4

Biomedical Science

The Institute of Medicine’s (IOM’s) commitment to providing rigorous, apolitical scientific advice—as well as to the advancement of the scientific enterprise—can be traced to its roots in the National Academy of Sciences (NAS). Founded in 1863 at the height of the U.S. Civil War, at a time when the government was most interested in understanding technological advances in weaponry, the NAS was created to “investigate, examine, experiment, and report upon any subject of science” (see Chapter 1). Notably, its founding members agreed to provide advice without personal remuneration, setting a standard of volunteerism that endures to the present day among members of all three of the National Academies (Seitz, 2007). The National Academies of Sciences, Engineering, and Medicine’s (the National Academies’) authority and influence are built on a foundation of unparalleled access to scientific expertise, as well as their independence from the U.S. government and the private and nonprofit organizations that sponsor studies.

Although the NAS was founded under a congressional charter signed by President Abraham Lincoln, the Academy’s explicit purpose was to provide advice that the government could trust to be free of partisan political influence. Thus, the organization was empowered to focus on the scientific evidence gathered and synthesized by its members. Over time, as the organization’s recommendations proved to be reliable and effective, the NAS’s authority and influence grew. The National Academy of Engineering and the IOM, founded as offshoots of the NAS charter in 1964 and 1970, respectively, operated with the same commitment to scientific rigor and independence and with the same reputation for trustworthy, impactful advice as previously established by the NAS.

Since its very first statement on the safety of heart transplants as the Board on Medicine in 1968 (see Chapter 1), the IOM, which became the National Academy of Medicine (NAM) in 2015 (in conjunction with the formation of the Health and Medicine Division [HMD]), has shaped national discussions related to cutting-edge medical treatments, new diagnostic tools, and scientific discoveries. Notable contributions have affected policy and practice related to organ transplantation, computed tomography (CT) scans, HIV transmission, embryonic stem cell research, and regenerative medicine, to name just a few (see Box 4-1). In addition to guiding the development and application of biomedical science and many other fields, the organization maintains a focus on the implications

of scientific discoveries and technological advances for health care, health policy, and population health—including their impacts on health equity.

The following sections describe the IOM’s, the NAM’s, and the HMD’s major contributions to four key areas: the human genome, vaccine safety and efficacy, childhood and adolescent development, and cancer. A final section details the organization’s role as a scientific advisor to several departments and agencies within the U.S. federal government, as well as international partners in Africa. The activities described in this chapter were led by IOM, NAM, or HMD staff in collaboration with NAM member and non-member expert volunteers.

THE HUMAN GENOME: FROM SEQUENCING TO EDITING

Alongside the NAS, the IOM played a leading role in the human genome sequencing project from its very beginnings in the late 1980s. Today, the NAM continues to be a driving force in current discussions about the rapidly developing field of human genome editing. In 1988, the seminal report Mapping and Sequencing the Human Genome, which was released by the National Research Council (NRC), served as a blueprint for what would become the Human Genome Project, an historic international effort to map more than 20,000 genes that make up the human genome and determine the sequence of 3 billion chemical base pairs (Oak Ridge National Laboratory, n.d.). The committee—which was chaired by Bruce Alberts, who would later be selected as the NAS president in 1993—set goals for the complex endeavor, described organizational strategies, and even suggested funding levels. In April 2003, just 13 years after it was launched, the Human Genome Project reached completion, setting the stage for a new era of biomedical research; the potential to unlock new diagnostic and treatment options for an array of diseases and disorders; and an opportunity to create a more personalized, gene-based approach to medicine (NHGR, n.d.; see Figure 4-1). It should be noted that not all were in favor of the Human Genome Project—scientists worried before the project began that “it [may have] generated enormous reams of uninterpretable and … useless data … with few clues about how any of that genetic material works or can trigger disease” (Angier, 1990). Other scientists fundamentally disagreed with the entire project, noting that a better understanding of genetics would provide no insight into better understanding the human race (Langer, 2021).

In the field of genomics, as in many other fields, translating scientific advances into practice and ultimately into improvements in human health required building bridges between scientific research and medical practice—a role the National Academies and the IOM had played for decades. To facilitate this journey and realize the potential of this new area of scientific research, the IOM launched the Roundtable on Translating Genomic-Based Research for Health in 2007. The roundtable brought together interested sponsors and stakeholders who represented academia, the pharmaceutical industry, patient and health care provider organizations, and the government for open discussions in a neutral environment (IOM, 2008e; NASEM, n.d.a). The roundtable organized its work into focus areas, which have covered a wide range of evolving topics including precision therapeutics; education, engagement, and cultural change; digital health; implementation of public health systems; and evidence for policy and practice (NASEM, n.d.a, n.d.p). From 2007 through 2015, the roundtable held 27 meetings and 22 public workshops, and it released 21 workshop summaries, commissioned several papers, and published a number of discussion papers and commentaries, all of which contributed a wealth of information to the field (NASEM, 2015). In 2014, under the auspices of the roundtable, an Action Collaborative called the Global Genomic Medicine Collaborative was launched and incorporated as a 501(c)(3) nonprofit organization with administrative support from the Global Alliance for Genomics and Health. The Action Collaborative hosted a series of international meetings in Washington, DC; Singapore; and Athens that assembled participants from more than 25 countries to develop and implement a “global toolbox” for advancing and deploying genomic medicine.¹

In 2015, Geoffrey Ginsburg and Sharon Terry—external volunteers who served as co-chairs of the Roundtable on Translating Genomic-Based Research for Health—announced that the roundtable would be renamed the Roundtable on Genomics and Precision Health (NASEM, 2015). This change coincided with the launch of the Obama administration’s Precision Medicine Initiative, which aimed “to enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care” (The White House, President Barak Obama, n.d.). At this time, the roundtable updated its mission “to explore strategies for improving health through the implementation of genomics research findings, as well as other related technologies that inform individual health choices, into medicine, public health, education, and policy” (NASEM, 2016m, p. 2; NLM, n.d.). Today, the revitalized roundtable serves as an important convening activity for a diverse set of stakeholders and sponsors, contributing to the advancement of genomics and precision medicine.

During this same time period, advances in human genome editing technology became a topic of interest and concern for scientists, regulatory bodies, and the public. Genome editing, which involves laboratory methods to create changes in DNA, had recently been aided by new molecular biology research that improved both the accuracy and flexibility of the editing capabilities. These new advances held great potential for treating and possibly eradicating genetic diseases. In the laboratory, using human cells, scientists could locate a gene in which a mutation resulted in a specific disease and edit the gene to eliminate that mutation. Germline gene editing might, for example, change the genes that were responsible for diseases inherited from one or both parents, such as cystic fibrosis and sickle cell anemia. Gene editing had reached a stage at which its promise was recognized. However, these new methods had to be refined and perfected, and the ethical and societal implications had to be examined and seriously considered across the scientific community in collaboration with many other stakeholders.

In December 2015, just a few months after the creation of the NAM, an International Summit on Human Gene Editing convened in Washington, DC, at the NAS Building (see Figure 4-2). The NAM, along with the NAS, The Royal Society of the United Kingdom, and the Chinese Academy

___________________

¹ Evaluation of Impact from IOM Reports (Database), IOM/NAM Records.

of Sciences, hosted the 3-day event. David Baltimore, an NAM/NAS member and Nobel laureate who had played a major role in the IOM’s response to the HIV/AIDS epidemic, told an audience of more than 500 people that, “we could be on the cusp of a new era in human history.” There was a sense that “we are close to being able to alter human heredity” and the question was “how, if at all, do we as a society want to use this capability.”

During the final session of the conference, the 12-member organizing committee, which was chaired by Baltimore,² articulated some of the conclusions that had been reached at the summit. The committee noted that additional research was needed and should continue with appropriate ethical and legal oversight, warning that edited embryos or germline cells should not be used to induce pregnancy. The committee encouraged the study of gene therapies that would involve editing somatic cells within existing regulatory frameworks, calling for rigorous evaluation to facilitate a better understanding of the potential risks and benefits of this type of editing. As for editing germline cells, which would be carried by all the cells of the child and then passed on to future generations, the organizing committee said it would be “irresponsible” to proceed with the clinical use of germline editing until the safety and efficacy issues were resolved and there was a “broad societal consensus about the appropriateness of the proposed application.” The committee called on the host organizations, including the NAM, to establish an ongoing international forum to continue discussions and work toward harmonized global regulations. For the NAM, this recommendation represented an opportunity to lend its voice to a major scientific global initiative from the beginning. NAM President Victor Dzau signed a statement in which he and his fellow Academy presidents welcomed the call “to continue to lead a global discussion on issues related to human gene editing” (Cicerone et al., 2015).

___________________

² David Baltimore was the President Emeritus and the Robert Andrews Millikan Professor of Biology at the California Institute of Technology during this time.

Building an international framework for human genome editing became an important part of the NAM’s programmatic portfolio. The subject of human genome editing fit within with the NAM’s strategic goal to “actively identify and address critical issues … and lead and inspire action on bold ideas to impact science, medicine, policy, and health equity domestically and globally.” Within the National Academies, the Human Genome Editing Initiative became a joint activity of the NAM and the NAS that was co-chaired by NAM members R. Alta Charo³ and Richard O. Hynes.⁴ The activity represented the type of collaboration that the creation of the NAM was meant to foster. In 2017, the NAS and the NAM jointly issued a consensus report called Human Genome Editing: Science, Ethics, and Governance, which continued the discussion from the 2015 summit. The report offered a set of principles for the governance of human genome editing, including the promotion of “well-being, transparency, due care, responsible science, respect for persons, fairness, and transnational cooperation.” These principles informed the recommendation that research and clinical trials that involved somatic gene editing be limited to the prevention and treatment of disease and disability. Research involving germline genome editing should be undertaken only for the treatment or prevention of serious disease or disabilities and only when strict oversight is in place. The report concluded that all research efforts should be limited to the treatment or prevention of disease, not for human enhancements such as making a person physically stronger or altering physical appearances. The report helped lay the groundwork for the Second International Summit on Human Gene Editing, which was held in Hong Kong in 2018 (NASEM, 2017b).

Following the summit in Hong Kong—at which a Chinese scientist announced that embryonic germline editing had been used to establish a pregnancy that resulted in the birth of twins—an International Commission on the Clinical Use of Human Germline Genome Editing was launched in the spring of 2019 (NASEM, 2019a). In a statement announcing the new commission, Dzau and Sir John Skehel, the Vice-President of The Royal Society of the United Kingdom, highlighted the urgent need for a global framework to guide researchers and regulators. The NAM, the NAS, and The Royal Society of the United Kingdom, with engagement from other international academies of medicine, would work together “to develop a framework for scientists, clinicians, and regulatory authorities to consider when assessing potential clinical applications of human germline genome editing” (NASEM, 2019b).

In 2020, the NAM, the NAS, and The Royal Society issued the commission’s consensus report, titled Heritable Human Genome Editing. The report concluded that human embryos whose genomes have been edited should not be used to create a pregnancy until it was established that precise genomic changes could be made reliably and without introducing undesired changes—criteria that had not yet been met. The report specified stringent preclinical and clinical requirements for establishing safety and efficacy and for undertaking long-term monitoring of outcomes. Furthermore, it called for extensive national and international dialogue before any nation decided whether to permit clinical use of heritable human genome editing and identified essential elements of national and international scientific governance and oversight for the field. A third international summit was scheduled to take place in London in 2023.

VACCINE SAFETY AND EFFICACY

One of the most widely recognized public health achievements of the 20th century is the development and widespread use of vaccines. Establishing and maintaining public trust in the efficacy and safety of vaccines, however, has required ongoing research and public communication strate-

___________________

³ R. Alta Charo was the Sheldon B. Lubar Distinguished Chair and the Warren P. Knowles Professor of Law and Bioethics at the University of Wisconsin–Madison when this report was released.

⁴ Richard O. Hynes was an Investigator at the Howard Hughes Medical Institute and the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology when this report was released.

gies. Throughout its history, the IOM has actively participated in many national vaccine conversations and reviewed research associated with the safety and efficacy of various vaccinations. Polio was one of the first diseases targeted for vaccine development, and the IOM was there to advise the nation on the implementation of a new version of the vaccine in the 1970s. The IOM took part in discussions about the widespread implementation of anthrax vaccines after terrorist attacks in 2001 and also contributed a strong, evidence-based voice in disputing a 1998 Lancet article that falsely connected the measles, mumps, and rubella (MMR) vaccine with autism (Wakefield et al., 1998). Over the years, the IOM became one of the nation’s most trusted advisors on a topic that was often contentious and emotional for concerned parents throughout the United States. Vaccine-related work is one of the IOM’s core activities, and the IOM has now released more than two dozen reports on various topics related to vaccines.

The first polio vaccine was developed by Jonas Salk and approved for use in 1955. Like the influenza vaccination, also developed by Salk, the polio vaccine used an inactive (sometimes referred to as “killed”) form of the virus that was administered via injection (Science History Institute, n.d.; see Figure 4-3). Also in the 1950s, Albert Sabin developed another polio vaccine that used live-attenuated forms of the virus and was administered orally. Sabin’s vaccine was approved in 1961. Despite successful trials of the new vaccine, there were concerns about the possibility that a vaccine containing a live form of the virus carried risks of causing polio (IOM, 1998a). In 1977, the IOM released a report called Evaluation of Poliomyelitis Vaccines: Report of the Committee for the Study of Poliomyelitis Vaccines, which studied the relative merits of the two widely available polio vaccines. The report confirmed the safety of Sabin’s oral vaccine and recommended its continued use as the primary option for vaccinating children (IOM and NAS, 1977). A 1988 report titled An Evaluation of Poliomyelitis Vaccine Policy Options also reached the same conclusion, reiterating the value of the oral vaccine until a time when a combination vaccine that covered polio and other diseases (e.g., tetanus, diphtheria) became available (IOM, 1988c). These reports helped ease the public’s fears associated with the live vaccine, and established the IOM as a trusted voice that could assuage public concern with evidence (IOM, 1998a, p. 113).

Over the years, the IOM encouraged the continued development of new vaccines and improvements to existing vaccines and also advised the nation on vaccine policy and disease surveillance strategies. The IOM recognized that federal and state governments needed to take the lead on combating infectious diseases and that greater efforts were needed to develop and implement surveillance strategies in collaboration with the Centers for Disease Control and Prevention (CDC). To protect against an unanticipated infectious disease outbreak, the IOM stated that the nation needed to create an “arsenal of drugs, vaccines, and pesticides.” The government also needed to actively create stockpiles of selected vaccines and establish “a surge capacity for vaccine development and production that could be mobilized quickly” in the event of an infectious disease outbreak (IOM, 1992a).

In 1986, Congress passed the National Childhood Vaccine Injury Act (NCVIA) following a series of lawsuits by people who believed they had been injured by the diphtheria, pertussis, and tetanus vaccine, which had resulted in damage to the vaccine market and a deficit in public trust (CDC, n.d.a). The NCVIA called for two consensus studies to be undertaken by the IOM to determine the safety of childhood vaccines. The first, Adverse Effects of Pertussis and Rubella Vaccines (published in 1991), was chaired by future IOM President Harvey Fineberg, then dean of the Harvard School of Public Health (IOM, 1991e). Fineberg was a noted expert in vaccine science and policy, having co-authored an influential report titled The Swine Flu Affair: Decision-Making on a Slippery Disease (Neustadt and Fineberg, 1978), which sharply criticized the Ford administration’s hasty response to an outbreak that did not ultimately materialize. The 1991 report was followed in 1994 by Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality (chaired by NAM member Richard B. Johnston, Jr.) (IOM, 1994a).⁵ The IOM reports resulted in changes to the Vaccine Injury Table, a list of conditions associated with vaccines mandated to be reported by the NCVIA (Evans, 2006).

Public concerns about vaccine safety grew exponentially with the publication of the 1998 Lancet article that inaccurately associated the MMR vaccine with autism. Once again, the IOM found itself as a mediator of scientific and public debate. The IOM released Immunization Safety Review: Vaccines and Autism in 2004, marking the culmination of an immunization safety project that had been funded by the CDC and the National Institutes of Health (NIH). The project, which was launched in 2001, convened a carefully selected committee that was composed of experts in pediatrics, neurology, genetics, public health nursing, and ethics who were not engaged in vaccine research and who had no other apparent conflicts of interest.⁶ IOM President Ken Shine noted that he was “heavily criticized by the vaccine community” because the committee did not include vaccine experts, but the success of the study proved the effectiveness of using a group of “wise but disinterested people.”⁷ Chaired by NAM member Marie McCormick,⁸ the Immunization Safety Review Committee investigated nine areas of vaccine safety over the course of 3 years. The topics included vaccines and sudden unexpected death in infancy, cancer, immune dysfunction, autism, and other neurologic concerns (NASEM, n.d.b).

When the IOM accepted the immunization safety review assignment, its first task consisted of examining a possible relationship between the MMR vaccine and autism. The public held strong opinions on the possible connections, and some parents who had children with autism were convinced that the vaccine had caused autism in their children. In a report to the IOM Council, Susanne Stoiber, IOM Executive Officer at the time, noted that these beliefs represented an “erosion of public trust in those responsible for vaccine development, licensure, scheduling and policymaking.”

___________________

⁵ Johnston was the Senior Vice President for Programs and the Medical Director of the March of Dimes Birth Defects Foundation and an Adjunct Professor of Pediatrics at the Yale University School of Medicine when this report was published.

⁶ Susanne A. Stoiber to IOM Council, “Overview of IOM Program Activity,” July 9, 2001, IOM/NAM Records.

⁷ Private correspondence, Kenneth Shine to Laura H. DeStefano, April 18, 2020.

⁸ Marie McCormick was the Sumner and Esther Feldburg Professor of Maternal & Child Health in the Department of Society, Human Development, and Health at the Harvard T.H. Chan School of Public Health during this time.

Immunization safety had become “a contentious area of public health policy, with discourse around it having become increasingly polarized and exceedingly difficult.”⁹

The Immunization Safety Review Committee worked quickly and produced its first report on vaccines and autism in a 3-month period. In that timeframe, the committee conducted a careful, but expedited, review of the published and unpublished literature on the statistical linkages between the MMR vaccine and autism and also the biologic mechanisms by which the vaccine might cause autism. In its report, the committee stated that it had found “no credible evidence” linking autism to the MMR vaccine. However, it did not completely dismiss the possibility that such a link might exist. Thus, the committee urged the CDC and the NIH to study the biological mechanisms that could possibly cause the MMR vaccine and other childhood vaccines to trigger autism (IOM, 2001a).

Unfortunately, the nuances of the report and calls for additional research were overlooked by the media, and the headline became “no link found between MMR and autism.” This conclusion was not readily accepted by the public and some lawmakers. As a strong believer in the MMR-autism theory, Representative Dan Burton (D-CA), who chaired the House Committee on Government Operations, was particularly dissatisfied with the committee’s work and the report’s findings. Burton issued subpoenas requesting recordings of the committee’s deliberations, but he could find nothing concerning.¹⁰ Meanwhile, McCormick and the IOM staff members who supported the committee received what Stoiber described as “a number of very harsh and emotional letters from parents and advocacy groups.”¹¹ Shine stepped in and leveraged his relationship with Representative Henry Waxman (D-CA), whom Shine knew from his time at UCLA. Shine called on Waxman to help defuse the situation with Burton.¹²

Each of the Immunization Safety Review Committee’s eight reports (see Box 4-2) covered a controversial and emotionally charged topic, such as possible linkages between the additive thimerisol—a preservative used in some vaccines—and neurodevelopmental disorders, including autism. In its October 2001 report, the committee reached the same conclusion on thimerosal as it did in the report evaluating the MMR vaccine: no clear evidence to establish a connection to autism or other neurodevelopment disorders (IOM, 2001b). However, the committee did support previous policy decisions to remove thimerisol from vaccines and recommended the use of thimerisol-free vaccines whenever possible.

___________________

⁹ Susanne A. Stoiber to IOM Council, “Overview of IOM Program Activity,” July 9, 2001, IOM/NAM Records.

¹⁰ Private correspondence, Kenneth Shine to Laura H. DeStefano, April 18, 2020.

¹¹ Susanne A. Stoiber to IOM Council, “Overview of IOM Program Activity,” July 9, 2001, IOM/NAM Records.

¹² Interview between Kenneth Shine and Edward Berkowitz, November 2018.

In 2004, the IOM issued its capstone report in the series, Immunization Safety Review: Vaccines and Autism, which offered an opportunity to revisit its earlier findings concerning possible connections between the MMR vaccine and the additive thimerosal and autism. The committee reviewed the new literature that had been released during the 3-year span of its work, but the committee’s conclusions did not change based on any of the newly available literature. The committee’s final report upheld the conclusions in its earlier reports, and recommended that “available funding for autism research be channeled to the most promising areas” (IOM, 2004c).

The stakes were high for the IOM in its role as mediator and scientific advisor to the nation on such a controversial topic. An overwhelming majority of the public health community believed that vaccinations, although not completely without risk, were critical to preventing the spread of infectious disease and improving the nation’s health, particularly among children in the first years of life. The IOM’s reports strongly supported the consensus within the public health community. For IOM members the primary concern was not the safety of vaccines, but rather the barriers that prevented people from being immunized (Durch and Klerman, 1994; IOM, 2013a), which included public misinformation, fear, and lack of trust. In its 2001 report on thimerosal, the committee stated that “it is important to do everything possible to restore, maintain, and build trust in vaccines” (IOM, 2001b, p. 8). The statement served as the foundation for much of the IOM’s work in vaccines. The immunization safety review series played an important part in public discourse and immunization policy decisions in the United States at a critical time. The series provided state and federal government agencies with a balanced, scientific assessment of the risks associated with vaccines, and it provided public health and medical authorities a scientific foundation to rebut controversial theories about the safety of vaccines, specifically those related to autism.¹³

Studying vaccine safety became an ongoing activity, not only because of recurring vaccine scares but also because of changes in the disease and political environments. Following the terrorist attacks of September 11, 2001, anthrax was identified as a possible biologic weapon that could be deployed against the public, as was demonstrated by several instances of contaminated mail targeting media outlets and political offices (see Figure 4-4). A vaccine against anthrax had been developed in the 1970s but had primarily only been used for people who were routinely exposed to anthrax through contact with animals. In the 1990s, during the Gulf War, the Department of Defense (DOD) had confirmed the existence of an Iraqi bioweapons program and was concerned that anthrax might be used against military personnel. At that time, the DOD began widely vaccinating members of the military and announced in 1997 that all military personnel would eventually be vaccinated against anthrax. However, questions about the vaccine’s safety and efficacy persisted among the public and prompted the initiation of an IOM study in 2000. The attacks on September 11 and the anthrax mailings increased the urgency of the committee’s work, in case the widespread use of the vaccine was deemed necessary as a public safety measure. The IOM’s 2002 report The Anthrax Vaccine: Is It Safe? Does It Work?, which was chaired by NAM member Brian L. Strom,¹⁴ concluded that the existing vaccine was safe and effective. However, it also called for the development of a better vaccine that would not require six doses and annual boosters to maintain efficacy, as was necessary with the existing vaccine (IOM, 2002e). Following the release of the report and its confirmation of vaccine safety, the DOD decided to continue its plan to vaccinate military personnel against anthrax, especially those serving in high-risk areas, and the Department of Health and Human Services (HHS) continued to purchase and maintain its supply of the vaccine.¹⁵

In 2011, HHS commissioned the IOM to conduct a study focused on the potential adverse effects associated with vaccines against measles, mumps, and rubella (MMR); varicella (chicken

___________________

¹³ Impact of IOM Reports (Database), IOM/NAM Records.

¹⁴ Brian L. Strom was a Professor and the Chair of Biostatistics and Epidemiology at the University of Pennsylvania Perelman School of Medicine when this report was published.

¹⁵ Impact of IOM Reports (Database), IOM/NAM Records.

pox); influenza; hepatitis A and B; human papillomavirus (HPV); meningitis; and diphtheria, pertussis, and tetanus (DPT). This report was designed to follow up and build on the IOM’s previous vaccine safety work. The resulting report, Adverse Effects of Vaccines: Evidence and Causality, was released in August 2011. The committee, which was chaired by NAM member Ellen Wright Clayton,¹⁶ concluded that “vaccines remain one of the greatest tools in the public health arsenal” (IOM, 2011a). The HHS applied the data and analysis presented in the report to update the National Vaccine Injury Compensation Program’s (VICP’s) Vaccine Injury Table, which defined specific injuries, disabilities, and illnesses that would qualify a claimant for compensation through the VICP (CDC, n.d.b; HRSA, n.d.). Following the release of the report, HHS indicated that it would use the report to provide “a scientific basis for future review and decisions on VICP claims” (CDC, n.d.b).

In late 2020, as the first-ever mRNA vaccines against COVID-19 were given emergency authorization by the Food and Drug Administration (FDA), the NAM and HMD became heavily involved in advising government, health leaders, and the public about the safety and efficacy of the vaccines, as well as their equitable allocation and distribution (see Chapter 7).

THE SCIENCE OF CHILDHOOD AND ADOLESCENT DEVELOPMENT

From early in its history, the IOM and its leadership promoted the idea that social factors were prominent influences associated with health outcomes. As research on brain development and gene–environment interactions evolved, the organization quickly identified the potential lifelong impact of these interactions, especially exposures and life circumstances from before birth through adolescence. Over time the organization cultivated a body of work dedicated to advancing the science of childhood and adolescent development with a concentration on the complex interactions across a constellation of biological, social, behavioral, and environmental factors. The IOM strongly encouraged the application of science and evidence as a basis for the funding and implementation of programs geared toward children and youth. The organization also consistently highlighted the importance of continued research in areas of childhood and adolescent development to ensure children had the opportunity to fulfill their potential and lead healthy lives.

___________________

¹⁶ Ellen Wright Clayton was the Craig-Weaver Professor of Pediatrics, the Director of the Center for Biomedical Ethics and Society, and a Professor of Law at Vanderbilt University at the time.

From Neurons to Neighborhoods

In 2000, the NRC, in collaboration with the IOM,¹⁷ issued a major report on early childhood development called From Neurons to Neighborhoods: The Science of Early Childhood Development. This report, which was produced by a committee chaired by NAM member Jack P. Shonkoff,¹⁸ became one of the IOM’s most recognizable reports in the field, delving into questions related to the ongoing nature versus nurture debate. Through the report’s 14 chapters, the committee examined evidence surrounding “the nature and tasks of early development” and the “context of early development,” with chapters dedicated to communication and learning; building friendships and interacting with peers; brain development; nurturing relationships and families; child care; and neighborhoods and communities. In presenting the report’s 11 recommendations, the committee concluded that “the nation has not capitalized sufficiently on the knowledge that has been gained from nearly half a century of considerable public investment in research on children from birth to age 5” (IOM and NRC, 2000, p. 384).

What distinguished this report from previous work in this area was that it brought together the latest scientific research on brain development with recent findings in social science on environmental influences on childhood development. The report marked a step forward in assessing the relative effects of gene–environment interactions on development, and it informed policy decisions, programs, and interventions across the nation for many years to come. For example, the report was cited in several pieces of legislation after it was released (e.g., Keeping Children and Families Safe Act of 2003, the 2004 reauthorization of the Individuals with Disabilities Education Act). The report was also cited as the basis for the growing emphasis on early childhood learning programs in a 2012 Wall Street Journal article. Betty Holcomb of the Center for Children’s Initiatives indicated that “the turn toward very early education began with a 2000 study from the National Research Council that brought together years of research arguing that the first three years of life are crucial in a child’s development” (Ensign, 2012).

A decade after the release of From Neurons to Neighborhoods, the IOM and the NRC partnered again to hold a 2-day workshop that was designed to explore advances that had been made since the release of the report. The workshop summary that resulted from the meeting—From Neurons to Neighborhoods: An Update (2012)—captured presentations and discussions from breakout sessions. During the workshop, participants focused on the original report’s four major themes:

1. All children are born wired for feelings and ready to learn.
2. Early environments matter and nurturing relationships are essential.
3. Society is changing and the needs of young children are not being addressed.
4. Interactions among early childhood science, policy, and practice are problematic and demand dramatic rethinking. (IOM and NRC, 2012, p. 43)

In addition to assessing progress that had been made, the workshop participants also considered outstanding challenges and opportunities to promote additional progress in early childhood development research. In his closing remarks, committee chair Shonkoff stated that he believed that the first two themes had “stood the test of time” with new research contributing to the field in those areas (IOM and NRC, 2012, p. 43). He identified the third and fourth themes as urgent needs

___________________

¹⁷ From Neurons to Neighborhoods: The Science of Early Childhood Development was a product of the Board on Children, Youth, and Families, which was administratively positioned within the National Research Council’s Division of Behavioral and Social Sciences and Education (DBASSE) when the report was released. Throughout its history, the BCYF rotated every 5 years between the IOM and the NRC’s DBASSE until 2015 when it found a permanent home within DBASSE.

¹⁸ Jack P. Shonkoff was at the Heller Graduate School of Brandeis University when this report was released.

that required additional attention in order to “dramatically improve the lives of children and their prospects for the future” (IOM and NRC, 2012, p. 44).

The National Children’s Study

In October 2000, Congress passed the Children’s Health Act, which authorized the “National Institute of Child Health and Human Development [NICHD] to conduct a national longitudinal study of environmental influences (including physical, chemical, biological, and psychosocial) on children’s health and development” (IOM and NRC, 2008b, p. 1). The National Children’s Study (NCS), which would be a collaborative effort across the U.S. government, was designed to follow approximately 100,000 children from before birth through the age of 21, representing “the largest long-term study of environmental and genetic effects on children’s health ever conducted in the United States” (IOM and NRC, 2008b, p. 1). Upon request of the NICHD, the National Academies convened a joint NRC and IOM committee chaired by NAM member Samuel H. Preston¹⁹ that was charged with evaluating the “scientific rigor of the NCS and the extent to which it is being carried out with methods, measures, and collection of data and specimens to maximize the scientific yield of the study” (IOM and NRC, 2008b, p. 2). In its report, The National Children’s Study Research Plan: A Review, which was released in 2008, the committee provided an assessment of the strengths and weaknesses of the study design and offered specific recommendations to further improve the plan for the NCS. The committee concluded that the NCS provides “an excellent opportunity” to advance research related to gene–environment interactions and the influence of those interactions on health outcomes and childhood development (IOM and NRC, 2008b, p. 2). Following the release of the report, the NIH released a statement indicating that it would delay a planned expansion of recruitment for individuals to join the NCS that was set to begin in 2009 as a result of the IOM’s report and recommendations (IOM and NRC, 2014b).

In 2013, Congress requested the National Academies to evaluate the NICHD’s revised study plans, resulting in a report called The National Children’s Study 2014: An Assessment (IOM and NRC, 2014b). Following its evaluation, the committee offered a set of recommendations focused on the “overall study framework, sample design, timing, content and need for scientific expertise and oversight” (NAP, 2014). The committee, which was chaired by NAS member Greg J. Duncan,²⁰ reiterated the potential value of the NCS (IOM and NRC, 2014b). However, in December 2014, following the release of the report, Francis Collins, the NIH Director, released a statement that ended the NCS. Citing budget constraints, concerns that were highlighted by the joint NRC and IOM committee, and findings from an internal NIH advisory committee, Collins stated that the NCS was not feasible, indicating optimism “that other approaches will provide answers to these important research questions” (NIH, 2014).

Health Equity and Development

Continuing its commitment to advancing the science of childhood development with an emphasis on complex biological, social, and environmental interactions, the National Academies released a report in 2019 called Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity (NASEM, 2019d). The report was part of the NAM’s Culture of Health Program (COHP; see Chapter 7), and it built on the NRC/IOM’s From Neurons to Neighborhoods work, the 2017 HMD report Communities in Action: Pathways to Health Equity (also part of the COHP;

___________________

¹⁹ Samuel H. Preston was in the Department of Sociology at the University of Pennsylvania when this report was published.

²⁰ Greg J. Duncan was in the School of Education at the University of California, Irvine, during this time.

NASEM, 2017o), and new research in neurobiological and socio-behavioral sciences. Emphasizing the importance of “early experience and life circumstances,” the interactions across biological, psychosocial, and environmental factors, and the influence these interactions and experiences have on health and well-being throughout the course of life, the new report evaluated the evidence behind the causes and consequences of health inequalities for children living in the United States (NASEM, 2019d). The committee, which was chaired by NAM member Jennifer E. DeVoe,²¹ concluded that “reducing health disparities by addressing their systemic root causes, including poverty and racism, is foundational to advance health equity” (NASEM, 2019c, p. 3). In an effort to reduce known disparities and improve outcomes for young children and their families, the committee developed a set of recommendations and a roadmap that government officials, policy makers, and leaders in health care, public health, social services, early care and education, and the justice system could use to apply science to early development. The committee also identified priorities for future research that included studies related to “discrimination and structural racism, trauma-informed care, and development of culturally tailored interventions” (NASEM, 2019c, p. 3).

While Vibrant and Healthy Kids concentrated on development that occurs during the prenatal and early childhood phases of life, the Board on Children, Youth, and Families—now a collaborative activity between HMD and the Division of Behavioral and Social Sciences and Education (DBASSE) (NASEM, n.d.c)—released a report in 2019 as part of the COHP that explored adolescent development. The report was called The Promise of Adolescence: Realizing Opportunity for All Youth (NASEM, 2019f). Like the Vibrant and Healthy Kids report, The Promise of Adolescence examined brain development, the complex interactions between biology and the environment, and health disparities. Following its review of the available evidence, the committee found that “changes in brain structure and connectivity that happen in adolescence present young people with unique opportunities for positive, life-shaping development, and for recovery from past adversity” (NASEM, 2019e, p. 1). To promote health equity and to ensure that adolescents have the opportunity to realize their full potential, the committee—chaired by NAM member Richard J. Bonnie²²—made specific recommendations directed toward the education system, the health system, the child welfare system, and the justice system. In terms of future research, the committee called for further investments in research to expand data and knowledge linked to developmental processes, supportive socio-environmental factors, and understanding and overcoming inequalities for adolescents. Underscoring the need for action, the committee indicated that “our society has a collective responsibility to build systems that support and promote positive adolescent development” (NASEM, 2019f, p. 13).

Advancing Health and Well-Being Throughout Childhood and Adolescence

As with other organizational priorities of ongoing interest and importance, the IOM created two forums in 2014 that were dedicated to advancing children’s health and well-being by applying science and evidence to policy making. The stated goal of the Forum on Investing in Young Children Globally was to ensure that “decision-makers around the world use the best science and evidence for investing to optimize the well-being of children and their lifelong potential” (Huebner et al., 2016). The purpose of the Forum for Children’s Well-Being: Promoting Children’s Cognitive, Affective, and Behavioral Health was to convene discussions that would “strive[s] to advance effective, affordable, and equitable systems that promote well-being and foster evidence-informed prevention, treatment, and implementation research and practice” (NASEM, n.d.d). Both forums

___________________

²¹ Jennifer E. DeVoe was a Professor and the Chair of the Department of Family Medicine at Oregon Health & Science University when this report was published.

²² Richard J. Bonnie was at the University of Virginia during this time.

brought together diverse groups of sponsors, experts, and interested stakeholders for workshops with the common goal of ensuring the best health possible for children and youth across the globe. In addition to the forums and reports described above, the Board on Children, Youth, and Families, in collaboration with other parts of the IOM and the National Academies (e.g., the NRC’s DBASSE), produced numerous consensus reports focused on childhood development and wellbeing over the years, such as those listed in Box 4-3.

FACILITATING PROGRESS IN CANCER RESEARCH

Cancer is a collection of complex diseases that manifest themselves in different ways in different individuals at any point throughout one’s lifespan. Cancer has, arguably, garnered more attention and consideration from a scientific, social, cultural, and political standpoint than any other disease in human history. The IOM started prioritizing cancer as an organizational area of interest in the 1990s when it released its first report entirely dedicated to a cancer-related topic; the report, Oral Contraceptives and Breast Cancer, provided a summary of the potential benefits and risks associated with oral contraceptives based on the latest available evidence and offered recommendations for future research (IOM, 1991a). In 1997, the IOM established the National Cancer Policy Board. During its existence, the board was dedicated to the study of the “prevention, control, diagnosis, treatment, and palliation of cancer.” In 2005, a structural reorganization transformed the National Cancer Policy Board into the National Cancer Policy Forum. The forum continued a

range of activities related to cancer research, diagnosis and treatment, and public health and health policy concerns (see also Chapter 5). Since 2005, the forum has released more than 40 publications resulting from public workshops (NASEM, 2021c).

Although the IOM studied a wide range of topics related to cancer, including quality of care, palliative care (see Chapter 5), and cancer control efforts in low- and middle-income countries (see Chapter 6), a large portion of the IOM’s, and subsequently the HMD’s, cancer work focused on research questions that revolved around what caused cancer, how it might be prevented, and how it could be diagnosed, treated, and possibly cured using cutting-edge technologies. Over the years, the National Cancer Policy Board/Forum served as the organization’s driving force for discourse on advancing cancer research—from improving clinical trials to leveraging informatics and nanotechnology in research. Box 4-4 provides examples of the research-oriented publications released by the National Cancer Policy Board/Forum.

In addition to the work of the National Cancer Policy Board/Forum, the organization also released numerous consensus reports and other workshop summaries that were developed to accelerate and improve cancer research. Some of the publications were generally focused on screening, drug development, and new research tools and techniques (examples described below), while others were tailored to more specific areas of cancer research, such as environmental risk factors associated with cancer. For example, in 2002, the IOM published a summary of a workshop hosted by the Roundtable on Environment Health called Cancer and the Environment: Gene–Environment Interaction (IOM, 2002a). The workshop, which was chaired by NAM member Paul G. Rogers,²³ initiated broad discussions about potential interactions between genes and environmental factors based on recent progress in genomic research, and it provided a venue to explore next steps for research in this area. A decade later, the IOM released Breast Cancer and the Environment: A Life Course Approach (2012b), which considered environmental risk factors specific to breast cancer, how those risk factors could be mitigated throughout the lifespan, and additional research needs. The environmental health section in Chapter 6 provides more information on these two reports. Another area that the IOM and HMD revisited often was cancer research and care for women. Box 4-5 provides samples of reports that were dedicated to meeting the unique needs of women in terms of cancer prevention, detection, and treatment through advances in research.

Cancer Research and Drug Development

As described below and in previous chapters, the IOM and later the HMD have had a long history with the NIH in which the IOM provided advice to the NIH on its research agenda and strategies to ensure progress and equity in scientific research. For example, in 1999 the IOM released a report called The Unequal Burden of Cancer: An Assessment of NIH Research and Programs for Ethnic Minorities and the Medically Underserved. The committee, chaired by NAM member M. Alfred Haynes,²⁴ offered the NIH a set of recommendations devised to ensure that ethnic minority and medically underserved populations were included in and benefited from NIH-funded cancer research programs (IOM, 1999b) (described in more detail in Chapter 5).

A little more than a decade after the release of The Unequal Burden of Cancer, the IOM continued its investigation of the NIH’s cancer research infrastructure with its report, A National Cancer

___________________

²³ Paul G. Rogers was a partner at Hogan & Hartson in Washington, DC, at the time.

²⁴ M. Alfred Haynes was a Former President and the Dean of the Drew Postgraduate Medical School and the Former Director of the Drew-Meharry-Morehouse Consortium Cancer Center in Rancho Palos Verdes, California, during this time.

Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program (IOM, 2010a). As described in the report, clinical trials provided the crucial link between biomedical research findings and advances in cancer prevention, detection, and treatments in clinical practice. For more than a half century the NIH supported the nation’s largest clinical trials network—the Clinical Trials Cooperative Group Program, which was established in 1955 (IOM, 2010a)—and by the early 2000s engaged “more than 3,100 institutions and 14,000 investigators who enroll more than 25,000 patients in clinical trials each year” (IOM, 2010a, pp. 2–3). Following its review, the committee, which was chaired by NAM member John Mendelsohn,²⁵ concluded that “one of the Program’s strengths is the extensive involvement of physicians and patients from the community setting.” However, the program faced significant hurdles in its “ability to conduct the timely, large-scale, innovative clinical trials needed to improve patient care” (IOM, 2010a, p. 2). In response to these findings, the committee offered four goals and a series of recommendations to enhance cancer clinical trials supported by the NIH and its National Cancer Institute (NCI). The committee’s goals involved increasing efficiency, innovation, and physician and patient participation in clinical trials.

Following the release of the 2010 report, the National Cancer Policy Forum continued the conversation with two implementation-oriented workshops that resulted in publications called Implementing a National Cancer Clinical Trials System for the 21st Century (IOM, 2011b, 2013b). In 2014, based, in part, on the IOM’s recommendations and the ongoing discussion through the National Cancer Policy Forum, the NIH restructured its role in and support of clinical trials by establishing the National Clinical Trials Network, which replaced the Clinical Trials Cooperative Group Program (NIH, n.d.b). The NCI also committed to improving the program’s efficiency by shortening timelines for initiating new trials, streamlining the program’s information technology system, and consolidating the nine groups that conduct adult oncology trials into four.²⁶

In response to continuing advances in biomedical research, the IOM released its 2007 report, Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment. The committee explored the use of biomarkers²⁷ as an opportunity to improve cancer outcomes through early detection, precision diagnosis, and the development and use of more personalized treatment options. The committee, chaired by NAM member Harold L. Moses,²⁸ concluded that “progress overall has been slow, despite considerable effort and investment” (IOM, 2007a, p. 3). In its report, the committee provided 12 recommendations that were organized into three categories related to research and tools, guidelines and standards, and methods and processes that could be employed to promote the development, validation, and adoption of biomarkers in research and, eventually, clinical practice. The committee noted that if its recommendations were implemented, they held the potential to streamline biomarker research, making “effective use of the available resources [and creating] a pathway for success that balances the need to encourage innovation while also ensuring that adequate standards for validation and qualification are met” (IOM, 2007a, p. 4). In March 2009, Senator Edward Kennedy (D-MA) sponsored a bill called the 21st Century Cancer ALERT (Access to Life-Saving Early detection, Research and Treatment) Act, which included provisions based on the IOM’s report. The bill also cited the IOM’s 2008 report, Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs (U.S. Congress, Senate,, 2009) (see Chapter 5).

___________________

²⁵ John Mendelsohn was President of the University of Texas M.D. Anderson Cancer Center when this report was published.

²⁶ Impact of IOM Reports (Database), IOM/NAM Records.

²⁷ The committee defined biomarkers as “any characteristic that can be objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or of pharmacological response to a therapeutic intervention” (IOM, 2007a, p. 4).

²⁸ Harold L. Moses was the Ingram Professor of Cancer Research, the Chair of the Department of Cancer Biology, and the Director Emeritus of Vanderbilt-Ingram Cancer Center at this time.

The IOM released two more reports that also contributed to scientific discussions about how to promote advances in biomedical research and drug development in light of new findings, recent technology innovations, and novel opportunities identified by the research community: Large-Scale Biomedical Science: Exploring Strategies for Future Research (IOM and NRC, 2003a) and Evolution of Translational Omics: Lessons Learned and the Path Forward (IOM, 2012a). Although these reports were not focused solely on cancer research, the scientific and biomedical principles described in them and the reports’ recommendations were very much applicable to cancer research, its scientific underpinnings, and its applicability to cancer drug development. For example, Large-Scale Biomedical Science described how new tools and technologies were expanding the scope and scale of biomedical research designed to study complex biological systems. In its report, the committee, which was chaired by external volunteer Joseph V. Simone,²⁹ presented seven recommendations that were intended to “facilitate a move toward a more open, inclusive, and accountable approach to large-scale biomedical research, and help strike the appropriate balance between large- and small-scale research to maximize progress in understanding and controlling human disease” (IOM and NRC, 2003a, p. 11). Evolution of Translational Omics³⁰ reviewed opportunities to “strengthen omics-based test development and evaluation,” with the “ultimate goal of guiding therapeutic decisions to improve patient outcomes” (IOM, 2012a, p. 4). The committee—chaired by NAM member Gilbert S. Omenn³¹—made recommendations to “enhance development, evaluation, and translation of omics-based tests while simultaneously reinforcing steps to ensure that these tests are appropriately assessed for scientific validity (NASEM, n.d.c1).” After evaluating the report’s findings and recommendations, the National Cancer Institute of the NIH developed a checklist that included 30 criteria that were based on the principles set forth in the IOM report. The purpose of the checklist was to determine the readiness of an omics test for use in guiding patient care in clinical trials.³²

Advancing Cancer Prevention and Screening

In addition to its work to support progress in cancer clinical trials and biomedical research broadly, the IOM also contributed to research related to the prevention, screening, and diagnosis of cancer (see related reports in Box 4-6). In 2003, the National Cancer Policy Board released Fulfilling the Potential of Cancer Prevention and Early Detection, which argued that more could be done to reduce rates of cancer. Citing the immense burden of cancer on individuals, families, and the nation, the report presented a national strategy “to realize the promise of cancer prevention and early detection” (IOM and NRC, 2003b). The committee, also chaired by Simone, explored opportunities to prevent cancer through lifestyle changes (e.g., smoking cessation, improvements in diet and exercise), improve outcomes though screening and early detection, leverage primary care settings to implement cancer prevention and control strategies, expand education and training programs, and accelerate research. The committee set forth a dozen recommendations intended to guide a national strategy that could reduce the burden of cancer in the United States. Highlighting available evidence to support screening and prevention efforts, the committee urged policy mak-

___________________

²⁹ Joseph V. Simone was with Simone Consulting in Dunwoody, Georgia, at the time.

³⁰ The term “omics” encompasses “multiple molecular disciplines that involve the characterization of global sets of biological molecules such as DNAs, RNAs, proteins, and metabolites. For example, genomics investigates thousands of DNA sequences, transcriptomics investigates all or many gene transcripts, proteomics investigates large numbers of proteins, and metabolomics investigates large sets of metabolites” (IOM, 2012a, p. 1).

³¹ Gilbert S. Omenn was a Professor of Internal Medicine, Human Genetics, and Public Health, and the Director of the University of Michigan Center for Computational Medicine and Bioinformatics at the University of Michigan Medical School in Ann Arbor when this report was published.

³² Impact of IOM Reports (Database), IOM/NAM Records.

ers, government agencies, health insurance companies, and others to implement evidence-based guidelines, programs, and policies.

In 2010, the IOM released a report called Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C, which reviewed opportunities to prevent chronic liver disease and liver cancer. The committee, chaired by external volunteer R. Palmer Beasley,³³

___________________

³³ R. Palmer Beasley was the Ashbel Smith Professor and the Dean Emeritus of the University of Texas School of Public Health in Houston when this report was released.

estimated that in the United States approximately 150,000 people would die in the next decade as a result of liver disease or cancer caused by hepatitis B and C (IOM, 2010b). Although there is a vaccine against hepatitis B, preventing hepatitis C relies on strategies to eliminate exposure to the blood-borne pathogen. Like the IOM’s 2003 report Fulfilling the Potential of Cancer Prevention and Early Detection, this new report outlined a national strategy focused on screening and prevention. Following a review of available evidence, the committee offered recommendations to improve surveillance, increase knowledge and awareness, expand rates of hepatitis B vaccination for at-risk populations, and strengthen programs for screening for, preventing, and controlling hepatitis B and C infections (IOM, 2010b). The committee also called for additional research to develop a vaccine for hepatitis C and research on the “effectiveness and safety of peripartum antiviral therapy to reduce and possibly eliminate perinatal hepatitis B virus transmission” (IOM, 2010b, p. 6).

SCIENTIFIC ADVISOR TO THE U.S. GOVERNMENT

The IOM’s mission to provide evidence-based advice, often in response to developments in scientific research, requires establishing effective ongoing relationships with many federal, state, and local agencies, such as the NIH, the FDA, the Department of Veterans Affairs (VA), and many others, as well as non-profit and international organizations, such as the African Academy of Sciences. Because of the IOM’s reputation and its charter under the National Academies, agencies and organizations from around the world have relied on the IOM, and now the NAM and HMD, to provide evidence-based recommendations that are unbiased and removed from partisan politics. For the past half-century, the IOM, the NAM, and the HMD have brought together the most well-respected experts to evaluate available research and to inform advances in scientific research and policy.

Advising the National Institutes of Health

As the federal government’s leader in medical sciences and research, the NIH has a long history with the IOM that dates back to its origins as the Board on Medicine. At that time, NIH Director James Shannon served as an advisor in the creation of what would become the IOM (see Chapter 1). The IOM’s second president, Donald Fredrickson, was also a long-time NIH employee who left his position as IOM President to serve as the NIH’s Director, and David Hamburg, the IOM’s third President, spent a significant portion of his career at the NIH (see Chapter 2). Numerous other NIH leaders have been elected as IOM and NAM members, including NIH Director Francis Collins and the Director of the National Institute of Neurological Disorders and Stroke, Story Landis. Additionally, many IOM/NAM members have received research funding at their home institutions through NIH research programs and grants. These close connections have fostered a productive relationship in which the NIH has sponsored numerous IOM/NAM studies and roundtables throughout the years. Leaders and researchers from the NIH were often called on by IOM committees to present and inform their deliberations. In return, the IOM served as an advisor to the NIH, often providing guidance on its research agenda, its organization, and its policies and programs. The NIH’s ongoing relationship with the IOM continues today through new collaborations with the NAM such as the Action Collaborative on Countering the U.S. Opioid Epidemic (see Chapter 7). The NIH also continues to sponsor new HMD studies and participates in the division’s roundtables and forums (e.g., Roundtable on Genomics and Precision Health, the Forum on Neuroscience and Nervous System Disorders, and the National Cancer Policy Forum).

The subject of the NIH’s organization and how it should conduct its major research activities has arisen many times during the IOM’s history. This topic has always been crucial to the academic research community, as the NIH’s organizational structure in many ways shapes the funding structure and grant opportunities available to academic researchers across the United States. Look-

ing back, during the Reagan era, the IOM studied the organization of the NIH for the first time. Released in 1984, the IOM’s brief report—Responding to Health Needs and Scientific Opportunity: The Organizational Structure of the National Institutes of Health—advised against the creation of institutes to address such subjects as nursing and arthritis, as Congress was considering at the time. The report suggested that the NIH needed to have organizational coherence and stability, stating that there should be a “presumption—to be overridden only in exceptional circumstances—against additions at the institute level” (IOM, 1984a, p. 20).

In 1990 and 1998 the IOM returned to questions related to the NIH’s structure and priority setting process. The 1990 report—Consensus Development at the NIH: Improving the Program, which was chaired by J. Sanford Schwartz, an NAM member and Councilor (2019–2021)³⁴—reviewed the structure and function of the NIH’s Consensus Development Program (IOM, 1990a). The NIH program was charged with releasing consensus statements that reviewed available evidence related to current topics in medicine and medical research, not unlike the mission of the IOM (NIH, n.d.c). The 1998 report, Scientific Opportunities and Public Needs: Improving Priority Setting and Public Input at the National Institutes of Health, proved to be particularly influential in the NIH’s operations. In the report, the IOM committee, which was chaired by NAM member Leon E. Rosenberg,³⁵ called on the NIH to “strengthen its analysis and the use of health data, such as burdens and costs of disease” when setting its research priorities (IOM, 1998d, p. 5). The report also recommended ways the NIH could assess the potential for scientific progress in a particular area and means by which to balance the goals of treating illnesses and investing in research focused on prevention. The report highlighted the need for better tracking and data related to the amount of funding the NIH dedicated to research related to specific diseases. The IOM also urged the NIH’s institutes and centers to develop multi-year strategic plans and encouraged the development of an office focused on gathering public input. The report noted that the organizational structure of the NIH required periodic review in “light of changes in science and health needs of the public” (IOM, 1998d, p. 11). Following the release of the report, the NIH implemented the Research, Condition, and Disease Categorization process, which was used to track and report spending on different diseases and research areas.³⁶

In addition to reviewing the NIH’s structure and priority setting processes, the IOM also contributed to national discussions about the environment in which all medical research on humans was conducted and the ethical questions associated with the use of chimpanzees in medical research. In 2003, the IOM released Responsible Research: A Systems Approach to Protecting Research Participants. The report was commissioned by HHS in response to public concern that originated from isolated but widely reported incidents involving research participants, such as the death of a volunteer in an asthma study. Injuries and deaths associated with research participation led to questions about the safety of human research funded by the NIH and other government and industry sponsors. In its report, the committee, which was chaired by NAM member Daniel D. Federman,³⁷ emphasized the necessity of pursuing “every promising mechanism to maximize the protection of individuals participating in research” (IOM, 2003a, p. viii). The report presented a three-part strategy that included refocusing Institutional Review Boards on “thorough ethical review and oversight of research protocols,” integrating research participants into the system, and maintaining “high

___________________

³⁴ J. Sanford Schwartz was the Executive Director of the Leonard Davis Institute of Health Economics, an Associate Professor of Medicine and Health Care Systems, and the Robert D. Eilers Associate Professor of Health Care Management and Economics at the University of Pennsylvania when this report was published. J. Sanford Schwartz passed away in 2021.

³⁵ Leon E. Rosenberg was a Professor in the Department of Molecular Biology and the Woodrow Wilson School of Public and International Affairs at Princeton University during this time.

³⁶ Impact of IOM Reports (Database), IOM/NAM Records.

³⁷ Daniel D. Federman was the Carl W. Walter Distinguished Professor of Medicine and Medical Education at Harvard University in Boston, Massachusetts, during this time.

standards for and continuing review of Human Research Participants Protection Programs” (IOM, 2003a, p. 5). The report stated that throughout the process, the needs of the research participants—not of the institution conducting the research—should be paramount. The report stressed the importance of recognizing research participants’ contributions to science and stated that injuries acquired as a result of study participation should be adequately compensated without regard to fault (IOM, 2003a).

Because chimpanzees often served as a proxy for humans in medical research, the NIH turned to the IOM and the NRC’s Board on Life Sciences in December of 2011 to help determine whether the use of chimpanzees in medical research was still necessary given the availability of new research technologies, techniques, and cell lines. In its report—Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity—the committee indicated that the chimpanzee’s genetic proximity to humans “not only make[s] it a uniquely valuable species for certain types of research” but also demands “a greater justification for conducting research using this animal model” (IOM and NRC, 2011a, p. 2). The committee, which was chaired by NAM member and Councilor (2020–2022) Jeffrey P. Kahn,³⁸ came to an unexpected conclusion that had a wide impact on medical research across the county, stating that “while the chimpanzee has been a valuable animal model in past research, most current use of chimpanzees is unnecessary” except for a few very specific cases (IOM and NRC, 2011a, p. 4). In January 2013, the NIH released a response on how it would implement the committee’s recommendations, accepting 28 out of 29 of the recommendations.³⁹ By August 2016, the NIH had developed a plan to retire all of the chimpanzees used in research to a federally owned sanctuary (NIH, n.d.d; see Figure 4-5). The NIH’s response and actions demonstrated the very tangible impact of the IOM’s work on the conduct of medical research in the United States.

___________________

³⁸ Jeffrey P. Kahn was with the Johns Hopkins University Berman Institute of Bioethics at this time. Jeffrey P. Kahn concluded his term as Councilor in 2021 but assumed the seat of J. Sanford Schwartz after his passing, also in 2021.

³⁹ “Impact of IOM Reports and Activities, Documented April–June 2014,” in IOM Council Minutes, July 1, 2014; “Inspiring Action,” IOM Council Minutes, April 15, 2015,

Continuing its service as an advisor to the NIH, the IOM released The CTSA Program at NIH: Opportunities for Advancing Clinical and Translational Research in 2013. The NIH had commissioned the IOM to review its Clinical and Translational Science Awards Program (CTSA). The CTSA Program had been established in 2006 “to provide integrated intellectual and physical resources for the conduct of original clinical and translational research” and to expedite the translation of basic and clinical research “into clinical and community practice” (IOM, 2013c, p. 1). In the program’s first 7 years, it grew from 12 to 61 research sites. The program aimed to link these sites and their research, creating a national consortium that promoted the application of best practices in clinical and translational research. A CTSA Consortium Coordinating Center at Vanderbilt University served as a central hub for disseminating research and other resources to the participating sites. The committee was chaired by Alan I. Leshner, an active NAM member who served on its Council from 2007 to 2012 and sat on HMD’s Division Committee from 2018 to 2021.⁴⁰ During its review, the committee identified widespread support of the CTSA program, and noted that it had succeeded in establishing the CTSA sites as “academic focal points for clinical and translational research” (IOM, 2013c, p. 4). The task ahead involved transforming the CTSA program and its sites into a “tightly integrated network” (IOM, 2013c, p. 4) in which researchers actively engaged in “substantive and productive collaborations” (IOM, 2013c, p. 4). The committee concluded that the CTSA program was fulfilling its mission and “should be the national leader for advancing innovative and transformative clinical and translational research to improve human health” (IOM, 2013c, p. 13). In response to the IOM’s report, the NIH’s National Center for Advancing Translational Sciences (NCATS) Advisory Council released a report in May 2014 called the “NCATS Advisory Council Working Group on the IOM Report: The CTSA Program at NIH” (NCATS, 2014, p. 1). The advisory committee’s report was drafted to respond to the IOM’s recommendations and “to provide guidance on programmatic changes needed to implement the report’s recommendations” (NCATS, 2014, p. 1).

Food and Drug Administration: Promoting the Development and Regulation of Safe Medical Products

For more than a century, the FDA has had the difficult task of approving new drugs and therapies to protect the public without unduly delaying access to potentially life-saving treatments. Over the years, many of the FDA’s leaders were also IOM members and served in IOM leadership roles, including Jane Henney and Margaret Hamburg, who served as IOM’s Home and Foreign Secretaries, respectively. IOM members Rob Califf, Lester Crawford, Charles E. Edwards, Scott Gottlieb, Jere Goyan, Don Kennedy, David Kessler, Mark McClellan, and Frank E. Young also served as FDA commissioners over the years. Although the FDA had sponsored IOM reports previously, the IOM’s relationship with the FDA solidified in the beginning of the 21st century when the IOM was called on to provide an unbiased assessment of the FDA’s regulation of drugs following a turbulent period in the history of pharmaceutical policy and drug safety.

In the last two decades of the 20th century, the FDA faced sharp political and public criticism over the slow speed of its drug approval process. During the peak of the HIV/AIDS epidemic in the 1980s, delays in the drug approval process were widely publicized and protestors accused the FDA of blocking access to experimental drugs that held promise to treat HIV/AIDS (Aizenman, 2019). During the next decade, House Speaker Newt Gingrich called the FDA the “leading job killer in America,” and pharmaceutical companies threatened to move their operations overseas. In an effort to reduce the length of time required for the drug review process, Congress passed the Prescription

___________________

⁴⁰ Alan I. Leshner was with the American Association for the Advancement of Science in Washington, DC, when this report was published.

Drug User Fee Act in 1992, which allowed the pharmaceutical industry to pay the FDA user fees. While the 1992 act did shorten the drug approval process, there were concerns of unintended safety consequences associated with approving drugs that had not been fully evaluated in larger numbers of people in the general population (Applebaum, 2005; Wadman, 2005).

During the first few years of the 21st century, a number of serious drug safety issues came to light that amplified criticism of the FDA. On September 30, 2004, Merck withdrew the anti-inflammatory Vioxx—a drug used by at least two million people with arthritis and other painful conditions—due to reports of increased risks of heart attacks and strokes. The Senate Finance Committee investigated the withdrawal and found evidence that Vioxx had caused at least 88,000 heart attacks, of which 30 to 40 percent were fatal. David Graham of the FDA’s Office of Drug Safety told the senators that “Vioxx is a terrible tragedy and a profound regulatory failure.” In April 2005, the FDA asked Pfizer to withdraw Bextra, another popular drug used to treat rheumatoid arthritis and osteoarthritis, because of risks it posed to the heart, stomach, and skin (Wadman, 2005).⁴¹ Safety concerns with other classes of drugs also arose at this time. Anti-depressants such as Paxil were linked to suicides among adolescents. Crestor, a cholesterol medication used by 2.8 million people, was associated with a muscle-destroying condition called rhabdomyolosis. Hormone replacement therapies used by hundreds of thousands of women over several decades were linked to increased risk of breast cancer, heart disease, stroke, and blood clots.

In 2005, the FDA commissioned an IOM report to evaluate the existing systems for drug approval and post-market surveillance and to “make recommendations to improve risk assessment, surveillance, and the safe use of drugs” (IOM, 2006g, p. 3). Throughout the study, the committee and its deliberations were closely monitored by interested stakeholders including the media, the FDA, and Congress. The committee’s first public meeting included testimony from Janet Woodcock, Deputy Commissioner of Operations at the FDA, who told the committee that the system had “obviously broken down to some extent.” Woodcock cautioned, however, that risk-free drugs were not possible. “One of the questions on the table, really,” she said, “is how much uncertainty are we willing to tolerate.”⁴² On September 22, 2006, the IOM released the committee’s much anticipated report, The Future of Drug Safety: Promoting and Protecting the Health of the Public. In its findings, the committee—chaired by NAM member and Councilor (2012–2018) Sheila P. Burke⁴³—highlighted the overall consensus among stakeholders that improvements were needed in the drug approval process, signaling an openness to change. In an effort to guide that change, the committee offered 25 detailed recommendations to strengthen the pre- and post-approval phases in the areas of organizational culture, science and expertise, regulation, communication, and resources. The committee encouraged a lifecycle approach to the drug safety system in which newly available data would continuously inform a more complete risk and benefit profile of approved drugs that could then be used to update regulatory decisions in a more transparent way (IOM, 2006g).

To promote continuous open dialog about drug development among stakeholders, including the FDA, NIH, pharmaceutical companies, academic researchers, and patient organizations, the IOM launched the Forum on Drug Discovery, Development, and Translation in 2005 (IOM, 2010g). In its 15-year history, the forum has held almost 50 meetings and released 30 publications. In its early days, the forum’s work continued and expanded on many of the discussions initiated after the release of the 2006 Drug Safety report, including a 2007 workshop that focused on the implication of the report’s recommendations and the next steps for the FDA in fulfilling those recommendations (IOM, 2007c). The forum also tackled overarching topics related to the development of medical

___________________

⁴¹ “Timeline and Key Stakeholders,” IOM Committee on the Assessment of the U.S. Drug Safety System, Background Information, May 9, 2005.

⁴² “Transcript,” The Nightly Business Report, June 8, 2005, IOM/NAM Records.

⁴³ Sheila P. Burke was the Deputy Secretary and the Chief Operating Officer of the Smithsonian Institution in Washington, DC, during this time.

products such as understanding and communicating uncertainty on product risks and benefits (IOM, 2007d), advancing regulatory sciences, and examining real-world evidence (NASEM, 2016a). Over the years, the forum’s work stretched beyond the borders of the United States and served as a venue to discuss global topics related to drug development including drug-resistant tuberculosis and the harmonization of global drug regulation (IOM, 2013f). Following the transition from the IOM to HMD, the forum established four thematic priorities to guide its activities: innovation and reform of the drug discovery and development enterprise, science across the drug development and discovery lifecycle, clinical trials and clinical product development, and infrastructure and workforce (NASEM, 2019i). In a 2015 congressional report, Senators Lamar Alexander (R-TN) and Richard Burr (R-NC) cited the forum “as a foundational resource in identifying and addressing the challenges facing the U.S. clinical trials enterprise.”⁴⁴

In an effort to improve post-market evaluation and regulation of drugs, following the enactment of the Food and Drug Administration Act of 2007, the FDA called on the IOM to “convene a committee to evaluate the scientific and ethical issues involved in conducting studies of the safety of approved drugs” (IOM, 2012c, p. 4). The committee released a letter report in July 2010 that offered a framework for evaluating data from post-market studies. The committee’s final report, Ethical and Scientific Issues in Studying the Safety of Approved Drugs, which was released in 2012, concluded that the “FDA’s current approach to drug oversight in the post-marketing setting is not sufficiently systematic and does not ensure continued assessment of benefits and risks of drugs associated with a drug over its lifecycle” (IOM, 2012c, p. 14). The committee, which was co-chaired by NAM members Ruth R. Faden⁴⁵ and Steven N. Goodman,⁴⁶ offered 22 recommendations and called on the FDA to establish a standardized, yet flexible, regulatory framework to make the agency’s “decision-making process more predictable, transparent, and active” (IOM, 2012c, p. 14). Echoing sentiments from the 2006 report, the committee encouraged the FDA to “embrace more fully a lifecycle approach to drug safety oversight” (p. 1), emphasizing the importance of post-market review as a critical part of ensuring the safety of medical products used by millions of Americans every day.

Veterans Health Administration: Occupational and Environmental Exposures During Military Service

The VA operates the largest direct service health care system in the United States, the Veterans Health Administration (VA, n.d.a). Some of the more than 9 million American veterans who seek care through the VA each year are living with the aftereffects of exposure to dangerous environments and hazardous substances that were encountered during military service. These types of exposures to chemicals, radiation, and other pollutants and health hazards, including risk factors for posttraumatic stress disorder (see Chapter 6) and traumatic brain injury that might occur during the course of military service, are considered a unique type of occupational health concern. As with other types of occupational and environmental exposures to hazardous substances, the long latency period between exposure during military service and the manifestation of disease makes establishing causality difficult. As demonstrated in the following sections, the recognition and study of hazardous exposures unique to military service has expanded over time with each war and military conflict and have sometimes been associated with increasing pressure from veterans, their families,

___________________

⁴⁴ Impact of IOM Reports (Database), IOM/NAM Records.

⁴⁵ Ruth R. Faden was the Philip Franklin Wagley Professor of Biomedical Ethics and the Executive Director of the Berman Institute of Bioethics at the Johns Hopkins University in Baltimore, Maryland, at this time.

⁴⁶ Steven N. Goodman was a Professor of Medicine and Health Research and Policy and the Associate Dean for Clinical and Translational Research at the Stanford University School of Medicine in Stanford, California, when this report was published.

and advocates. The studies evolved from WWII exposures associated with nuclear and chemical weapons testing to Agent Orange exposure during the Vietnam War to air pollutants from burn pits that were used to dispose of waste during conflicts in Iraq and Afghanistan. Working with the VA to study veterans’ health and the possible linkages with exposure to hazards as part of military service was a core activity of the IOM’s Medical Follow-Up Agency (MFUA) for more than 70 years.

Founded by Michael DeBakey in 1946 within the NRC, the Medical Follow-Up Agency conducted ongoing clinical studies designed to evaluate injuries and disease associated with veterans’ service in World War II. In 1955 the MFUA initiated a long-term effort to create a twins registry that would include verified sets of twins, both of whom had served in World War II. During its more than half-century existence, the registry grew to include nearly 16,000 twin pairs and served as the basis for numerous epidemiologic and heritability studies, including psychological studies and studies of a range of diseases such as cancer, Alzheimer’s disease, and Parkinson’s disease (Gatz and Butler, 2020). Access to the registry was strictly managed through a committee, and proposed research studies had to meet Institutional Review Board requirements. The comprehensive nature of the registry and the records associated with it made the registry “one of the most valuable longitudinal cohorts of aging men available” (IOM, 2003k, p. 115).

In 1988, the MFUA moved from the NRC to the IOM where it evolved to focus more broadly on epidemiologic studies of veteran populations and their health concerns. The MFUA’s work was not entirely free of controversy, which stemmed, in part, from veterans’ disability compensation programs in which payments varied according to the severity of the injury. The VA looked to the IOM to review the evidence associated with exposures during military service, and the VA would then use the IOM’s findings to inform decisions regarding the compensation programs and which diseases would be covered (Panangala et al., 2014). Determining compensation for occupational diseases was particularly challenging because it was sometimes hard to separate health problems caused by military service from those that were associated with a person’s lifestyle (e.g., lung diseases and cancer) or with other occupational exposures (e.g., agriculture, mining, manufacturing).

Although the MFUA conducted numerous epidemiologic studies of veterans over the years, there were times when the agency concluded that epidemiologic studies were not feasible. Following World War II, a number of soldiers were present at the sites where atmospheric tests of nuclear weapons were conducted between 1945 and 1962. In subsequent years, these veterans, who were referred to as “atomic veterans” were concerned about possible adverse reproductive outcomes for their spouses and possible genetic defects and disease for their children and grandchildren. In 1994, the VA asked the IOM to assess the feasibility of conducting epidemiological studies to evaluate possible effects in the spouses, children, and grandchildren of the atomic veterans. The challenge with diseases caused by radiation was that they were “generally indistinguishable from those that occur naturally in the population from other causes.” In 1995, the IOM released Adverse Reproductive Outcomes in Families of Atomic Veterans: The Feasibility of Epidemiologic Studies, which was authored by a committee chaired by external volunteer William J. Schull.⁴⁷ The committee concluded that epidemiological studies among the families of atomic veterans would be infeasible (Miller, 1995). For example, finding and engaging a large enough sample size of children and grandchildren of atomic veterans to study was difficult. Additionally, establishing the levels of radiation that the veterans had been exposed to would have been challenging, and the estimates that were available suggested that the exposures during the weapons testing were generally below common forms of additional background radiation exposures (e.g., living at a high altitude, receiving CT scans) (IOM, 1995).

Some of the IOM’s epidemiologic studies evaluated direct hazard exposures that resulted from

___________________

⁴⁷ Willliam J. Schull was the Director of the Center of Demographic and Population Genetics at the School of Public Health at the University of Texas at Houston when this report was released.

classified experiments involving military personnel. During World War II, War Department officials were concerned by the threat of chemical weapons. In an effort to protect soldiers in war zones from mustard gas and an arsenic-containing agent called lewisite, the War Department initiated a chemical defense research program that tested protective clothing against these gases. In the studies, military personnel wearing the test clothing were exposed to mustard gas or lewisite in a gas chamber until the soldier developed erythema, indicating a failure of the clothing. At the conclusion of the research program, more than 60,000 military personnel had been involved in the testing. Over time, some of the veterans who had participated in the tests began experiencing health problems they thought could be related to their exposures to the poisonous gases. Some sought benefits from the VA, only to have their claims denied because of the secrecy of the test programs. Eventually the VA identified seven conditions, including asthma and chronic bronchitis, that might be related to participation in the tests. In 1991, the VA asked the IOM “to assess the strength of association between exposure to these agents and the development of specific diseases” (IOM, 1993a, p. 2).

The IOM released Veterans at Risk: The Health Effects of Mustard Gas and Lewisite on January 6, 1993. The study committee found it difficult to draw conclusions from the thousands of scientific reports it reviewed and testimony from the affected veterans it heard during its open information-gathering sessions. However, the evidence did support a causal relationship between exposures to the poisonous gases and a variety of diseases that included respiratory diseases and cancers, skin diseases and cancer, various eye conditions and diseases, leukemia, psychological disorders, and reproductive dysfunction. The committee also uncovered evidence that the participants’ exposure may have been higher than originally reported. The committee was dismayed by the lack of follow-up health assessments and epidemiologic studies, which diminished the availability of data. In its report, the committee noted that the secrecy surrounding the program and testing “impeded well-informed health care for thousands of people” (IOM, 1993a, p. 8). The committee, chaired by NAM member and Foreign Secretary (1994–1998) David P. Rall,⁴⁸ recommended that the VA establish a program to identify, notify, evaluate, and follow veterans who had participated in this chemical defense research program and had been exposed to mustard gas and lewisite (IOM, 1993a; Pechura, 1993).

Subsequent wars and conflicts led to different types of occupational exposures and health concerns for veterans who had served their country. For Vietnam veterans, exposure to Agent Orange and other herbicides used on the battlefield created the potential for long-term health problems (see Figure 4-6). In 1991, Congress passed a law that called on the IOM to complete a biennial review of available medical and scientific literature related to exposure to the herbicides that were used in the Vietnam War (see Box 4-7). To conduct the work, the IOM appointed a new committee to review the available literature for each update, and the committees were sometimes asked to focus on specific health outcomes that might be related to exposure. For example, the 1996 update identified “limited or suggestive” evidence of the presence of spina bifida in children of fathers who were Vietnam veterans with exposure to herbicides. This finding supplemented findings from previous updates that highlighted “sufficient evidence of an association” between exposure to herbicides and soft-tissue sarcoma and Hodgkin’s disease.

Unlike other IOM activities, the ongoing mechanism by which the Agent Orange series revisited the literature identified new connections as the veterans aged and as new diseases were manifested. It also allowed for amending previous findings based on new evidence. For example, the 2012 update indicated “limited or suggestive” evidence of linkages between exposure and strokes (IOM, 2014a), and the 2014 update concluded that Parkinson’s-like symptoms and Parkinson’s disease were associated with exposure, while also downgrading the spina bifida evidence

___________________

⁴⁸ David P. Rall was a retired Director of the National Institute of Environmental Health Sciences at the National Institutes of Health in Washington, DC, at the time.

from the 1996 update to “inadequate/insufficient” (NASEM, 2016b). The findings from this series of reports improved the medical care that Vietnam veterans received by increasing the awareness of VA clinicians who cared for these patients. The findings also improved the veterans’ disability compensation system by improving the accuracy and completeness of the list of diseases and con-

ditions associated with exposures to herbicides, and therefore, eligible for compensation (IOM, 1996a). The last report in the series was released in November 2018 and served as the 11th biennial update (NASEM, 2018a).

During the Vietnam War era, between 1962 and 1973, the military conducted testing that was referred to as Project SHAD (Shipboard Hazard and Defense). The goal of the tests was to assess the susceptibility of naval ships to chemical and biological agents that could be deployed in war time. It is estimated that approximately 6,000 Navy and Marine Corps personnel were exposed to various agents during these tests, and not all of them were made aware of the testing at the time (IOM, 2007b). In 2002, the VA commissioned the IOM to conduct an epidemiologic study after numerous veterans who had been exposed to hazardous agents during Project SHAD raised health concerns that could be connected to their exposures. The IOM and the National Academies went on to release two reports: Long-Term Health Effects of Participation in Project SHAD (Shipboard Hazard and Defense)⁴⁹ (IOM, 2007b) and Assessing Health Outcomes Among Veterans of Project SHAD (Shipboard Hazard and Defense) (NASEM, 2016c).

The first study, which was released in 2007, “found no difference in all-cause mortality between SHAD veterans and the comparison group, but there was an increased risk of death from heart disease among some SHAD veterans” (IOM, 2007b, p. 2). Subsequent survey results also determined that SHAD participants reported “poorer overall physical and mental health” (NASEM, 2016c, p. 1). The second study, which was released in 2016, analyzed 7 years of additional data and some newly available diagnostic data. The findings from the follow-up report generally aligned with findings from the first report, but “it did not find an elevation in heart disease mortality” (NASEM, 2016c, p. 1). Following the two studies, the committee, which was chaired by external volunteer David J. Tollerud,⁵⁰ concluded that “the results of the analyses provide no evidence that the health of SHAD veterans overall or those in the exposure groups is significantly different from that of similar veterans who did not participate in these tests” (NASEM, 2016c, p. 9).

Beyond the epidemiologic studies conducted by the MFUA that focused primarily on WWII and Vietnam era veterans, MFUA and the IOM’s other boards also conducted studies relevant to the health of U.S. veterans following exposures to hazardous materials and physical and psychological stressors during more recent military conflicts. For example, in the early 1990s, the United States deployed nearly 700,000 military personnel to the Persian Gulf region to fight in and support Operation Desert Shield and Operation Desert Storm. Upon returning home, some of the veterans reported health concerns that they attributed to their military service and exposures during that time. As public scrutiny increased and symptoms were documented in 25 to 35 percent of veterans who served (IOM, 2013d), Congress and the VA commissioned the IOM to conduct a range of studies to understand the long-term health outcomes of service in the Gulf War. The studies were designed to evaluate best practices for collecting and analyzing data, provide comprehensive literature reviews on the health effects of specific exposures, conduct ongoing and long-term review of the health effects of serving in the Gulf War, and recommend treatment strategies. In the quarter century following the end of the Gulf War, the IOM, and subsequently the HMD, released more than two dozen reports dedicated to the health of Gulf War veterans (see Box 4-8). The series of reports covered a variety of potential exposures that military personnel encountered from different types of radiation (e.g., depleted uranium) and chemicals (e.g., insecticides, combustible products) to infectious diseases to physical and psychological consequences of serving in the Gulf War. Many of these exposures were unique to military service when compared to occupational and environmental

___________________

⁴⁹ This report was authored by three IOM staff members—William F. Page, Heather A. Young, and Harriet M. Crawford—with oversight from an advisory panel that was chaired by Daniel H. Freeman, Jr.

⁵⁰ David J. Tollerud was a Professor and the Chair of the Department of Environmental and Occupational Health Sciences at the University of Louisville School of Public Health and Information Sciences when this report was released.

exposures in other types of more traditional occupational settings, requiring long-term assessment to fully understand the health effects of these exposures.

The Gulf War and Health series of reports shaped the VA’s policies related to the benefits and services that are provided to Gulf War veterans, and in some cases the VA expanded benefits available to veterans as a direct result of the reports’ findings. For example, the VA classified certain symptoms and illnesses identified in the IOM’s reports (e.g., ALS, functional gastrointestinal illnesses, certain medically unexplained illnesses) as “Gulf War Presumptive Illnesses,” which resulted in an expedited benefits application process for veterans with these illnesses and symptoms (VA, 2016, n.d.b). In 2013, citing Volume 7 of the IOM’s Gulf War and Health series, the VA expanded available benefits for veterans who had experienced traumatic brain injuries and added five conditions associated with service-related traumatic brain injuries to its list of presumptive illnesses: Parkinson’s disease, certain types of dementia, depression, unprovoked seizures, and

certain diseases of the hypothalamus and pituitary glands.⁵¹ The VA also used the series of reports and the findings included in the reports to increase the available funding for research. For example, following the release of the 2013 and 2014 reports on chronic multi-symptom illnesses, the VA allocated $2.8 million to assess possible treatments for the conditions experienced by Gulf War veterans.⁵² In 2016, following the release of the tenth volume of the Gulf War and Health series, the VA extended the deadline for veterans seeking benefits for illnesses associated with service in the Gulf War by 5 years to 2021. In making its decision, which was based on the report’s finding, the VA noted that “symptoms could manifest in Gulf War veterans at any point, and there was no basis for stopping veterans from seeking benefits at the end of 2016.”⁵³

Following the terrorist attacks of September 11, 2001, the United States deployed military forces to Afghanistan and Iraq to lead and support armed conflicts that lasted nearly two decades. During these conflicts the military used open air burn pits to dispose of waste (e.g., plastic, metal, wood, solvents, medical waste, human waste, petroleum) (NASEM, 2017c; see Figure 4-7); one of these pits, located outside of Baghdad, was used to burn “up to 200 tons of waste per day in 2007” (IOM, 2011c). The emissions from these burn pits raised questions about possible adverse health effects for military personnel exposed to these pits during their military service. On two separate occasions, the VA asked the IOM and then the HMD to conduct studies related to the burn pits.

In 2011, the IOM released Long-Term Health Consequences of Exposure to Burn Pits in Iraq and Afghanistan, which concluded that there was insufficient evidence available to provide concrete conclusions regarding the long-term health effects of burn pit exposure. The committee, also chaired by Tollerud,⁵⁴ recommended “more efficient data-gathering methods” along with another study that would “evaluate the health status of service members from their time of deployment over many years to determine their incidence of chronic diseases” (IOM, 2011c). In 2010, prior

___________________

⁵¹ Impact of IOM Reports (Database), IOM/NAM Records.

⁵² Ibid.

⁵³ Ibid.

⁵⁴ David J. Tollerud was a Professor and the Chair of the Department of Environmental and Occupational Health Sciences at the University of Louisville School of Public Health and Information Sciences when this report was released.

to the release of the IOM’s report, Congress banned the use of open air burn pits, and in 2013, the VA established a registry at the direction of Congress to better document personnel who had been exposed (NASEM, 2017c). In 2017, the HMD released a second report called Assessment of the Department of Veterans Affairs Airborne Hazards and Open Burn Pit Registry, which reviewed the design of the registry and the use of its data. In its report, the committee, which was chaired by NAM member David A. Savitz,⁵⁵ provided a set of recommendations directed at improving the registry in terms of “addressing the future medical needs of the affected groups … and collecting, maintaining, and monitoring information collected” (NASEM, 2017c, p. 13).

The MFUA remained part of the IOM until 2015, when it was transferred to the HMD following the creation of the NAM. However, today MFUA’s activities are limited and only represent a small fraction of the work it once did. In many ways, the MFUA’s work was unique among the IOM’s portfolio. For example, some of the work was ongoing in nature (e.g., Agent Orange series) and some of it involved original research that was conducted by statisticians and epidemiologists on the MFUA staff who collaborated with clinical investigators from academic medical centers (Berkowitz and Santangelo, 1999). The MFUA maintained its twins registry and also established a cohort catalog, a “collection of study populations of former military personnel assembled as part of proposed or completed research dating back to the 1940s” (Butler, n.d.). Under HMD, the MFUA became part of the Board on Military and Veterans Health.

Advising Other Government Agencies

In addition to its work with the NIH, the FDA, the VA, the IOM, the NAM, and the HMD built and maintained strong relationships with numerous other government agencies throughout its history. For example, the IOM provided advice to the CDC through its Leading Health Indicator reports, which the agency used to guide its Health People reports—the national agenda for improving the public’s health (see Chapter 6). The IOM and the HMD also offered guidance to the National Highway Traffic Safety Administration in its Crisis Standards of Care reports as well as through the work of the organization’s Forum on Medical and Public Health Preparedness for Disasters and Emergencies (see Chapter 6). In terms of providing advice intended to advance research and the implementation of research findings in government policy, the IOM and now the HMD have also provided advice to the National Institute for Occupational Safety and Health (NIOSH), the National Aeronautics and Space Administration (NASA), and the Social Security Administration (SSA), as described below.

Advising NIOSH

NIOSH, a branch of the CDC, has the mission “to develop new knowledge in the field of occupational safety and health and to transfer that knowledge into practice” (CDC, n.d.c), which supports its vision for “safer, healthier workers.” In 2005, NIOSH provided support for the IOM to establish the Standing Committee on Personal Protective Equipment (PPE) for Workplace Safety and Health, which was designed “to provide strategic guidance in addressing PPE issues for a wide range of workers” (NASEM, 2019g, p. 20). PPE is deployed to protect workers exposed to a variety of environmental and occupational hazards, including chemicals, radiation, particulate matter in the air, heights, infectious pathogens, and anything else that may pose a risk to worker health and safety. PPE, such as protective clothing, respirators, face masks, safety harnesses, and lift-assistance devices, is used in any occupational setting where hazards exist— from hospitals and nursing homes to construction sites, mines, and farms. Over the years, the standing committee has held more than two dozen meetings to

___________________

⁵⁵ David A. Savitz was the Vice President for Research, a Professor of Epidemiology, and a Professor of Obstetrics and Gynecology at Brown University in Providence, Rhode Island, when this report was published.

support NIOSH in fulfilling its research-oriented mission as it relates to PPE. The standing committee has hosted a number of public workshops and meetings, and several ad hoc consensus studies have spun off of the work of the standing committee (NASEM, n.d.e) (see Box 4-9).

In addition to the standing committee, NIOSH also commissioned the IOM, in partnership with other divisions within the National Academies, to conduct a series of evaluative studies to review a selected group of research programs at NIOSH. Over the course of 3 years (2006–2009), the IOM, with the NRC, released eight reports that provided in-depth reviews of specific NIOSH research programs (e.g., traumatic injury, health hazards, PPE, mining safety and health, and construction) (see Box 4-9). The committees conducting the program reviews also examined the “relevance and impact of NIOSH’s work” in fulfilling its vision and mission (IOM and NRC, 2009a). To complete this work and develop recommendations to improve the NIOSH research programs, the assigned committees used a common evaluation framework and scoring criteria for assessing the relevance

and impact of the institute’s work. The final report in the series—Evaluating Occupational Health and Safety Research Programs: Framework and Next Steps—was released in 2009. It provided detailed information on the framework and scoring criteria the committees used, as well as a handful of recommendations that could be applied to continuously evaluate and improve research, surveillance, and efforts to translate research into policy and practice.

Advising NASA

The IOM’s mission to improve health for all (later adopted by the NAM and HMD) has not been limited to U.S. borders, nor even to the boundaries of Earth’s atmosphere or orbit. In 2000, NASA commissioned an IOM study “to develop a vision for space medicine for long-duration space travel” (IOM, 2001c). The resulting 2001 report, Safe Passage: Astronaut Care for Exploration Missions, called on NASA to establish “a comprehensive health care system for astronauts to capture all relevant epidemiological data” and institute “a long-term, focused health care research strategy to capture all necessary data on health risks and their amelioration” (IOM, 2001c, p. 1). This committee, which was chaired by NAM member John R. Ball,⁵⁶ and its resulting report marked the start of a long-term relationship between the IOM and NASA that included NASA’s sponsorship of the Standing Committee on Aerospace Medicine and the Medicine of Extreme Environments (NASEM, n.d.f). The standing committee was designed to support NASA in considering scientific, technical, and policy factors related to areas such as “the development of optimal aerospace medicine healthcare as an evolving multidisciplinary and international enterprise; health maintenance and care policies related to aerospace medicine; [and] clinical research requirements and clinical strategies” (NASEM, n.d.f).

Building on the standing committee’s work, NASA also sponsored a range of IOM studies that focused on risk reduction, the health of humans in space, and long-term health outcomes for those who had traveled to space previously (see Box 4-10). For example, in 2008, the IOM released a letter

___________________

⁵⁶ John R. Ball was an Executive Vice President Emeritus of the American College of Physicians in Havre de Grace, Maryland, during this time.

report called Review of NASA’s Human Research Program Evidence Books: A Letter Report, which was developed to advise NASA on its plan “to assemble the available evidence on human health risks of spaceflight and moves forward in identifying and addressing gaps in research” (IOM, 2008a, p. 1). Ultimately, NASA developed a set of 30 “evidence reports” that compiled evidence linked to space travel-related risks such as cardiovascular disease, cancer, radiation syndrome, cognitive and behavioral conditions, psychiatric disorders, and bone fractures and osteoporosis. In 2013, NASA asked the IOM, and subsequently the HMD, to review the evidence reports in terms of “quality of the evidence, analysis, and overall construction of each report” (IOM, 2008a; NASEM, 2017d). Each year between 2014 and 2018, the IOM, and then the HMD, released a letter report that reviewed a subset of NASA’s 30 evidence reports, identifying gaps in the content of the reports and suggesting opportunities and sources for strengthening the reports (NASEM, 2017d). In its final letter report, the committee commended NASA’s evidence reports, stating that the collection “will contribute to improving the health and performance of future astronauts and enhancing future human spaceflight endeavors” (NASEM, 2017d, p. 47).

Advising SSA

The Social Security Act of 1935 established what became the SSA, which was developed to administer retirement and disability benefits in the United States. Under the umbrella of SSA disability benefits, SSA manages the Social Security Disability Insurance (SSDI) program, which was established under the Eisenhower administration in 1956, and the Supplemental Security Income (SSI) program, which was signed into law by Nixon in 1972. As the programs evolved, the SSA built a relationship with the National Academies, including the IOM and now the HMD, to provide advice related to the improvement of the SSA disability determination process. For example, in 1987 the IOM released its first report commissioned by SSA: Pain and Disability: Clinical, Behavioral, and Public Policy Perspectives. In its report, the committee—chaired by NAM member Arthur Kleinman⁵⁷—reviewed available evidence on pain and described how the SSA could evaluate claims related to chronic pain (IOM, 1987). In 2004, the SSA commissioned the IOM “to study its medical procedures and criteria for determining disability and to make recommendations for improving the timeliness and accuracy of its disability decisions” (IOM, 2007e, p. 1). The committee, which was chaired by NAM member and Councilor (2003–2005) John D. Stobo,⁵⁸ produced a report that was released in 2007 called Improving the Social Security Disability Decision Process. The 2007 report followed an interim report released in 2006 and provided 11 recommendations to improve the processes used to make decisions regarding eligibility for disability benefits. Box 4-11 includes a list of additional reports that were commissioned to advise the SSA and the administration of its disability programs.

At the request of SSA, the HMD also formed the Standing Committee of Medical and Vocational Experts for the Social Security Administration’s Disability Programs, which was tasked with surveying, collecting, and analyzing “literature, clinical practices, and published studies related to disability” (NASEM, n.d.g). The standing committee was also established to provide a neutral venue for “discussions of disability issues and the SSA’s sequential evaluation process” (NASEM, n.d.g). To fulfill this objective, the committee was specifically asked to organize conferences in the Baltimore, Maryland, or Washington, DC, areas to engage the public. The standing committee serves as another mechanism by which the HMD can serve the SSA in its efforts to ensure that its disability programs are built on a strong foundation of the most up-to-date evidence and meet the needs of the programs’ beneficiaries.

___________________

⁵⁷ Arthur Kleinman was a Professor of Medical Anthropology and Psychiatry at the Harvard Medical School and on the Faculty of Arts and Sciences at Harvard University at the time.

⁵⁸ John D. Stobo was the President of the University of Texas Medical Branch at Galveston when this report was released.

BUILDING CAPACITY OF INTERNATIONAL SCIENCE ACADEMIES

The IOM also serves as an advisor to peer organizations around the globe, with the African Science Academy Development Initiative (ASADI) illustrating this aspect of the IOM’s work with particular clarity. In 2004 the Bill & Melinda Gates Foundation awarded the National Academies a 10-year, $20 million grant “to strengthen the capability of African science academies to provide independent, evidence-supported advice to inform African government policy making and public discourse related to improving human health” (NASEM, n.d.h). Oversight of the initiative was shared between the NRC’s Policy and Global Affairs division and the IOM, which created a new board called the Board on African Science Academy Development. Unlike other IOM boards, the new board would not conduct consensus studies or initiate roundtables or forums; instead it would offer advice and support to 14 African science academies with an emphasis on developing “infrastructure, personnel, relationships between the academy and its government, and rigorous procedures for providing policy advice” (NASEM, n.d.h).

The stated goal of the ASADI was “to develop African science academies so that they are regarded as trusted sources of credible scientific advice in each nation” (NASEM, n.d.h). The project originally concentrated on science academies in seven countries, with Nigeria, South Africa, and Uganda competitively selected to participate in the program “at the most intensive level,” with an emphasis on capacity building. As the academies matured and achieved greater degrees of independence and proven capacity, they “graduated” from the program. The Academy of Science of South Africa, for example, achieved financial self-sustainability and graduated from the program in 2011. The Ugandan Academy remained in the program until 2014, when the ASADI grant ended. The ASADI sent staff and members from the National Academies to each of the countries to work directly with local personnel, sharing knowledge, insights, and best practices. Throughout the lifespan of ASADI, the National Academies needed to maintain a careful balance in offering advice and encouraging growth and independence among the African science academies without heavily influencing the direction of the academies or dictating to the host countries, unconsciously echoing past imperialist and colonialist administrations.

As part of the ASADI, an annual conference was hosted by one of the African academies. The primary goals of the conferences were to “enhance cooperation among African science academies,

strengthen relationships among representatives of the academies and the policymaking community, and foster a greater understanding and appreciation of the value of evidence-based policy advice” (NASEM, n.d.h). The conferences also provided an opportunity for National Academies’ staff to further engage with staff from the African academies. Not all of the ASADI activities took place in Africa. Officials from the African science academies also visited the United States to observe the IOM and the National Academies in action. In September 2009, the Board on African Science Academy Development, working in collaboration with the Network of African Science Academies, hosted a week-long training program in Washington, DC, for 23 African program and research staff. The participants engaged in sessions on how the IOM conducts its work and develops evidence-based recommendations in the United States, as well as discussions of the various models of convening activities the IOM uses, such as forums, roundtables, and consensus studies, to fulfill its mission as advisor to the nation.⁵⁹

CONCLUSION

Improvements in human health—from disease prevention to cure—depend on advances in biomedical research and the translation of research findings into clinical and public health policy and practice. Throughout its history, the IOM was fully committed to advancing scientific research in order to realize better health outcomes and well-being across the life course for all populations. Over the years, the IOM was called on to provide recommendations in a wide range of scientific areas, such as those described in this chapter—including human genome research, vaccine safety and efficacy, childhood and adolescent development, and cancer. Thanks to the dedication and expertise of the IOM’s leadership, members, and committee members, the IOM was able to provide unbiased evidence-based recommendations on how best to facilitate progress in research to a range of government agencies, nonprofit organizations, and international partners. Through its forums, roundtables, and standing committees, the IOM was also able to bring together representatives from academia, government, the pharmaceutical and health care industries, and other interested stakeholders and experts to have conversations that might not otherwise be possible. Today, the NAM and the HMD continue the IOM’s legacy to facilitate and promote the acceleration of biomedical research and its translation, whenever possible, while also maintaining responsible and equitable research practices that comply with agreed-upon ethical standards and regulations.

___________________

⁵⁹ 59 IOM Council Board Report: Board on African Science Academy Development,” September 2011, IOM/NAM Records.