Comments on Medical Research and the Publication of Scientific Papers

The unfortunate death of a healthy volunteer in a research project at the Johns Hopkins University Medical Center a few months ago highlights several features of modern research that deserve discussion.

The project in question involved physiologic mechanisms in asthma. The drug under study was hexamethonium, a ganglion blocker that had been extensively studied in the early 1950s by several investigators. ¹ , ² , ³ , ⁴ It is a potent sympathetic and parasympathetic blocking agent, which was used in the treatment of peripheral vascular disease and hypertension. It is no longer on the market. Several cases of interstitial pneumonitis had been reported following its use. The Hopkins investigators, presumably depending on Internet research, apparently failed to uncover the reports of pulmonary side effects of this agent, since these had appeared in the literature in 1950–1955, prior to the usual cut‐off date for Internet data recovery. When their first patient developed symptoms of lung disease, it was attributed to an upper respiratory infection, or the “vehicle” used for inhalation of the drug. Had the more distant data from the early 1950s been available, it is conceivable that the investigators might have stopped the study instead of modifying the drug delivery system and continuing the trial.

This incident highlights one of the problems of present‐day research efforts. There may be too much dependence on the Internet, on MEDLINE, and on other computer databases. Computer‐based research has, of course, proved extremely valuable, and often has uncovered data that may not have been found with a non‐Internet‐based search. However, there may be a down side. The use of libraries in most hospitals and in many medical centers is decreasing; and there is less and less chance of finding results of research that may have been carried out prior to the late 1950s and early 1960s. Importantly, there may be less opportunity for “chance” findings or “serendipitous” discovery. This is one of several problems facing the clinical research community.

The type of “mechanism” research that the Hopkins investigators were pursuing must not be discouraged. It is basic to our understanding of disease processes, but more diligence in searching the literature is clearly indicated.

HOW DO WE DEFINE CLINICAL RESEARCH?

The definition of clinical research has undergone a major change. Years ago, a new drug or treatment was studied by physicians who were usually experts in their field. If, in the course of the study, a specific effect was noted, the physician was able to change direction and pursue another line of inquiry. This was clearly illustrated by the study of chlorothiazide, the first effective oral thiazide diuretic. This agent was originally studied in heart failure. It was quite evident from early observations that the medication was a potent antihypertensive agent, ⁵ , ⁶ and the research emphasis was changed. Today, collection of data on the blood pressure‐lowering effects of this drug would have been delayed. Current clinical research is strictly protocol‐driven, carefully designed and conducted, with specific objectives. Deviation from the initial protocol is discouraged and often leads to elimination of a group from the trial. Patients or investigators may be “dropped” from the study if, for example, a patient misses several doses of the medication or paperwork is not meticulously completed. Perhaps this is necessary because of the large number of physicians currently involved in “clinical research” in their private practices or as part of a consortium of investigators. Often, these physicians are not experts in the diseases being studied.

Protocols are often necessary to ensure that physicians or researchers will abide by certain guidelines and rules. This is especially true in large‐scale studies involving many physicians over several years. Many of these trials have been important in deciding on courses of therapy. In fact, many of the international studies involving thousands of patients could not have been undertaken and finished without a specific protocol. But imagination, intuition, and judgment are being utilized far too infrequently in modern clinical medical research.

The research in clinical centers that are involved in protocol research are often directed by personnel other than the designated investigator. Physicians in charge pay some attention, but often on a part‐time basis. When the studies are finished, data are usually compiled by the study sponsor. Far too often, research papers are written by a science writer under contract. Many physicians, even the principal investigators in a trial, are too busy preparing for the next study to write their own reports of the research results.

THE PROBLEM OF WHO WRITES THE PAPERS

Increasingly troublesome problems relate to this activity. Editors of scientific journals are having a harder time determining which submitted papers are written by science writers and signed off by prominent “experts,” and which papers are actually written by the physicians involved in the research effort. This has become an important issue in the hypertension and cardiovascular literature. Science writers often do a good job, but may have a clear conflict of interest. Until recently, there has been no disclosure of this specific type of activity.

The Journal of Clinical Hypertension has a policy of being particularly careful in reviewing papers that may have been submitted by an “agency,” but it may be time for another type of disclosure—time for the medical community to insist that if a paper is written primarily by a science writer, this should be disclosed. There is nothing wrong in having a statistician review data or having someone other than the investigator summarize the demographics of a trial population. However, far too many “opinion leaders” are submitting papers that are clearly not written by them. In many cases, they are being paid to do this. Again, there may be nothing wrong with a physician receiving a grant to summarize research, as long as the paper is written by the scientist and presents a fair and balanced summary, but readers and journal editors should know about it.

Many journals now insist on a listing of possible conflicts of interest—consultancies, speakers' bureaus, research grants, and so forth are all listed. A statement that each of the authors had a meaningful role in the collection of data or in the writing of the paper is also requested. Perhaps it is time to go one step further and request full disclosure not only of the involvement of each investigator in the study but also of any payments or grants involved in a specific report and, importantly, whether or not a contract writer contributed substantially to the final document. The judgment regarding acceptance or rejection of the paper would then be made with full knowledge of the source.

PUBLICATION OF NEGATIVE DATA—ANOTHER DILEMMA

Another problem with modern‐day clinical research relates to trials that do not turn out the way the sponsors had intended. Somehow, negative trial data must also find its way into the literature. At present, many of these studies are buried, either because of contractual relationships with sponsors or lack of interest in reporting them. For example, publication of recent data on the effects of garlic on cholesterol and blood pressure was delayed for more than 6 months by the sponsor because of negative results. ⁷ This paper was published only after the persistence and insistence of the authors. The report of a comparative study of a calcium channel blocker and diuretic was delayed for months and revised many times because the results indicated advantages of the diuretic over the calcium channel blocker in the management of hypertension. ⁸ Efforts should be made to report results even if they do not indicate that a newer medication, procedure, or treatment is better than an older one.

The Johns Hopkins group was investigating mechanisms, an important aspect of medical research. This should be encouraged. The Hopkins incident was unfortunate, but any new approach to disease management presents a risk. We can help to minimize risks if we can somehow supplement computer research with rekindling of the curiosity that was so common years ago when medical students, residents, and researchers would spend hours in the library looking for clues and pathways to follow, rather than sit at a computer and punch in data requests, as many now do. We can improve the quality of medical literature by insisting on full disclosure and reporting of research by researchers rather than by individuals who may have a clear conflict of interest.