7
IMPROVING ACCESS TO CARE

The previous chapters in this report focused on mechanisms for expanding access to investigational drugs. This chapter addresses a related but slightly different issue: the role of clinical trials and expanded access programs in improving access to health care for the disenfranchised populations that make up the fastest-growing segment of the AIDS epidemic.

By the end of the 1980s it became clear that the demography of the AIDS epidemic was shifting: the rate of new HIV infections among homosexual and bisexual men in major urban centers appears to have dropped. A comparison of AIDS cases reported to the Centers for Disease Control before 1985 and those reported during the first six months of 1989 shows an 11 percent decrease in the proportion attributed to homosexual behavior. In contrast, the proportion attributed to intravenous drug abuse increased by 28 percent. The largest percentage increase—100 percent—occurred among the heterosexual partners and children of intravenous drug abusers.

The men, women, and children at greatest risk of acquiring HIV infection through intravenous drug abuse are among the most disadvantaged members of society. The socioeconomic factors associated with high rates of drug abuse in minority populations are also associated with high rates of HIV infection. Blacks, who make up only 11.6 percent of the U.S. population, account for 27 percent of adult and 52 percent of pediatric AIDS cases. Hispanics, who represent 6.5 percent of Americans, account for 15 percent of adult and 23 percent of pediatric AIDS cases. More than 70 percent of all women with AIDS are black or Hispanic.

This chapter is based on the presentations of Gerald Friedland, Lawrence S. Brown, Jr., Mark Smith, Deborah Cotton, Philip Pizzo, and Harvey Makadon.



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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary 7 IMPROVING ACCESS TO CARE The previous chapters in this report focused on mechanisms for expanding access to investigational drugs. This chapter addresses a related but slightly different issue: the role of clinical trials and expanded access programs in improving access to health care for the disenfranchised populations that make up the fastest-growing segment of the AIDS epidemic. By the end of the 1980s it became clear that the demography of the AIDS epidemic was shifting: the rate of new HIV infections among homosexual and bisexual men in major urban centers appears to have dropped. A comparison of AIDS cases reported to the Centers for Disease Control before 1985 and those reported during the first six months of 1989 shows an 11 percent decrease in the proportion attributed to homosexual behavior. In contrast, the proportion attributed to intravenous drug abuse increased by 28 percent. The largest percentage increase—100 percent—occurred among the heterosexual partners and children of intravenous drug abusers. The men, women, and children at greatest risk of acquiring HIV infection through intravenous drug abuse are among the most disadvantaged members of society. The socioeconomic factors associated with high rates of drug abuse in minority populations are also associated with high rates of HIV infection. Blacks, who make up only 11.6 percent of the U.S. population, account for 27 percent of adult and 52 percent of pediatric AIDS cases. Hispanics, who represent 6.5 percent of Americans, account for 15 percent of adult and 23 percent of pediatric AIDS cases. More than 70 percent of all women with AIDS are black or Hispanic. This chapter is based on the presentations of Gerald Friedland, Lawrence S. Brown, Jr., Mark Smith, Deborah Cotton, Philip Pizzo, and Harvey Makadon.

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary Very few of these patients have a regular relationship with a health care provider; as a result, they often lack access to the life-prolonging drugs and services that have become the mainstay of treatment for HIV infection. Some advocates argue that clinical trials and expanded access protocols could be a major avenue for bringing state-of-the-art medical care to this population. (In the past, white males have predominated in almost all clinical trials.) They suggest that including these patients in drug trials would meet several goals: (1) improved medical care for a population that traditionally has been underserved; (2) a more equitable distribution of health care resources; and (3) collection of vital scientific information about the ways in which people of different backgrounds respond to specific investigational drugs. Other scientists, some with a great deal of experience in providing care to AIDS patients, say that it is not realistic to expect clinical trials or other drug protocols to solve the problem of access to health care. They, too, would like to accomplish the above goals but believe that economic, ethical, and social barriers limit what can be accomplished through drug research. In fact, some health care providers are concerned that parallel track and other expanded access mechanisms will actually widen the gap in access to medical care between wealthy and indigent populations. Patients who have private physicians with the time and resources to fill out data forms and comply with other requirements of the parallel track will have access to new drugs at the earliest possible moment; patients who do not have primary care providers or who must depend on the overworked staffs of large inner-city hospitals, and those without insurance or other means to pay the costs associated with drug delivery, will be much less likely to gain entry into an expanded access system. To redress this imbalance, efforts to increase access to investigational drugs must be accompanied by broader measures to improve health care for the entire spectrum of AIDS patients. Ideally, such measures would be incorporated into efforts to improve access to care for all indigent populations in the United States. In the short term, however, AIDS-specific actions must be taken to help states and cities whose health care systems are faltering under the medical and financial burdens of the epidemic.

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary PEOPLE OF COLOR Physicians who care for minority AIDS patients list three major barriers to the use of clinical trials as a means of improving access to care for people of color. First, many of the institutions that serve low-income minority patients are already overburdened; they simply are not prepared to follow substantial numbers of patients on new investigational drugs. Second, many people of color view the research establishment and the institutions behind it with suspicion; they may not be willing to participate in programs based at these institutions. Third, the lack of options for impoverished patients raises strong ethical concerns about their ability to give genuine informed consent. Resource Considerations Advocates for people with AIDS, government scientists, and physicians all agree that clinical trials should include a more balanced sampling of the population infected with HIV. In the early years of the AIDS epidemic, almost all trials of prospective AIDS drugs involved white gay men. Then scientists became concerned that the results of such trials might not be applicable to the growing population of individuals infected with HIV through intravenous drug abuse, many of whom were people of color. The latter tended to have more concurrent infections, poorer nutrition, and a different natural history of disease—for example, a lower incidence of Kaposi's sarcoma—all of which may alter how drugs work to fight HIV infection. Moreover, clinical trials represented the only access to potentially life-saving drugs; basic considerations of equity argued that they should not be restricted to one patient group. Increased access for minorities was one rationale behind the Community Programs for Clinical Research on AIDS. In addition, NIAID created a program to support minority medical institutions in developing the necessary operational capabilities for an AIDS clinical trials unit (ACTU) and provided increased funding for existing ACTUs to help them recruit and retain previously underserved populations. The situation is improving. In 1987, only 6.5 percent of the subjects in protocols being run by the NIAID AIDS Clinical Trials Group were black, and 10.6 percent were Hispanic. By 1989, 13.9 percent were black, and 14.1 percent were Hispanic. Some health care providers say, however, that it may be difficult to progress much beyond these levels. Most of the public hospitals

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary and clinics that serve indigent patients are understaffed and over-crowded. Providing them with funds to conduct clinical trials enables them to hire special research staff, but it does not solve the space problem. In the absence of capital improvements, these institutions might have trouble meeting new expectations. One of the common goals of community-based trials and expanded access protocols is to enable patients to receive investigational drugs through their own physicians. But many of these physicians are not equipped to determine eligibility for drug trials, to follow and monitor patients on new therapies, and to report on laboratory parameters and adverse reactions. For example, the director of the Boston AIDS Consortium reports that physicians from the city's neighborhood health centers are beginning to attend meetings of the consortium's Clinical Providers Group but that at this time they are more concerned with how to provide basic primary care than with the design and implementation of sophisticated clinical trials. He says: Their concerns are about how to keep records confidential; where to get CD4 testing done reliably and at a reasonable cost; how to administer, bill, and get reimbursed for aerosolized pentamidine treatments; and how to get their neighborhood pharmacies to carry AZT. I hope it is clear that if we are to be realistic, the issue of expanding access must be viewed from a broader perspective and has to be considered in the context of our capability to provide primary care generally, our preparedness to provide this for people with HIV infection, and the fact that even when we are doing this, unfortunately, to a great extent, we must weigh competing demands, offering detection, counseling, and initiation of standard antiretroviral therapy versus expanding access to clinical trials. Programs to place clinical trials in primary care settings often fail to deal effectively with reimbursement issues. New York State has developed enhanced reimbursements for physicians seeing patients with AIDS in designated centers, but this is by no means universal. In most cases, time spent on clinical investigations is added to time spent doing routine care and, often, finding appropriate treatment for patients with drug abuse problems. All of these tasks together may be reimbursed at the same level as a routine office visit. Whatever the means that are finally adopted, government planners must deal effectively with these resource issues to enhance access to investiga-

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary tional drugs through the primary care providers that serve low-income minority patients. Suspicion Increasing minority enrollment in clinical trials also depends on greater understanding of the deep ambivalence that exists among people of color with regard to the premier academic research institutions in this country. An AIDS physician from Johns Hopkins University reports that he was greeted with hostility and suspicion when he first attempted to make contact with members of the black community in Baltimore. He discovered that some people growing up in the neighborhoods around the medical center had been told as children that scientists from the medical school snatched black people off the streets at night and put them in the basement to experiment on them. It was clear that the people who told these stories did not believe them in a literal sense, but the fact that they repeated them indicated a general level of unease with the medical establishment. Individuals in the community also were extremely familiar with the details of the infamous Tuskegee study, in which members of the Public Health Service followed hundreds of poor black men with syphilis for four decades (1932–1972) without offering them treatment. The subjects neither knew nor consented to their role in this ''scientifically controlled experiment.'' Fears associated with both real and imagined abuses by the research community, combined with persistent memories of segregated care, will continue to hamper recruitment efforts for clinical trials unless they are discussed openly. Too often, there is a tendency to respond with a joke when a patient says, "So you mean I'm going to be a guinea pig, doc?" For people of color—as well as other patients—the question could mask a serious plea for reassurance. Informed Consent Reassurance takes on even greater importance for patients who feel they have no alternative to participation in a clinical trial. Chapter 2 explores the difficulties of obtaining genuine informed consent in AIDS-related drug trials. Poor patients may not have the option of forgoing randomization and obtaining a desired drug through some other mechanism.

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary Some patients also may be at a disadvantage because they do not have the educational skills necessary to understand the complex details of a research protocol. One way to make protocols more responsive to the needs of such patients is to broaden membership on local institutional review boards (another option discussed in Chapter 2). This would provide a forum for members of the community to educate clinical investigators about the best ways to present new treatment options. WOMEN An experienced research nurse at a major academic medical center recently told the principal investigator at her institution that she would much rather see a 40-year-old male engineer in her clinical trials than a young woman with two children who has forgotten the baby's bottle and diapers. This sentiment illustrates just one of the problems with the expectation that clinical trials could be a major avenue for increasing access to care for women with HIV infection. In most hospitals, the clinics that monitor AIDS drug trials do not have the resources or facilities—in terms of transportation, babysitting services, and staff members knowledgeable about women's health care issues—to meet the needs of women. The Gender Perspective In fact, the problems go much deeper than resource issues. The AIDS epidemic among women differs in almost every respect from the AIDS epidemic among men. For example, the growth of the epidemic among women is very different. One scientist suggests that the majority of men who will develop HIV-related illnesses in the next 10 to 20 years are already infected; moreover, a significant proportion have progressed to the symptomatic stages of disease. In contrast, most HIV-infected women are in the early stages of disease and there is a large population of high-risk women who have yet to become infected. (This situation has arisen because of the transmission patterns in the United States; early in the epidemic, most transmission occurred through male homosexual activity and intravenous drug abuse—about 70 percent of IV drug abusers are men. Heterosexual transmission did not become a major factor until later.) Physicians who provide health care to women are concerned that too

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary much emphasis on enrolling women in clinical trials could overshadow the tremendous opportunities that still exist for prevention. Risk Factors Prevention education and recruitment for clinical trials both require identification of a target population, which raises another difference between men and women with respect to HIV infection. Almost all HIV infection in men is associated with their own personal behavior—either homosexual sex or IV drug abuse. Recent decreases in new infections among gay men and IV drug abusers indicate that educators can reach out to these populations and help them alter the behaviors that place them at risk (for example, by practicing safer sex or "AIDS-safer" injection). Among women, however, a relatively large percentage of cases occur in individuals with undetermined risk. Many women are infected by sexual partners who have not been truthful about previous high-risk experiences. These women may be completely surprised when they develop symptoms of HIV-related disease or bear an HIV-infected infant. It is extremely difficult to direct educational efforts toward a population whose members do not realize they are at risk. It is even more difficult to incorporate this population into clinical trials. Protocol Development Several drug protocols have been developed recently to study the safety and efficacy of anti-HIV therapy in pregnant women. Although the need for such therapy is clear, protocol development has been problematic for many reasons. First, scientists know very little about the natural history of HIV infection in women in general, and even less about the natural history of the disease in pregnant women. Uncertainty about transmission rates also presents a problem. Several years ago, HIV-infected women were told that they had a 60 percent chance of transmitting the virus to their fetus and that all infected children would die within one to two years. Today, scientists believe that the transmission rate is in the range of 25 to 30 percent and that some infected children will live well beyond their toddler years. But the scientific community still has not determined when in gestation a woman transmits the virus to her fetus. Given these

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary uncertainties, it may be very difficult for a woman to decide whether or not to participate in a clinical trial. The second problem with recent drug protocols is that they do not take account of the realities of the health care setting. The low-income women who are at greatest risk of HIV infection often have poor prenatal care, late prenatal care, or no prenatal care at all. The expectation that many of them will be identified and enrolled in clinical trials during the first trimester of pregnancy is probably unrealistic. Women as Vectors The dominant problem with the protocols for pregnant women, however, is that their major focus is on interrupting perinatal transmission. This reflects a tendency in society to consider women with AIDS only in relation to their ability to transmit infection to their male sex partners or their infants. One arm of a protocol now in the planning stages would identify HIV-infected women early in pregnancy but not treat them until the onset of labor. Studies in men have shown that early treatment with antiviral agents can delay AIDS-related symptoms, but no one knows the effects of these agents on the developing fetus. Thus, the decision to delay therapy raises very complex issues about the rights of the mother versus the rights of the child. A New Approach Efforts to increase access to clinical trials for women will be most successful if they are part of a new gender-specific approach to HIV education and therapy. Such an approach might include greater support for research on the natural history of HIV infection in women, a commitment to include physicians who are knowledgeable about women's health issues in the design of clinical trials, and a unified approach to the scientific, medical, and ethical issues surrounding clinical trials in pregnancy. Women should be viewed as primary recipients of care, and every effort should be made to repudiate the characterization of HIV-infected women as vectors, transmitters, or vessels of disease. Today, an HIV-infected woman with an infected child is often required to broker her care among four different providers: her routine provider, her clinical trial site, her child's routine provider,

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary and her child's clinical trial site. Even a woman with extraordinary financial and emotional resources would find such a task difficult. For the average woman with HIV infection, who must worry about feeding, clothing, and housing her healthy children as well as her sick children, it is almost impossible. Future efforts to increase access to investigational drugs for women will be most effective in centers that integrate clinical trials with routine medical care for both women and children. THE PEDIATRIC POPULATION The AIDS epidemic has produced a dramatic change in the way the scientific community approaches clinical trials in children. In the past, clinical trials were generally not begun in children until safety, and perhaps even efficacy, had been established in adults. The rationale for the delay was that it protected children from exposure to unnecessary experimentation. But the severity of HIV infection and the steady increase in infected children (government officials estimate that the number of HIV-infected children in the United States is between 6,000 and 20,000) have created incentives for change. Government scientists now recognize the need to begin phase 1 trials in children concurrently with or just slightly after the start of adult trials, which should help avoid the types of problems that arose with zidovudine (AZT). Zidovudine was approved for adults in 1987, but children did not have access to the drug outside of traditional clinical studies until October 1989, when the FDA approved a treatment IND for the pediatric population. Parents and physicians of children with HIV continued to have difficulty obtaining the drug until May 1990, when the FDA waived rules for separate efficacy studies in children and approved the drug for anyone above three months of age. Over the next few years, clinical trials may play a greater role in pediatric AIDS therapy than in adult therapy, in part because the total number of recognized cases remains relatively small. Also, clinical trials provide a controlled environment in which to begin addressing the scientific and social problems that now impede the delivery of care to children with AIDS.

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary Scientific Issues The scientific problems result primarily from lack of experience in conducting clinical trials in newborns and young children and from the paucity of information about the natural history of HIV infection in this age group. In fact, three-quarters of the drugs that are now part of standard formularies were never tested in children; they are simply used by extension. Because pharmaceutical companies have very little incentive to produce formulations specifically for the pediatric population, the pace of future clinical trials in children will depend in part on developing such incentives and increasing the availability of appropriate substances. Scientists also need more information about the progression of HIV-related diseases in children with perinatal infection. As noted earlier, more HIV-infected children survive infancy than was previously expected, and some children do not develop symptomatic disease until well after their fifth birthday. Investigators cannot completely assess the efficacy of drug candidates until they understand the factors that determine the onset and pace of disease in the absence of drugs. Social Issues Earlier sections have alluded to the fact that most children with perinatal HIV infection come from severely impaired families. In some cases, the day-to-day demands of poverty and drug abuse may prevent parents from taking an active role in their children's care; in other cases, parents may be severely ill themselves. Pediatric clinical trials among this population must offer much more than investigational drugs and research-related medical care. Compliance with trial regimens depends on the availability of a broad range of services to provide physical and emotional support for the entire family. The multidisciplinary teams developed for pediatric clinical trials could become a model for pediatric AIDS care in other settings. HIV-infected children who have no family support usually enter the foster care system, a circumstance that raises additional issues. Foster care agencies vary from city to city in their policies on investigational therapies. The implementation of AIDS-related clinical trials may be difficult in areas where the foster care system does not recognize the importance of access to experimental drugs. In addition to infants born to high-risk women, one other pediatric population is at great risk of HIV infection: adolescent runaways (officials estimate that there are about a million teenage

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary runaways across the United States). In large cities, such as New York and San Francisco, runaways often use sex as a way of earning a living, which places them at enormous risk of infection from all types of venereal diseases. Providing regular health care for these homeless children is extremely difficult; the potential for including them in clinical trials is limited. The most urgent task with regard to teenage runaways is AIDS prevention education; communications skills developed to help adolescents avoid HIV infection might be used later to promote long-term care for this very challenging target group.