Toward protecting the safety of participants in clinical trials

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Abstract

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

Introduction

Protecting the rights, interests and safety of participants in research is an ethical mandate. Although risk is inevitable in clinical research, it is essential that this risk is minimized and that any unanticipated harm be rapidly detected and contained. Recent reports of deaths of research participants and deficiencies in the monitoring of clinical trials at major institutions have led to a widely held belief that the current system of oversight of clinical research, including the means of assessing risks and minimizing harm to participants in clinical trials, could be considerably improved [1], [2], [3]. Current systems for safety monitoring include Research Ethics Review Boards (RERBs; a term used to encompass groups such as Institutional Review Boards [IRBs], Research Ethics Boards and Institutional Ethics Committees [IECs]), Data and Safety Monitoring Boards or Data Monitoring Committees (DMCs), clinical investigators and their research staffs, clinical research sites, sponsors and regulators. In theory, the activities of all these groups should be integrated to avoid duplication of efforts and inefficiency. An ideal system would be one in which careful study of adverse events (AEs), with input from each group commensurate with its role, would lead to a reduction in harms and risks without creating unnecessary consternation and possibly inappropriate responses to individual AEs. We do not believe that the current system lacks the necessary parts, but rather, has inefficiency, duplication of effort, overemphasis on the monitoring ability of some groups such as RERBs or investigators, underemphasis on others such as DMCs and sponsors and confusion about responsibilities for safety that may overburden those responsible for protecting participants in clinical trials. Also, where there may be excessive duplication of effort for large, multicenter studies, there may be inadequate safeguards in place for small, single-institution studies that have resulted in some of the most high-profile lapses of participant safety, such as the Gelsinger, hexamethonium and melanoma vaccine cases [4], [5], [6]. An ideal system would be plastic enough to use the functions of each monitoring group in different ways for research studies performed in different venues. An ideal system would also allow the collection of data that would clarify how to better integrate the groups with trial-monitoring responsibilities.

In this paper, we address what we believe to be an increasingly apparent problem. Attempts to intensify the monitoring responsibilities of each group as a way to address particular problems in clinical trials have removed focus from the bigger issue of creating a system of research protections that can reliably identify, and react quickly and appropriately to, instances of harm to participants. No single group can adequately protect participants' safety, and the many groups charged with monitoring safety are not sufficiently integrated to provide adequate protection. In this commentary, we discuss the limitations of each oversight group's ability to ensure the safety of trial participants. We also examine how problems with the interactions among these groups during the course of research further weaken the possibility of optimally protecting participants. We conclude with recommendations for improving the current system (Table 1).

Although this article discusses the issues primarily from a U.S. perspective, the implications are applicable elsewhere. Attempts to harmonize AE reporting across the European Union with the European Directive on Clinical Trials certainly represents a reasonable first step, but it will remain to be seen whether this reduces inefficiency [7].

Section snippets

Research ethics review boards

RERBs are empowered to protect trial participants by reviewing initial research plans and providing continuing review of approved research [8], [9]. Three to four decades ago, when the structure and function of RERBs were first being codified, an individual, local RERB was expected to review the protocol and its informed-consent document and make an initial judgment about the potential risks relative to the potential benefits of the proposed study and the appropriateness of communications about

Data monitoring committees

The DMC was developed as an independent means of examining objectively the accruing data for indications of harm (from adverse effects from the therapy being tested, from being treated with a clearly inferior therapy or from participating in a study with no hope of a positive result) as well as benefit (evidence that an intervention being evaluated is clearly beneficial) [17], [18]. Typically, a DMC focuses on the total safety experience in a trial and not on individual AE reports. As

Sponsors

Sponsors have substantial responsibility for protecting the safety of participants in clinical research [22]. A sponsor is one who takes responsibility for and typically initiates a clinical research study [23]. We consider a sponsor to be any entity that funds the research, including the medical-products (pharmaceutical and medical devices) industry, foundations, governmental agencies and, for “unfunded,” single-site studies, the institution conducting the research study. At the outset of

Clinical investigators and their staffs

In multicenter trials, participant safety is best served by clinical investigators and their staffs who have a systematic approach to collecting and reporting study data and are attentive to details of study conduct such as strict adherence to inclusion and exclusion criteria and stopping rules, accuracy in collecting and recording data, expeditiously reporting AEs to RERBs and study sponsors and obtaining valid informed consent. Single-center studies also require the investigator to maintain

Clinical research sites

The clinical site is the place to make fundamental observations critical to ensuring participants' safety. The clinical site includes various entities that participate in the clinical trial beyond the clinical investigator and study coordinator; these include local scientific reviewers, pharmacy staff and grants and contracts personnel. Ideally, each clinical site that conducts clinical research has a detailed set of standard operating procedures that promote adherence to the specifics of how

Regulators

Regulators are responsible for ensuring that (1) products that come to market are safe and effective (in the United States, this is the purview of the FDA through the Food, Drug, and Cosmetic Act) and (2) the human participants in the research have been protected in the conduct of the trials necessary to achieve these goals [8], [9], [31]. Ideally, there would be agreement among the various national regulatory agencies and consistency in international policy.

Despite these important roles, the

Recommendations

Having described some of the limitations in the current system, we offer the following recommendations to enhance safety in clinical studies. To achieve a congruent and effective system with adequate protection of human research participants, the design of each study must be sound, the blueprint for it must be followed, and a system must be in place combining expertise and processes that can detect when deviations from the plan are needed. Neither thorough understanding of study design and data

Acknowledgments

The Duke Clinical Research Institute provided financial support for the meeting that led to work on this paper, with unrestricted educational donations from AstraZeneca, Boehringer-Ingelheim Canada Ltd., Eli Lilly and Company, Key Pharmaceuticals, King Pharmaceuticals, Inc., Medco Research, Pfizer Central Research and Rhone-Poulenc Rorer. The opinions and recommendations in this article are those of the authors and may not necessarily reflect the views of members of the Duke Working Group on

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