The Publication of Commercially Supported Supplements Statement

In Response: We have no disagreement with the basic principles that underlie the comments of Cullen and of Hornbein et al., but we strongly disagree with the accusation that we have violated these principles in the Phase IV supplement. In fact, we will demonstrate that the principles they espouse--about authorship and responsibility, the quality and value of the information published, and the balance between scientific integrity and marketing goals--were strictly adhered to in the supplement. Consider first the issue of authorship and responsibility. Authors are responsible for the quality, validity, and scientific integrity of what appears under their names. Authorship should confer credit, denote responsibility for research, and reflect actual contributions to the work [1]. The letter writers question the appropriateness of credit in this instance and argue that it would be impossible for us to assume responsibility. They are wrong on both counts. We had little to do with the data collection or design of the original marketing study, but our efforts to explore the value of the information once obtained were thorough and performed without bias. A similar condition exists in every meta-analysis, for authors generally have not themselves collected the data in the studies they analyze. The database we used and our approach to it is no different from that taken by investigators who use Medicare claims data for outcome analysis, hospital admissions data, cancer registry data, and survey results regarding use of health care resources from commercial and governmental agencies. Were editors to follow the advice of Hornbein et al., such valuable contributions as meta-analysis, economic analysis, most case-controlled studies, and all retrospective epidemiologic studies would have to be dismissed. Concerning authorship, Rennie has argued elsewhere that a manuscript's list of authors should not contain "guests" who did not participate in the fundamental work of a paper or omit "ghosts" who have done the bulk of the writing or another aspect of the research [2]. We agree, and a more detailed description of our methods and purpose should make clear that authorship of papers in the symposium was consistent with this principle. (The longer description of our methods was removed in the peer review process.) The initial design of our study was devised by Roizen, Apfelbaum, Grasela, and Thisted with the assistance of the other investigators. The question of greatest interest to us was this: How much (if anything) could be learned from an existing database collected primarily for marketing and not for clinical research purposes? The investigators were chosen by Roizen in private consultation with members of the Food and Drug Administration Center for Drug Evaluation and Research and its Epidemiology Section. All authors participated in subsequent planning and data analysis sessions. Our group began by listing research questions that we wanted to have answered from the information collected. After that planning session, we critically examined each question to determine whether the data set could in principle address the question. When the answer was affirmative for a question, we examined the strengths and weaknesses of the data set in this context. Many of these discussion and analysis sessions were electronic conferences between the investigators. After settling on the major questions, which became the individual papers in the supplement, we split into working groups on each topic. The working groups then reported to the planning group as a whole in a day-long session when an outline for each project was established. After this meeting, the data were analyzed and disseminated to the participants. At another meeting, we again divided into working groups, with one person in each group designated to prepare the first draft of the manuscript, which was subjected to the other investigators' review. The reviewed drafts were then polished and revised by the first author for circulation to all participants. Every manuscript was reviewed by every author, and most authors made substantive suggestions, emendations, and corrections at this stage. In short, we each took responsibility for the contents of each submission. With regard to purpose, our intention was not to study propofol or promote it, and it is disconcerting to learn that careful readers of our work have arrived at such an erroneous conclusion. We feel compelled to note that none of the papers in the supplement purports to show any therapeutic, economic, or other advantage for propofol over any other anesthetic drugs or techniques. Most of the papers have little to do with propofol, but instead investigate participants in Phase IV studies (nurses, physicians, patients) and their behavior (selecting patients, diligence in completing data records, attention to adverse events). Our intent was to explore the particular limits of these data as collected to determine whether their limitations could have been remedied by better design. The subject of the supplement was not the marketing of a specific pharmaceutical agent, but rather what constitutes a good Phase IV study. The propofol database, with information from one of the largest Phase IV studies, served only as a "case study." Although the results of our scrutiny underwent peer review, we did not aim for the "comprehensive perspective of a critical review article" but for the perspective of health services research. We examined the data collection processes in a typical Phase IV study to see whether such studies--which rarely yield useful data--could be redesigned or the resources redeployed to produce findings more useful to scientists, clinicians, and patients. The reason for publishing the tests of different hypotheses in one symposium issue was to influence readers to conclude, as we did, that valuable (and limited) resources could be better allocated in future Phase IV studies by using a different study design. Proof of the value of this aggregation of studies is that the supplement has already generated an important result. Two pharmaceutical firms have told us that they redesigned their plans for Phase IV studies after reading our findings. Another two pharmaceutical firms have asked anesthesiologists knowledgeable in study design to work prospectively in the design (or redesign) of their Phase IV studies. The influence of these papers on clinical research capital has reached far beyond our hope. Finally, we cannot agree with the analogy that we have, in writing the articles for the supplement, mixed "church and state," thereby making "church" less credible. It is possible for church and state to coexist with mutual cooperation and for the state to ensure the church's freedom of expression. In this instance, a review of a project fostered by the "state" (a pharmaceutical company's Phase IV study) has advanced one work of the "church" (more meaningful science) through discovery of a better plan for Phase IV studies. Michael F. Roizen, MD Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637 Jeffrey L. Apfelbaum, MD Thaddeus H. Grasela, PharmD Carl C. Hug, Jr., MD, PhD Charles H. McLeskey, MD Michael L. Nahrwold, MD Theodore H. Stanley, MD Ronald A. Thisted, PhD Cynthia A. Walawander, MA Paul F. White, MD, PhD, FFARACS

Topic: Health Sciences Research and Education
Subfield: General Health Professions
Field: Health Professions
Domain: Health Sciences