Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: the diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial.

In 1996, the US Food and Drug Administration (FDA) enacted Rule 21 CFR section 50.24, which allows a narrow exception to the requirement for prospective informed consent from human research subjects in clinical trials investigating potentially beneficial therapies for acute, life-threatening conditions. The first clinical trial to be conducted under this rule was sponsored by Baxter Healthcare Corporation and approved by the FDA on November 21, 1996. This large, multicenter, randomized clinical trial was designed to compare the addition of diaspirin cross-linked hemoglobin (DCLHb) with standard care in the initial resuscitation of adults experiencing severe, uncompensated, traumatic hemorrhagic shock. Before the first planned interim analysis of the data, review of fatal adverse events revealed an imbalance in mortality between the 2 treatment groups. The Data Monitoring Committee (DMC) recommended suspension of patient enrollment 24 days later. Additional data collection and analyses confirmed the excess number of deaths in patients treated with DCLHb but failed to reveal the cause of these deaths. The trial was formally terminated after only 112 of the planned 850 patients had been enrolled. We review the events leading up to and the rationale behind the DMC recommendations for suspension of patient enrollment and trial termination. Although the DCLHb trial was unsuccessful in achieving its goals, the monitoring process worked well. Emergency research was facilitated by DMC oversight, and the interests of research subjects were protected by the actions of the DMC.

An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility.

As genetic testing for susceptibility to breast cancer becomes more widespread, alternative methods for educating individuals prior to testing will be needed. Our objective was to compare face-to-face education and counseling by a genetic counselor with education by an interactive computer program, assessing the effects of each on knowledge of breast cancer genetics and intent to undergo genetic testing. We used a randomized, controlled trial. Seventy-two self-referred women with a first-degree relative with breast cancer received outpatient education and counseling at the Clinical Center of the National Institutes of Health (NIH). Twenty-nine received individualized counseling from a genetic counselor (counseling group), 29 received education from an interactive computer program followed by individualized counseling (computer group), and 14 were controls. Both pre- and postintervention assessment of knowledge about breast cancer genetics and intent to undergo genetic testing were measured. The control group participants correctly answered 74% of the knowledge questions; the counselor group, 92%; and the computer group, 96% (P <.0001). Unadjusted mean knowledge scores were significantly higher in the computer group than the counselor group (P =.048), but they were equivalent when adjusted for demographic differences (P = 0.34). Intent to undergo genetic testing was influenced by the interventions: preintervention, a majority in all groups (69%) indicated that they were likely (definitely and most likely) to undergo testing; after either intervention coupled with counseling, only 44% indicated that they were likely to do so (P =.0002; odds ratio = 2.8, 95% CI = 1.7-4.9). We concluded that a computer program can successfully educate patients about breast cancer susceptibility, and, along with genetic counseling, can influence patients' intentions to undergo genetic testing.

Education about genetic testing for breast cancer susceptibility: patient preferences for a computer program or genetic counselor.

The purpose of this study was to describe and compare patient preferences for a genetic counselor or an interactive computer program for various components of genetic education and counseling for breast cancer susceptibility. As part of a randomized intervention study on genetics education and counseling for breast cancer risk, 29 women at moderate risk were educated by both a genetic counselor and an interactive computer program. After both educational interventions, participants completed Likert-style and open-ended questionnaires about what they liked most and least about each intervention, and whether they preferred the counselor or computer for a variety of tasks. Participants were largely satisfied with both the computer program and the genetic counselor. A majority preferred the genetic counselor for addressing their concerns, discussing options and alternatives, being sensitive to emotional concerns, helping to make a decision, being a good listener, assuring understanding, helping to make a good choice, helping to understand genes and breast cancer, telling them what they needed to know, being respectful, setting a relaxed tone, and putting them at ease. However, a majority of the women either preferred the computer program or were neutral about allowing patients to learn at their own pace, helping to avoid embarrassment, making good use of time, explaining genes and breast cancer, and treating the patient as an adult. Qualitative analysis of open-ended questions affirmed that patients valued the personal interactions with the counselors, and liked having their specific questions answered. They liked that the computer was self-paced, informative and private, and could be used without causing embarrassment. We concluded that a computer literate, mostly white group of women at moderate risk for inherited susceptibility to breast cancer preferred interacting with a genetic counselor for personal, individualized components of the genetic counseling process, but accepted or preferred a computer program for being self-paced, private, and informative. By incorporating such a computer program into the genetic education process, it is possible that genetic counselors would be able to spend more time performing the personal, individualized components of genetic counseling.

Ethical issues in research and innovative therapy in children with mood disorders.

Research involving children with mood disorders should generally offer a reasonable prospect of benefit to those involved, unless the risks are minimal. While federal regulations require a prospect of direct benefit, from an ethical perspective indirect benefits, such as the advantages of being in a clinical trial, are relevant. Standard care should not be presumed to be preferable to treatment in the context of a clinical trial, particularly if it has not been evaluated in well designed studies involving groups comparable to the patient. Similarly, active treatments in a controlled trial should not be presumed to be preferable to placebos, particularly in studies involving mood disorders where the placebo effect is more likely to be substantial. Innovative therapy-using approved drugs for unapproved purposes-may be more problematic than research, on theoretical and empirical grounds. Studies with no prospect of direct benefit and more than minimal risk are problematic when the patient is incompetent to provide meaningful consent. Whether or not a controlled trial involving children with mood disorders can be ethically justified depends on several factors, including the validity of standard treatment, the seriousness of the disorder, the likelihood of adverse consequences if treatment is delayed, the burden of the proposed intervention, and value judgments by parents, working collaboratively with a caring physician.

Cystic fibrosis newborn screening: impact on reproductive behavior and implications for genetic counseling.

OBJECTIVE: To evaluate the impact of newborn screening for cystic fibrosis (CF) on the reproductive knowledge and behavior of CF families and to determine if heterozygote detection with the immunoreactive trypsinogen (IRT) method in conjunction with DNA analysis (IRT/DNA) influences knowledge and attitudes about reproduction in false-positive families. METHODS: The Wisconsin CF Neonatal Screening Project investigated 650 340 infants from 1985 to 1994 in a comprehensive randomized controlled trial to study both benefits and risks of newborn screening and to determine if early diagnosis would improve the prognosis of children with CF. Assessments of reproductive knowledge, attitudes, and behaviors of 135 families of children diagnosed as having CF in both the early treatment group and control groups were made 3 months after diagnosis using a questionnaire which was completed by 100 families. The same questionnaire was administered 1 year later to evaluate retention of information. It was completed by 71 families. A follow-up assessment tool was also administered in 1994 and responses obtained from 73 families. Knowledge, attitudes, and behavior among false-positive families were also assessed at the time of the sweat test in 206 families who experienced IRT screening and 109 families tested with the IRT/DNA method. Follow-up assessments were completed 1 year later in 106 IRT families and 63 IRT/DNA families. RESULTS: In families with a CF child, 95% initially understood that there was a 1 in 4 risk in subsequent pregnancies, and there was good retention of this information 1 year later. At the 1994 assessment, 52% of families had not yet conceived more children, but 74% of these already had children. In the couples in whom CF was diagnosed in the first child, 70% (95% confidence interval = 54% to 85%) conceived more children. There were 43 subsequent pregnancies in 31 families. Prenatal diagnosis was used by 26% of the families (8/31) for 21% of the pregnancies (9/43). There were 3 pregnancies with CF detected, all of which were carried to term. In the false-positive groups, >95% of families initially understood that their child definitely did not have CF. There was no difference between false-positive IRT and IRT/DNA groups, and the information was retained at 1 year. Follow-up assessment 1 year after negative sweat tests revealed that 7% of the IRT and 10% of the IRT/DNA families still thought about the results often or constantly. When asked whether the experience of screening affected feelings about having more children, an affirmative response was obtained in 4% of IRT families but in 17% of IRT/DNA families. One year later, more than half of the false-positive IRT/DNA families did not understand that they were at increased risk of having a child with CF. CONCLUSIONS: We conclude that CF neonatal screening does not have a significant impact on the reproductive behavior of most families and that prenatal diagnosis is not used by the majority of CF families. IRT/DNA testing experiences seem to affect attitudes about having more children, and some parents are confused about the implications of the results, even with genetic counseling. However, persistent concerns about the sweat test result are limited. Questions raised by this study confirm the need for more research regarding the process of genetic counseling and its impact on reproductive attitudes and behavior in the newborn screening setting.

Ethical dilemmas in medical innovation and research: distinguishing experimentation from practice.

The words research and experimentation continue to have the power to evoke fear in potential subjects. But much of standard practice, particularly in critical care settings, involves interventions of unknown efficacy and safety. Innovation also abounds in practice settings, typically unchecked by prospective or retrospective review. Historical attention has focused on the conflict of interest of the physician/investigator, but contemporary safeguards have reduced the risks of research and increased the likelihood that the patient/subject will have the opportunity to make an informed choice. Innovation and untested interventions in practice, in contrast, are often unknown to the patient and lack institutional safeguards. Some common cliches that suggest that research is more to be feared than standard practice will be examined, leading to the following conclusions: defining an intervention as experimental may be less important in ethical terms than the quality of prospective and retrospective review and the standards for informed consent, and the concerns that led to regulation of research should now be directed toward unproven interventions and innovation in the practice setting.

Who should provide genetic education prior to gene testing? Computers and other methods for improving patient understanding.

As numerous new gene tests are introduced into clinical practice, patients have a growing need for accurate and comprehensive information about the risks and benefits of gene testing. However, in the changing healthcare environment, it is not clear who will provide such information because genetic counselors are scarce and their services are not widely utilized, and primary care providers lack time and expertise in genetics. Interactive computers may help fill the information gap. We review a variety of educational modalities for providing patient education and argue that interactive computers have potential advantages over other educational methods for providing information and promoting informed consent to genetic testing. Finally, some questions for further research are raised.

An interactive computer program for educating and counseling patients about genetic susceptibility to breast cancer.

Educating individuals who seek information about genetic testing for cancer susceptibility is a complex task. Because of the psychological and social risks to patients of being identified as susceptible to a genetic disorder, it is important that education take place before a patient undergoes gene testing. However, it is not known who will provide such education. Since primary care physicians have limited knowledge, time, and confidence with genetic counseling, they are not ideal educators. Genetic counselors are well trained to provide the service, but many patients lack access to them. Other specialists are scare. Interactive computers hold much promise as a supplemental or alternative modality for education. The authors describe their experience with developing an interactive CD-ROM on gene testing and breast cancer, and respond to anticipated criticisms of this technology.

Informed consent in emergency research. Consensus statement from the Coalition Conference of Acute Resuscitation and Critical Care Researchers.

OBJECTIVE: A coalition conference of acute resuscitation researchers was held to discuss the feasibility of applying current federal research regulations regarding informed consent to the emergency setting. This article presents consensus recommendations for regulatory changes for consent in emergency research. PARTICIPANTS: Representatives from the Society for Academic Emergency Medicine and the American Heart Association identified several professional organizations as stakeholders in this issue, including research, clinical, bioethics, legal, and patient advocacy groups. The Office for Protection From Research Risks (OPRR), the Food And Drug Administration (FDA), and staff from specific legislative offices were also invited to observe. Forty-three participants attended, including representatives from 12 professional organizations, five medical institutions, and the FDA and OPRR. This was a closed meeting. Participants were self-funded or sponsored by their professional organizations. EVIDENCE: Before the meeting, a draft of a position statement was developed by the conference organizers based on the current literature and discussions with experts in the field. This draft, copies of the current federal research regulations, and supporting articles were distributed before the conference. CONSENSUS PROCESS: Participants rotated through moderated discussion sessions to comment on subsections of the draft. Following discussion, a working draft was developed and distributed to each participant and represented organizational board for final review. All comments were considered in the final version of the document. CONCLUSIONS: We believe there are circumstances when it is not feasible to obtain prospective or proxy consent for enrollment into an emergency research protocol. In these circumstances, patients are vulnerable, not only to research risks, but also to being denied potentially beneficial therapy when there is no known effective treatment for their life-threatening condition. We offer recommendations that should be met when the critical nature of the illness or injury or the need to apply an investigational therapy rapidly precludes prospective consent for participation in emergency research.