Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer's Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?

BACKGROUND: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence." CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.

The managed-care perspective for improving quality.

The role of managed-care organizations (MCOs) is to determine the existence of a benefit and how it is to be covered. Clinical guidelines and evidence-based medicine are critical parts of those decisions, and help drive much of the medical policies of MCOs. The goal is to identify and support medically appropriate and cost-effective interventions, and not cover treatments that do not have those characteristics. This will become increasingly important as more payers move to defined contribution plans, which place added responsibility for care decisions on the medical care consumer. Improving quality, creating consistency, and establishing the credibility of MCOs and their guidelines are imperative for integrating evidence-based medicine into coverage decisions. The ultimate outcome sought by MCOs and payers is improvement of the health of the populations they serve.

The next stage of managed care.

Since the turn of the century, we have gone from medicine as a cottage industry, based largely on barter, to the complex entity it is today. What we will see in the coming decade, if not sooner is the emergence of the next level of managed care. As managed care matures, contradictions in the health care system that we have not been able to resolve will be addressed, as well as other value-related issues. The ability to deliver value and then to monitor outcomes will be the nut to crack. The next big movement will be to hone in on outcomes and measurement. This will be the path to increasing the inherent value of the medical care system. This will go hana in hand with accountability, which is where physician-sponsored networks (PSNs) will be an indispensable tool. Centered as they are around accountability and responsibility, PSNs will be a natural starting point for developing the protocols to produce and collect this data. The standardization of care, anchored upon medical evidence, is the objective.

Managing organ transplant issues. A guide for approaching controversial, high tech procedures.

With the increase in the requests for high intensity medical procedures such as organ transplantation, the physician executive often is placed in the middle between competing interests. Whether he or she represents the provider or payer side, there is frequently great pressure to make decisions involving complex medical situations in short time-frames. It is necessary to have in place a fair, consistent approach to handling such issues in order to withstand both medical and ethical scrutiny. A process is detailed that will lead the organization to developing such an approach. Although presented in the context of transplant issues, this process can be applied to any similar high technology procedure.

Managed care matures. What's behind the wave of anti-HMO legislation?

At first glance, it may appear as if managed care itself may be doomed. The avalanche of bills, measures, initiatives, Federal regulations, etc., seemed overwhelming in late 1996. Did this, in fact, portend a national shift away from managed care? What does the consumer protection and regulatory activity really mean? What directions for the future can be identified? This article seeks to answer those questions and highlights a case study of "reform gone awry" that may hold lessons for the national scene. The anti-HMO legislation activity does not represent a repudiation of managed care. Rather, it may be seen as a maturing of the entire process of redefining our medical delivery and financing system.

Hospital-sponsored networks. The rush to consolidate and the future of medical practice.

As the medical delivery system undergoes fundamental change, there is a growing pressure on hospitals to form networks with physicians. The prime motivation for these entities is to preserve market share and fill beds. There is likewise intense pressure on physicians to join them, even if these networks do not serve their best interests, or the goal of fostering physician-centered practice. A transformation is under way, however, that may well place doctors again in the central role of guiding the new modes of medical practice in the United States.

Removal rates of subdermal levonorgestrel implants.

This study attempted to quantify an achievable removal rate of subdermal levonorgestrel implants (SLIs) in an unselected population and develop strategies for increasing continuation. Over 16 months, 1,076 SLIs were inserted in eligible patients from a lower socioeconomic group at high risk for unintended pregnancy. Extensive preinsertion and postinsertion counseling and follow-up care were given. Patients developing problems were counseled and managed conservatively. If a patient requested removal of the Norplant after this process, removal was done. Twenty-two removals occurred due to SLI-related problems, for a rate of 2.04%; no trends based on age or parity were found. The most common reasons for removal were bleeding/irregular menses (31.8%), headaches (18.1%) and hair loss (13.6%). An episode of thrombophlebitis, not thought to be caused by the SLI, led to one removal. Seventy-seven percent of removals occurred in the first six months, with peak rates in the fourth and fifth. Five patients became pregnant inadvertently within six months of removal. An extremely low removal rate and high continuation rate are possible in an inner city clinic population at risk for unintended pregnancy. Acceptance will increase if the SLI can be maintained at least past six months. Extensive counseling, patient support and conservative medical management constitute a successful approach.

Late registration for prenatal care in a high-risk population.

Late registration for prenatal care prevents many of the benefits of regular care from accruing to mother and fetus. For a high-risk, indigent population, this deficit becomes additionally important. We surveyed all patients presenting for care after 15 weeks gestation to elicit specific reasons for late registration, in an attempt to improve quality of care.

Strategies for avoiding episiotomies.

Changing trends in obstetrics have case serious doubt on the value of episiotomy. It may often be far more harmful than beneficial. This viewpoint is discussed and various methods for avoiding episiotomy in many situations are presented.

Vaginal birth after cesarean section. Experience in a community-based practice.

The option of vaginal birth after a previous cesarean section (VBAC) is widely recognized as a safe procedure for mother and infant as well as a means of reducing the cesarean section rate. Nevertheless, it remains underutilized in community, non-level III hospitals, where most births occur. Over a 30-month period, all patients presenting to a community-based practice who met the criteria for VBAC as outlined by the American College of Obstetricians and Gynecologists were offered this option. Of 72 candidates, 66 chose a trial of labor; only 4 failed to deliver vaginally. No complications were noted in any of the women or infants. This study demonstrated that in a community setting, VBACs are safe and can yield a high success rate.

Vaginal birth after cesarean section in an HMO.

Despite a large body of evidence that vaginal birth after a previous cesarean section (VBAC) is safe, acceptance of the procedure in the community has been slow. This is in spite of the spiraling cesarean section rate and the strong endorsement of the American College of Obstetricians and Gynecologists (ACOG). Over a 30-month period, all patients presenting to a staff model HMO practice who met the ACOG criteria for VBAC were offered this option. Of 72 candidates, 66 attempted a trial of labor; only four required a repeat cesarean section. No complications were noted in any of the patients or infants. VBAC is a safe procedure, appropriate for a community-based practice, and can yield a high success rate. The implications for HMO obstetric policy are discussed.