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Research practices and ethics
FDA regulations allow clinical investigators a great deal of latitude
 Research in human subjects is governed by FDA regulations that are written almost exclusively for the purpose of ensuring patient safety. According to the Code of Federal Regulations (21 CFR 312.60), “an investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation.” Specifically, the regulations dictate procedures for creating informed consent documents, keeping records, reporting adverse events, ensuring investigational board review, and handling investigational substances.
At first glance, all aspects of research conduct would appear to be governed. However, this is not actually the case as there are several legal vagaries that allow physicians tremendous freedom in which to conduct their trials. The existence of these “gray areas”, of course, affords physicians the latitude to treat patients without limiting their health care options. However, they also force physicians to make critical decisions in trials for which they are often well paid to recruit and retain patients.
Research coordinators and subinvestigators
The principal investigator (PI) is charged with either conducting research trials or supervising those who do. In reality, few physicians run their own studies. Instead, they hire coordinators to screen patients, conduct rudimentary procedures, dispense study medications, perform selected patient assessments, collect medical histories, and record adverse events. The regulations do not require that coordinators have any specific training or expertise; they do not have to be nurses or even college graduates. Therefore, the extent to which study procedures are delegated and the level of experience, training, and education of those to whom the tasks are delegated are left to the discretion of the PI.
In addition to coordinators, investigators frequently designate subinvestigators. Most often, “subs” are physicians or, in the case of teaching hospitals, medical residents (although there is no requirement that they have specific training or expertise). These individuals are ap pointed to act as the PI’s surrogates, and they work with the coordinators just as the PI would. Patients commonly assigned to physicians serving as subs rarely have any contact with the principal researcher. Of course, the requirement that PIs supervise those working on clinical trials remains, but there is no regulatory definition for what constitutes supervision. Thus, investigators have little regulatory guidance and must therefore be cautious in choosing, training, and supervising subs and in delegating responsibilities to them. These decisions can directly affect patient care; they are not just administrative or financial choices, but, in fact, ethical considerations.
Patient selection
Each study protocol begins with a comprehensive list of inclusion and exclusion requirements that define the patient population appropriate for study participation. As an example, the inclusion requirements for a hypothetical migraine study could be adults 18 and over who are able to give consent, have not received prescription migraine medication for at least 30 days prior to entry, and present moderate to severe headaches at least four days each week. Excluded patients for this same trial might be people with known allergies to certain medications, women who are pregnant, lactating, or of childbearing age (unless they are using acceptable birth control methods), and patients with clinically significant, abnormal laboratory values.
Initially, these criteria seem quite specific. In fact, there are several gray areas illustrated by this example. For example, to meet these entry requirements, investigators must accept a patient’s medical history as fact (unless charts and other documents are available for verification), determine what constitutes acceptable birth control and trust that the appropriate patients are actively using that method, define what qualifies as a moderate or severe headache, and address whether or not a patient actually has such an affliction. Beyond these concerns, researchers must also define “clinically significant”, abnormal laboratory values. Of course, determining significance should be based on a combination of the specific test result, the patient’s history and medical condition, and the physician’s clinical experience. However, external pressures to enroll patients rapidly can cloud these assessment issues. A worst-case result, then, would be the inclusion of patients who should not otherwise be considered for study enrollment. Therefore, physicians must be cautious and diligent in their medical review and screening practices.
One final concern regarding patient selection involves the “revolving door” of clinical trials. There is no regulation that limits the number of trials patients may participate in, nor is there even a formal requirement of a “washout” period between studies. As a result, some investigators shepherd their patients from one study to the next, often enrolling them in back-to-back trials for years. Although this practice certainly provides researchers with a steady pool of patients, it is rarely in the participant’s best interests, and physicians should endeavor to avoid it.
Adverse event reporting
The Code of Federal Regulations specifies that adverse drug experiences during the course of an investigational trial must be collected and, at some time, reported to the sponsor. For the case of “serious” adverse experiences, however, the regulations state that the events must be reported immediately. Adverse events (AEs) are not specifically defined, but serious adverse events (SAEs) are, and include any event during a trial that results in a life-threatening situation, an inpatient hospitalization, the need for surgical treatment, a persistent disability, a birth defect, or death. In practice, this means, for example, that an active research subject who slips on an ice patch, breaks a hip, and is subsequently hospitalized, has suffered an SAE. That there is no relation between the broken hip and the study drug is irrelevant; all serious events must be reported regardless of causation.
Thus, the gray area of AE reporting involves less serious treatment events. Coordinators and investigators, in fact, are notorious for omitting patient experiences that they think are either unimportant or unrelated to the trial at hand. Occasionally, it can even be the case that patients are led astray by queries concerning ailments they may not have. (For example, patients who claim no AEs during the course of a trial might reconsider when specifically asked about occasional headaches.) Therefore, it is possible that events could be inaccurately recorded, overlooked, or underreported. As a result, the predominance of certain adverse experiences might escape a sponsor’s notice until the point at which the health of participants becomes endangered.
Investigator payments
The FDA says little about the extent to which sponsors may pay their researchers. From a regulatory standpoint, minimal bias is presumed as long as investigators either disclose or have no financial stake in the outcome of an investigational product. The FDA further assumes that in Phase III and IV trials, when it is rare that a single investigator could direct the final outcome of a trial, the potential for bias is even lower. Although this is mostly true, it doesn’t address the fact that research fees are paid on the basis of the number of patients recruited, retained, and treated. Further, it does not address the pressures pharmaceutical companies place on researchers to produce clinical data quickly, and it certainly cannot address whether investigators allocate a portion of their research dollars to hiring and training employees. Thus, the monies inherent in research can color a physician’s view of a clinical trial, promote sloppiness in data collection, and impact patient care.
The ethical choices
The ultimate question for clinical researchers thus boils down to one of how best to juggle various powerful interests: patients’ health care needs, FDA regulations, study protocol requirements, and financial and professional pressures imposed by sponsoring agencies. The purpose of this article is to highlight many of the areas in which study protocols and governmental regulations fail to guide investigators. Most researchers are ethical and approach studies with the best interests of their patients at heart. Few would argue for further restrictions, and most appreciate the extent of regulatory latitude that exists. However, with these freedoms come crucial decisions that PIs must address both pragmatically and ethically. Obviously, the need to hire skilled people and provide them with sufficient training and oversight to ensure a patient’s welfare is of extreme importance. Doing this, however, requires significant investments of time, money, and patience. The benefits, though, pay off in the quality of data collected from, and the patient care provided by, a particular site. So, if physicians make appropriate, ethical choices and responsibly delegate their research-related duties, everyone wins: the physicians, the pharmaceutical companies, and most importantly, the patients.
Cullen T. Vogelson is an assistant editor of Modern Drug Discovery. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.
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