Data monitoring committees: Promoting best practices to address emerging challenges.

BACKGROUND AND PURPOSE: Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees' independence and effectiveness. METHODS: An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees. RESULTS AND CONCLUSIONS: Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee's independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

Last-resort options for palliative sedation.

Despite receiving state-of-the-art palliative care, some patients still experience severe suffering toward the end of life. Palliative sedation is a potential way to respond to such suffering, but access is uneven and unpredictable, in part because of confusion about different kinds of sedation. Proportionate palliative sedation (PPS) uses the minimum amount of sedation necessary to relieve refractory physical symptoms at the very end of life. To relieve suffering may require progressive increases in sedation, sometimes to the point of unconsciousness, but consciousness is maintained if possible. Palliative sedation with the intended end point of unconsciousness (PSU) is a more controversial practice that may be considered for much fewer refractory cases. There is more ethical consensus about PPS than PSU. In this article, the authors explore the clinical, ethical, and legal issues associated with these practices. They recommend that palliative care and hospice programs develop clear policies about PPS and PSU, including mechanisms for training and ensuring competency for clinicians, and approaching situations where individuals or institutions may conscientiously object.

Liability issues for data monitoring committee members.

In randomized clinical trials, a data monitoring committee (DMC) is often appointed to review interim data to determine whether there is early convincing evidence of intervention benefit, lack of benefit or harm to study participants. Because DMCs bear serious responsibility for participant safety, their members may be legally liable for their actions. Despite more than three decades of experiences with DMCs, the issues of liability and indemnification have yet to receive appropriate attention from either government or industry sponsors. In industry-sponsored trials, DMC members are usually asked to sign an agreement delineating their responsibilities and operating procedures. While these agreements may include language on indemnification, such language sometimes protects only the sponsor rather than the DMC members. In government-sponsored trials, there has been even less structure, since typically there are no signed agreements regarding DMC activities. This paper discusses these issues and suggests sample language for indemnification agreements to protect DMC members. This type of language should be included in DMC charters and in all consulting agreements signed by DMC members.

Quality of life and end-of-life decisionmaking.

Since 1976, when the New Jersey Supreme Court decided the Karen Ann Quinlan case (In re Quinlan, 355 A.2d 647 (NJ), 1976 cert. denied, 429 US 922, 1976), it has been apparent that the concept of quality of life is fundamental to end-of-life decisionmaking. Yet there has been a great deal of reluctance by courts--which have been the primary engine of lawmaking in end-of-life matters--to use this concept overtly.

Persistence of racial disparities in advance care plan documents among nursing home residents.

This paper analyzes the association between race and the presence of advance care plan documents (living wills, do not resuscitate (DNR) orders, and do not hospitalize (DNH) orders) in nursing home residents. We conducted secondary analysis of publicly available survey data from the 1996 Medical Expenditure Panel Survey-Nursing Home Component, a nationally representative survey of nursing home residents in the United States. There were 3,747 participants in the survey, weighted to represent 1.56 million nursing home residents in the United States. We found that 20% of U.S. nursing home residents in 1996 had documentation of living wills, 48% had DNR orders, and 4% had DNH orders. African Americans are about one-third as likely as Caucasians to have living wills and one-fifth as likely as Caucasians to have DNR orders; Hispanics are about one-third as likely as Caucasians to have DNR orders and just as likely as Caucasians to have living wills. In conclusion, we found that the presence of advance care plans is related to race, even after controlling for health and other demographic factors. These findings call attention to an area where further research is needed to determine whether residents' (and their families') preferences are being elicited and documented.

A retrospective on Cruzan.

In 1990, the United States Supreme Court issued a decision in the Cruzan case, the first "right-to-die case" to reach that Court. Prior to the Court's decision, there was wide-spread speculation as to what it would decide and what the impact of the decision would be. Speculation about the impact of the decision intensified after it was announced, with many suggesting that it would prove to be a serious setback to the consensus about the legality of terminating life-sustaining medical treatment that had evolved in the state courts since the Karen Quinlan case ushered in the era of right-to-die litigation in 1976. This article examines a number of aspects of the legal consensus about forgoing life-sustaining treatment that emerged prior to Cruzan and discusses their viability in light both of what Cruzan did and did not decide and in light of subsequent judicial decisions in right-to-die cases. Two years after the Supreme Court's decision, it is apparent that the pre-Cruzan legal consensus is stronger than ever.