Informing the Future: Critical Issues in Health: Fourth Edition (2007)

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Health Research: The Path to Knowledge Health Research: The Path to Knowledge Over the course of human history, advances through research have had un- paralleled impact on human health. The great improvements in our collective well-being have all come from revolutionary discoveries—the application of the scientific method to medicine, germ theory, and the structure of the human genome. For this path of knowledge to continue, the scientific community must con- stantly reevaluate its methods, results, policies, and organizational structures, as well as the ethical implications of its work. Scientists from disparate fields need the opportunity to come together with professional counterparts in other disciplines on a regular basis. Only through this kind of sharing of focused and independent knowledge can the best possible research be done and the smartest minds be brought to bear on problems of public health. Much of the Institute of Medicine’s (IOM’s) ethics-related work takes place in this arena. The issues of science policy, public support, research priorities, and collaboration are both sweeping in scope and critically important to our national well-being. The Promise of Stem Cells Stem cell treatments have the potential to revolutionize medicine. Stem cell–based treatments may be able to address diseases (including chronic heart disease, type I diabetes, and Parkinson’s disease) and tissue damage (including spinal cord damage, brain damage caused by The workshop and its report focused stroke, and damage to heart muscles caused by on the scientific and medical heart attacks). data about the potential risks of ovarian hyperstimulation syndrome, For several years, research on human embry- compromised future fertility, and onic stem cells has been mired in controversy. psychological consequences, as well Restrictions on the use of federal funds for stem as the increased possibility of ovarian cell research have led this research to be private- cancer. ly funded and often carried out under a patch- work of existing regulations that were not developed with stem cells in mind. As a result, states and private entities have developed stem cell research policies in a vacuum, without federal guidance. 55 

Informing the Future: Critical Issues in Health To enhance the integrity of human embryonic stem cell research by encour- aging responsible practices, a joint project of the IOM and the National Research Council (NRC) issued Guidelines for Human Embryonic Stem Cell Research (2005). The guidelines addressed the many ethical, legal, scientific, and policy issues that are of concern to the public and the scientific community. The report called for the establishment of a national body to periodically as- sess the adequacy of the guidelines in this rapidly changing field and to provide a forum for continuing discussion of human embryonic stem cell research. Toward this end, in response to requests from the scientific community, the IOM and NRC convened a Human Embryonic Stem Cell Research Advisory Com- mittee. The committee monitors and reviews scientific developments and the changing ethical, legal, and policy issues related to human embryonic stem cell research; discusses the need for revisions to the Guidelines for Human Embryonic Stem Cell Research; and updates the guidelines as needed. In the spring of 2007, the committee released its 2007 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research. The new report made several amendments to the 2005 version based upon feedback from the community. It addressed issues that were both in need of amendment and amenable to prompt solution. The advisory committee continues to gather information from public symposia and written comments from members of the scientific community on developments in stem cell science and new or changing is- sues in ethics and policy. The committee uses these and other sources of information to continue monitoring and revising guidelines on the conduct of human embryonic stem cell research. While this effort will go far to distill evidence-based in- formation and make recommendations for the research com- munity’s practices, the IOM and NRC have done additional work as well. Recognizing the potential of stem cell treat- ments, California’s Proposition 71 set up a 10-year, $3 billion program to build facilities for stem cell studies and to fund research with the ultimate goal of helping to develop thera- pies based on stem cells. This research, however, will require a steady supply of stem cells, particularly human embryonic stem cells. These cells are collected from developing human embryos that are created from eggs—or oocytes—harvested from the ovaries of female donors. 56 

Health Research: The Path to Knowledge This oocyte donation process is not without risk to donors. The California Institute for Regenerative Medicine asked the IOM and NRC to assemble a work- shop that would bring together experts from various disciplines to analyze these risks in terms of the known science, the research necessary, and the actions need- ed to minimize any lingering issues. In response, the IOM and NRC established the Committee on Assessing the Medical Risks of Oocyte Donation for Stem Cell Research, which held a workshop in September 2006. The resulting report, Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report (2007), synthesized the current state of knowl- edge in the field. The workshop and its report focused on the scientific and medical data about the potential risks of ovarian hyperstimulation syndrome, compromised future fertility, and psychological consequences, as well as the in- creased possibility of ovarian cancer. The workshop report did not review ethical and policy issues. Research with Prisoners Medical research involving prisoners raises a host of ethical concerns, es- pecially because such research has a tainted history. In the past, some scientific investigators used prisoners to study a variety of illnesses and toxins when hu- man experimentation in free society was not allowed. Many prisoners who par- ticipated did not give voluntary, informed consent or fully understand the risks or possible benefits of research protocols. In the late 1970s, the U.S. government implemented federal legislation to protect human subjects in scientific research, which included specific guidance on prisoners. In the past three decades, the U.S. prison population has expanded more than fourfold, and its makeup has changed dramatically. Correctional facilities are increasingly overcrowded and contain a diverse population, including some of the country’s most disadvantaged populations. Racial minorities, women, people with mental illness, and people with communicable disease such as HIV/AIDS, hepatitis C, and tuberculosis are increasingly under correctional supervision. Prisoners’ access to adequate health care has not always kept pace with this growth and diversity. These factors can be barriers to the prerequisites of ethical research, such as informed consent, privacy, and access to quality care. In fact, the situation is sometimes so stark that the choice to participate in research could be a desperate attempt to receive medical care. Most research using prisoners currently takes place outside the scope of federal regulations and often without the scrutiny of institutional review boards 57 

Informing the Future: Critical Issues in Health 48 TABLE 2-13 Likelihood of Injury Based on Time in Prison, 1999 Medical Problem Time Since Admission Injured (%) (Excluding Injury) (%) Less than 12 months 13.2 15.8 12–23 months 19.8 19.1 24–47 months 26.7 20.4 48–71 months 36.8 20.3 72 months or more 45.9 30.4 SOURCE: BJS, 2001b. Likelihood of Injury Based on Time in Prison, 1999. SOURCE: Ethical Considerations for Research Involving Prisoners, p. 48. (IRBs). Given these issues, the Department of Health and Human Services’ Office for Human Research Protections commissioned the IOM to review the ethical considerations regarding research involving prisoners. The goal, as stated in Ethical Considerations for Research Involving Prisoners (2007), is to “ensure rigorous responsible research that improves the well-being of prisoners, while taking great care to protect Prisoners’ access to adequate health their health, well-being, and human rights.” care has not always kept pace with this growth and diversity. These factors The report recommended several steps can be barriers to the prerequisites that should be taken to provide prisoners in- of ethical research, such as informed volved in research with critically important pro- consent, privacy, and access to quality tections. The definition of “prisoner” should be care. In fact, the situation is sometimes expanded to extend ethical protections to more so stark that the choice to participate people. Of the nearly 7 million people under cor- in research could be a desperate rectional custody in 2004, only 2.1 million were attempt to receive medical care. in prisons or jails. The rest were on parole or probation. These groups need to be considered “prisoners” under the law and thus covered by the same rigorous ethical rules. Protections should be applied uniformly to all subjects of prisoner research. Under today’s laws, research proposals involving prisoners are subject to reviews based on narrow categories that do not adequately consider the benefits and risks involved in the study. In addition, current reviews do not address the conditions of confinement or restrictions on the liberty of the subject. The IOM calls for a risk–benefit approach in evaluating research conducted on prisoners similar to that used for research involving children—a population with similar issues in terms of free will and capacity to make informed decisions without 58 

Health Research: The Path to Knowledge external influence. Therefore, ethically permissible research must offer prisoners potential benefits that outweigh the risks. As with any field of medical inquiry, all aspects of prisoner-based research, including design, planning, and implementation, should include the input of rel- evant stakeholders, such as prisoners, correctional officers, medical staff, and ad- ministrators. Systematic oversight of research involving prisoners should also be enhanced. Public Input on Clinical Trials The clinical trials process is perhaps the most critical step in determining the safety and effectiveness of a new drug or treatment. These trials, however, are often reported selectively and with a bias toward publishing positive results. The pharmaceutical industry is not motivated to publish the results of trials that do not support the introduction of a new product, and medical journals are more likely to publish positive results than negative results. As a result, the full range of results from clinical trials often is not part of the public record. To improve public confidence in clinical research and ensure that results from all clinical trials are made available, a number of groups have called for a pub- licly accessible, comprehensive, and transparent registry of relevant information on clinical trials for drugs and biologics. However, with their different interests, the public, consumer advocates, health care providers, researchers, editors of medi- cal journals, pharmaceutical companies, health insurers, and regulators may all have different expectations and perceived needs regarding such a program. The IOM Committee on Clinical Trial Regis- . . . the full range of results from tries hosted a workshop to obtain much-needed clinical trials often is not part of the input from members of these constituencies, to public record. examine the hard data elements that have been at the core of the debate, and to comment on the issues involved in enforcing compliance and implementing a national clinical trial registry. The results were published in Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Report (2006). The discussion centered on • the purposes of a registry; • the inclusion or exclusion of exploratory trials; • the need for a delayed disclosure mechanism for certain fields in the reg- istry at the time of trial initiation (for information such as the hypothesis 59 

Informing the Future: Critical Issues in Health statement, primary and secondary outcomes measures, and projected year of trial completion); • the timing and format for reporting results of completed trials; and • the appropriate roles of IRBs, the FDA, and others in ensuring compliance. HIPAA and Health Research When the Health Insurance Portability and Accountability Act (HIPAA) was enacted a decade ago, one of the law’s provisions was to simplify the exchange of electronic information for financial and administrative functions related to pa- tient care. However, concerns have been raised about the transmission of sensi- tive personal information, and a Privacy Rule was adopted in 2003 to protect indi- vidual health information. This restriction has had the unintended consequence of posing serious challenges to medical researchers who depend on patient data for their studies. Effect of the HIPAA Privacy Rule on Health Research: Proceedings of a Workshop Presented to the National Cancer Policy Forum (2006) summarized a series of pre- sentations from officials of the Department of Health and Human Services Office for Civil Rights, the National Institutes of Health, and other federal agencies, as well as from the pharmaceutical industry, experts in health law, privacy advocates, and academic leaders and researchers. The presentations described the 2003 regulations govern- ing the privacy of individually identifiable health information received by health plans, health care providers, and clearing- houses that engage in electronic transactions and the effects of those regulations on health research. The workshop was instrumental in defining the issues and enabling the IOM to design a study to investigate the impact of the HIPAA privacy rule on health research. The IOM, with support from federal agencies, private-sector associations, and foundations, has embarked on a major committee study Health Research and the Privacy of Health Information: The HIPAA Privacy Rule. The IOM committee is developing recommendations to facilitate important medical research while maintaining individual privacy. In conjunction with the study, the IOM has also commissioned several major surveys of U.S. epidemiologists, the HMO Research Network, and the public to strengthen the evidence base for examining the ef- fects of the Privacy Rule on health research. Several organizations are also initiat- 60 

Health Research: The Path to Knowledge ing surveys on their own and plan to provide input to the committee, including American Society of Clinical Oncology, the American Heart Association, Academy Health, the International Pharmacy Privacy Consortium, and the North American Association of Central Cancer Registries. The committee’s report, including find- ings and recommendations, is due at the end of 2008. The Future of the Life Sciences The field of life sciences is advancing with tremendous speed, enabling sci- entists to identify and manipulate features of living systems in ways never be- fore possible. On a daily basis and in laboratories around the world, biomedical researchers use sophisticated technologies to manipulate microorganisms in an effort to understand how microbes cause disease and to develop better measures for fighting them. Plant biologists are applying similar tools in their studies of crops and other vegetation—both to improve agricultural yield and to explore the potential for the use of plants as inexpensive platforms for vaccine, anti- body, and other product manufacturing. Similar efforts are underway with ani- mal husbandry. Moreover, fields not traditionally viewed as having applications to the life sciences enterprise—materials science, information technology, and nanotechnology—are being integrated into traditional experimental and applied Bacteria Eukarya Green filamentous Slime Spirochetes bacteria Archaea Entamoebae molds Animals Fungi Methanosarcina Gram Methanobacterium Halophiles Proteobacteria positives Plants Methanococcus T. culer Ciliates Cyanobacteria Thermoproteus Flagellates Planctomyces Pyrodictium Bacteroides Trichomonads Cytophaga Microsporidia Thermatoga Animals Aquifex Diplomonads Archaea represents one of the three domains of life, the other two being Bacteria and Eukarya. SOURCE: Globalization, Biosecurity, and the Future of the Life Sciences, p. 43. 1-2 NEW 61 

Informing the Future: Critical Issues in Health research approaches in extraordinary ways, enabling the development of previ- ously unimaginable technological applications. With this crucible of scientific exploration and insights into the way living systems “work,” the continuing threat of the offensive applications of these tools and technologies is an ever present reality. The global spread of expertise and information in biotechnology and biological manufacturing processes has raised concerns about how advancing technological prowess could enable the creation and production of new threats of biological origin that possess dangerous and largely unpredictable characteristics. Among the recommendations contained in the NRC/IOM report Globalization, Biosecurity, and the Future of the Life Sciences (2006) were proposals to encourage • the free and open exchange of scientific and technical information; • the adoption of a broader perspective of the “threat spectrum;” and • the enhancement of scientific and technical expertise within and across the national security communities. The NIH Health Disparities Research Plan “With the diversity of our population, it’s in our interests as a nation to make sure that all of our people are as healthy as they can be,” said former U.S. Surgeon General David Satcher. Unfortunately, Dr. Satcher’s comments remain an ideal and not a reality in today’s society. Evidence shows that Afri- can Americans are disproportionately likely to struggle with diabetes, Hispanics are more likely to die of AIDS, and Native Americans have a higher risk of dying in infancy. Poor and rural populations are also disproportionately unhealthy. Eliminating these health disparities among U.S. populations requires an ag- gressive research agenda. National concerns about these health disparities have been noted as a high priority in national health status reviews, including Healthy People 2000 and 2010. As the nation’s foremost research agency, the National Institutes of Health (NIH) naturally has a leading role in this effort, and the NIH ranks this issue among its top five priorities. The “NIH Strategic Research Plan and Budget to Reduce and Ultimately Elimi- nate Health Disparities” is intended to provide an overarching structure and co- ordination plan for research into these discrepancies by various NIH institutes 62 

Health Research: The Path to Knowledge and centers. Examining the Health Disparities Research Plan of the National Institutes of Health: Unfinished Business (2006) assessed how well the plan provides the nec- essary guidance and recommended ways to improve oversight and coordination of these research efforts. Battling Malaria Between 300 million and 500 million people worldwide will be treated for malaria infections this year. More than 1 million people will die from the disease. For more than 50 years, health care workers have effectively fought malaria with low-cost antimalarial drugs that have saved millions of lives. Unfortunately, these drugs are no longer effective against the deadliest forms of malaria. The U.S. military’s concern that malaria is a major threat to overseas troops, and its recognition of the need for a vaccine to ward off the disease, has led it and philanthropic foundations, such as the Bill and Melinda Gates Foundation, to invest in vaccine research and development efforts. During the past two decades, there have been two highly productive malaria vaccine research programs located at the Walter Reed Army Institute of Research (WRAIR) and the Naval Medical Research Center (NMRC). Although considerable col- laboration and cooperation has occurred between the highly committed and productive staffs of both programs, there has also been divergence of strategies and some duplication of resources. Recognizing the great complexity and expense of researching and develop- ing a vaccine in an era of scant resources, the Department of Defense (DoD) asked the IOM to conduct a programmatic review of the military Plasmodium falciparum malaria vaccine research and development program. The IOM report Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program (2006) concluded that malaria remains a severe and ongoing threat to many military deployments. The DoD Malaria Vaccine Program represents a large proportion of the global malaria vaccine effort and has unique capabilities not readily available elsewhere, such as a well-defined sporozoite challenge model and a pilot production facility that ensures good manufacturing practices. The program is pursuing three distinct approaches, each of which should continue, according to the report. However, the committee found a need to ag- gressively pursue fewer vaccine candidates within these approaches and to focus 63 

Informing the Future: Critical Issues in Health The malaria life cycle. SOURCE: Battling Malaria: Strengthening the U.S. Military Malaria Vaccine Program, p. 22-23. fig 3-1 Landscaspe view on human immune responses and correlates of protection. Clinical trials in non- immune adults visiting malaria-endemic sites were suggested as a possible ad- ditional approach for moving candidates forward. The report recommended that the program adopt a generational approach to vaccine development because even a partially protective first-generation vac- cine would be a useful adjunct to preventive drugs while research continues to develop a vaccine sufficiently effective to be used alone. It also recommended that the WRAIR and NMRC malaria vaccine programs be fully integrated into a unified organizational and legal entity—the Joint Task Force for Malaria Vaccines—with a single scientific director. The task force should 64 

Health Research: The Path to Knowledge be supported by an external scientific advisory board that would provide ongoing advice and assist in the selection of vaccine candidates. To use existing resources more efficiently, the report recommended an overhaul of the management structure of, and a significant increase in core sup- port for, the DoD malaria vaccine enterprise. It is a worthwhile program that can be made more effective with these straightforward and easily implemented modifications. Workplace Safety Every day, thousands of U.S. workers sustain disabling injuries on the job, more than a dozen die from injuries suffered at work, and at least a hundred workers die from work-related illnesses. Charged with pro- moting safe and healthy workplaces, the National Institute for Occupational Safety and Health (NIOSH) supports and spon- sors research to prevent work-related illnesses and injuries. In 2004, the agency asked the National Academies to con- vene committees to review up to 15 of its research programs. The NRC and IOM committees in charge of conducting these reviews are tasked with assessing the relevance and impact of NIOSH research programs in improving occupational safe- ty and health. The committees’ reports are also intended to identify emerging issues and make recommendations for ad- ditional research to improve worker protection. Hearing Loss Research at NIOSH (2006) was the first report in the series Reviews of Research Programs of the National Institute for Occupational Safety and Health. The report examined the problem of occupational hearing loss, a serious concern for many workers even though the number of people affected or at risk is uncertain. The report found that over the past decade, the Hearing Loss Research Program has made meaningful contributions to improving worker health and safety. Yet although some of its work is in high-priority subject areas and highly relevant to improvements in workplace protection, other efforts appear to be too narrowly targeted or directed to activities that are secondary to protecting the hearing of workers. To enhance the relevance and impact of the program’s work and fulfill its mission, the report recommended that the NIOSH Hearing Loss Research Pro- gram foster more effective leadership in program planning, implementation, and 65 

Informing the Future: Critical Issues in Health Every day, thousands of U.S. workers evaluation. It must gain access to additional in- sustain disabling injuries on the job, ternal and external expertise, especially in epi- more than a dozen die from injuries demiology and noise control engineering, and suffered at work, and at least a initiate and sustain efforts to obtain surveillance hundred workers die from work-related data for occupational hearing loss and workplace illnesses. noise exposure. The IOM considers these kinds of evaluations critical to ensuring the effec- tiveness of federal agency efforts in human health and safety. Future reports in the series will be a valuable contribution to the work of NIOSH. 66