding source, study design characteristics aimed at reducing bias, and other factors with the results and conclusions of randomized controlled trials (RCTs) of thiazolidinediones compared to other oral hypoglycemic agents.Methods and FindingsThis is a cross-sectional study of 61 published RCTs comparing a thiazolidinedione (glitazone) to another anti-diabetic drug or placebo for treatment of type 2 diabetes. Data on study design characteristics, funding source, author’s financial ties, results for primary outcomes, and author conclusions were extracted. Univariate logistic regression identified associations between independent variables and results and conclusions that favored the glitazone. Of the RCTs, 59% (36/61) were funded by industry, 39% (24/61) did not disclose any funding. Common study design weaknesses included inadequate blinding and lack of concealment of allocation. Trials that reported favorable glycemic control results for the glitazone were more likely to have adequate blinding (OR (95% CI) = 5.42 (1.46, 21.19), p = 0.008) and have a corresponding author with financial ties to the glitazone manufacturer (OR (95% CI) = 4.12 (1.05, 19.53); p = 0.04). Trials with conclusions favoring the glitazone were less likely to be funded by a comparator drug company than a glitazone company (OR (95% CI) = 0.026 (0, 0.40), p = 0.003) and less likely to be published in journals with higher impact factors (OR (95% CI) = 0.79 (0.62, 0.97), p = 0.011). One limitation of our study is that we categorized studies as funded by industry based on each article’s disclosure which could underestimate the number of industry sponsored studies and personal ties of investigators. Additionally, our study did not include any head-to-head comparisons of one glitazone to another.ConclusionsPublished RCT comparisons of glitazones with other anti-diabetic drugs or placebo are predominantly industry supported and this support, as well as the financial ties of study authors, appears to be associated with favorable findings.

Seeding Trials: Just Say “No”

A seeding trial is marketing in the guise of science. In 2003, Annals published a seeding trial sponsored by Merck & Co. No one told Annals the true purpose of the trial until the Editor received a...

Why Olanzapine Beats Risperidone, Risperidone Beats Quetiapine, and Quetiapine Beats Olanzapine: An Exploratory Analysis of Head-to-Head Comparison Studies of Second-Generation Antipsychotics

In many parts of the world, second-generation antipsychotics have largely replaced typical antipsychotics as the treatment of choice for schizophrenia. Consequently, trials comparing two drugs of this class--so-called head-to-head studies--are gaining in relevance. The authors reviewed results of head-to-head studies of second-generation antipsychotics funded by pharmaceutical companies to determine if a relationship existed between the sponsor of the trial and the drug favored in the study's overall outcome. The authors identified head-to-head comparison studies of second-generation antipsychotics through a MEDLINE search for the period from 1966 to September 2003 and identified additional head-to-head studies from selected conference proceedings for the period from 1999 to February 2004. The abstracts of all studies fully or partly funded by pharmaceutical companies were modified to mask the names and doses of the drugs used in the trial, and two physicians blinded to the study sponsor reviewed the abstracts and independently rated which drug was favored by the overall outcome measures. Two authors who were not blinded to the study sponsor reviewed the entire report of each study for sources of bias that could have affected the results in favor of the sponsor's drug. Of the 42 reports identified by the authors, 33 were sponsored by a pharmaceutical company. In 90.0% of the studies, the reported overall outcome was in favor of the sponsor's drug. This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared. Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings. Some sources of bias may limit the validity of head-to-head comparison studies of second-generation antipsychotics. Because most of the sources of bias identified in this review were subtle rather than compelling, the clinical usefulness of future trials may benefit from minor modifications to help avoid bias. The authors make a number of concrete suggestions for ways in which potential sources of bias can be addressed by study initiators, peer reviewers of studies under consideration for publication, and readers of published studies.

Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development

The concept of 'equipoise', or the 'uncertainty principle', has been represented as a central ethical principle, and holds that a subject may be enrolled in a randomized controlled trial (RCT) only if there is true uncertainty about which of the trial arms is most likely to benefit the patient. We sought to estimate the frequency with which equipoise conditions were met in industry-sponsored RCTs in rheumatology, to explore the reasons for any deviations from equipoise, to examine the concept of 'design bias', and to consider alternative ethical formulations that might improve subject safety and autonomy. We studied abstracts accepted for the 2001 American College of Rheumatology meetings that reported RCTs, acknowledged industry sponsorship, and had clinical end-points (n = 45), and examined the proportion of studies that favored the registration or marketing of the sponsor's drug. In every trial (45/45) results were favorable to the sponsor, indicating that results could have been predicted in advance solely by knowledge of sponsorship (P < 0.0001). Equipoise clearly was being systematically violated. Publication bias appeared to be an incomplete explanation for this dramatic result; this bias occurs after a study is completed. Rather, we hypothesize that 'design bias', in which extensive preliminary data are used to design studies with a high likelihood of being positive, is the major cause of the asymmetric results. Design 'bias' occurs before the trial is begun and is inconsistent with the equipoise principle. However, design bias increases scientific efficiency, decreases drug development costs, and limits the number of subjects required, probably reducing aggregate risks to participants. Conceptual and ethical issues were found with the equipoise principle, which encourages performance of negative studies; ignores patient values, patient autonomy, and social benefits; is applied at a conceptually inappropriate decision point (after randomization rather than before); and is in conflict with the Belmont, Nuremberg, and other sets of ethical principles, as well as with US Food and Drug Administration procedures. We propose a principle of 'positive expected outcomes', which informs the assessment that a trial is ethical, together with a restatement of the priority of personal autonomy.

Quantitative analysis of sponsorship bias in economic studies of antidepressants

BackgroundConcern is widespread about potential sponsorship influence on research, especially in pharmacoeconomic studies. Quantitative analysis of possible bias in such studies is limited.AimsTo determine whether there is an association between sponsorship and quantitative outcomes in pharmacoeconomic studies of antidepressants.MethodUsing all identifiable articles with original comparative quantitative cost or cost-effectiveness outcomes for antidepressants, we performed contingency table analyses of study sponsorship and design v. study outcome.ResultsStudies sponsored by selective serotonin reuptake inhibitor (SSR1) manufacturers favoured SSRIs over tricyclic antidepressants more than non-industry-sponsored studies. Studies sponsored by manufacturers of newer antidepressants favoured these drugs more than did non-industry-sponsored studies. Among industry-sponsored studies, modelling studies favoured the sponsor's drug more than did administrative studies. Industry-sponsored modelling studies were more favourable to industry than were non-industry-sponsored ones.ConclusionsPharmacoeconomic studies of antidepressants reveal clear associations of study sponsorship with quantitative outcome.

Quantitative analysis of sponsorship bias in economic studies of antidepressants.

Concern is widespread about potential sponsorship influence on research, especially in pharmacoeconomic studies. Quantitative analysis of possible bias in such studies is limited. To determine whether there is an association between sponsorship and quantitative outcomes in pharmacoeconomic studies of antidepressants. Using all identifiable articles with original comparative quantitative cost or cost-effectiveness outcomes for antidepressants, we performed contingency table analyses of study sponsorship and design v. study outcome. Studies sponsored by selective serotonin reuptake inhibitor (SSRI) manufacturers favoured SSRIs over tricyclic antidepressants more than non-industry-sponsored studies. Studies sponsored by manufacturers of newer antidepressants favoured these drugs more than did non-industry-sponsored studies. Among industry-sponsored studies, modelling studies favoured the sponsor's drug more than did administrative studies. Industry-sponsored modelling studies were more favourable to industry than were non-industry-sponsored ones. Pharmacoeconomic studies of antidepressants reveal clear associations of study sponsorship with quantitative outcome.

Conflict of interest in industry-sponsored economic evaluations: real or imagined?

As industry sponsorship of pharmacoeconomic studies has increased, concerns have been raised about potential biases, owing to the conflicts of interest that this sponsorship creates. A review of the literature indicates that there are some causes for concern, given the fact that most pharmacoeconomic studies report positive findings for the sponsor's drug. However, a more detailed analysis suggests that, although the methodologic quality of some published studies may be poor, the main reason for positive results is that companies only sponsor economic studies where a positive outcome is likely. Therefore, it is concluded that the best way of dealing with perceptions of sponsorship bias is not increased rhetoric, but rather increased public funding for economic evaluation of medicines, thereby creating a true mixed economy for research funding in this field.

Physicians and the Pharmaceutical Industry: Is a Gift Ever Just a Gift?

ContextControversy exists over the fact that physicians have regular contact with the pharmaceutical industry and its sales representatives, who spend a large sum of money each year promoting to them by way of gifts, free meals, travel subsidies, sponsored teachings, and symposia.ObjectiveTo identify the extent of and attitudes toward the relationship between physicians and the pharmaceutical industry and its representatives and its impact on the knowledge, attitudes, and behavior of physicians.Data SourcesA MEDLINE search was conducted for English-language articles published from 1994 to present, with review of reference lists from retrieved articles; in addition, an Internet database was searched and 5 key informants were interviewed.Study SelectionA total of 538 studies that provided data on any of the study questions were targeted for retrieval, 29 of which were included in the analysis.Data ExtractionData were extracted by 1 author. Articles using an analytic design were considered to be of higher methodological quality.Data SynthesisPhysician interactions with pharmaceutical representatives were generally endorsed, began in medical school, and continued at a rate of about 4 times per month. Meetings with pharmaceutical representatives were associated with requests by physicians for adding the drugs to the hospital formulary and changes in prescribing practice. Drug company–sponsored continuing medical education (CME) preferentially highlighted the sponsor's drug(s) compared with other CME programs. Attending sponsored CME events and accepting funding for travel or lodging for educational symposia were associated with increased prescription rates of the sponsor's medication. Attending presentations given by pharmaceutical representative speakers was also associated with nonrational prescribing.ConclusionThe present extent of physician-industry interactions appears to affect prescribing and professional behavior and should be further addressed at the level of policy and education.

Physicians and the Pharmaceutical Industry

Controversy exists over the fact that physicians have regular contact with the pharmaceutical industry and its sales representatives, who spend a large sum of money each year promoting to them by way of gifts, free meals, travel subsidies, sponsored teachings, and symposia. To identify the extent of and attitudes toward the relationship between physicians and the pharmaceutical industry and its representatives and its impact on the knowledge, attitudes, and behavior of physicians. A MEDLINE search was conducted for English-language articles published from 1994 to present, with review of reference lists from retrieved articles; in addition, an Internet database was searched and 5 key informants were interviewed. A total of 538 studies that provided data on any of the study questions were targeted for retrieval, 29 of which were included in the analysis. Data were extracted by 1 author. Articles using an analytic design were considered to be of higher methodological quality. Physician interactions with pharmaceutical representatives were generally endorsed, began in medical school, and continued at a rate of about 4 times per month. Meetings with pharmaceutical representatives were associated with requests by physicians for adding the drugs to the hospital formulary and changes in prescribing practice. Drug company-sponsored continuing medical education (CME) preferentially highlighted the sponsor's drug(s) compared with other CME programs. Attending sponsored CME events and accepting funding for travel or lodging for educational symposia were associated with increased prescription rates of the sponsor's medication. Attending presentations given by pharmaceutical representative speakers was also associated with nonrational prescribing. The present extent of physician-industry interactions appears to affect prescribing and professional behavior and should be further addressed at the level of policy and education.