Biennial Report of the Director

Overview of NIH Research Portfolio
Clinical Research

NIH places a high priority on clinical research as it is the primary source of insights about new means for reducing the burden of illness and improving public health. Clinical research is patient-oriented research that is conducted with human subjects (i.e., research that involves direct interaction between investigators and human subjects or the use of material of human origin, such as tissues, specimens, and data that retain information that would allow the investigator to readily ascertain the identity of the subject). Clinical research includes clinical trials, behavioral and observational studies including long-term natural history studies, and outcomes research.

At the overarching level of the NIH Office of the Director, the Office of Science Policy works on an array of issues and activities designed to harmonize regulatory aspects governing the conduct of clinical research to enhance the consistency of the rules and to ensure utmost consideration for the safety, rights, and welfare of subjects while minimizing unnecessary burdens on investigators. For example, NIH has partnered with several federal agencies to ensure that a standard reporting format called the Basal Adverse Event Report (BAER) is available for investigators to report adverse events associated with their clinical research. The BAER is designed to simplify and streamline the submission of safety reports to multiple agencies.

Clinical trials are a crucial subset of clinical research. They are the best method of determining whether interventions are safe and effective in people and assessing side effects or other complications. They are designed to answer specific research questions about biomedical or behavioral interventions. NIH supports many types of clinical trials. Treatment trials might test experimental drugs or devices, new combinations of drugs, or innovative approaches to surgery or radiation therapy. Prevention trials look for better ways either to prevent a disease or to keep it from returning, and they may employ research approaches assessing medicines, vaccines, and lifestyle changes, among other things. Screening and diagnostic trials are conducted to find better ways to detect or diagnose diseases or conditions, and quality-of-life trials (or supportive care trials) explore ways to improve people’s comfort and ability to continue the activities of daily life, even as they deal with chronic illnesses or approach the end of life.

The translation and transfer of research knowledge and clinical trial findings into hospitals, doctors’ offices, and community settings is essential if patients are to reap the benefits of clinical research. NIH nurtures strategies that bring basic research discoveries and clinical research into practice. NIH also developed an important educational site called NIH Clinical Research Trials and You to help people learn more about clinical trials, why they matter, and how to participate (see Information at the Service of Health).

The federal government plays a critical role by supporting important areas of clinical research that are unlikely or rarely addressed by other sectors (e.g., pharmaceutical companies, nonprofit organizations). Specifically, NIH supports clinical and translational studies unlikely to garner substantial investment from other sources because of insufficient financial incentives. Examples include studies that address rare diseases, are considered high risk, and/or are based on lifestyle alterations or behavioral changes rather than drugs or devices. NIH’s ICs oversee a broad portfolio of clinical research that encompasses intramural and extramural programs.

Clinical Resources and Programs

As described in the previous section, the CTSA program supports a national consortium of medical research institutions that are transforming the way biomedical research is conducted. Its goals are to accelerate the translation of laboratory discoveries into treatments for patients, to engage communities in clinical research efforts, and to train a new generation of clinical and translational researchers. Launched in 2006 by NIH, the CTSA program has enabled innovative research teams to speed discovery and advance science aimed at improving our nation’s health. The CTSA program encourages collaborative teams of investigators to tackle complex health and research challenges and then find ways to turn discoveries into practical solutions for patients. These teams are already making progress across a broad range of diseases and conditions, such as cancer, diabetes, neurological disorders, and heart disease. They also work with industry, manufacturers, patient groups, and nonprofit organizations to ensure that potentially life-saving new drugs and devices reach the public faster.

CTSAs provide a foundation for clinical and translational research by providing specialized infrastructure support to NIH-funded scientists, engaging community partners to connect scientists with those who both are underrepresented and could benefit from research, and helping to train the next generation of clinical and translational scientists. In addition, they provide tools and resources such as ResearchMatch, a secure electronic volunteer recruitment registry to provide individuals nationwide with opportunities to be considered for participation in research studies and clinical trials.29

29 For more information, please see: www.researchmatch.org Exit Disclaimer.

Examples of CTSA-enabled Clinical Research Advances

Stanford University’s Biodesign program trains interdisciplinary groups of graduate students in medicine, engineering, and business in the skill of medical “inventorship” and provides small proof-of-concept grants for projects with high potential to improve patients’ lives. Several new devices the students have created through this program, partially supported by the Stanford Center for Clinical and Translational Education and Research, are now being brought to market. These include a ventilator prototype designed for use during natural disasters, and the first inexpensive, natural-motion prosthetic knee for leg amputees in resource-poor countries.

With funding through the Translational Tool Pilot Program and Clinical Research Scholars Program at the University of Pittsburgh Clinical and Translational Science Institute, investigators have developed a device to translate brain commands into actions for assisted devices, potentially improving quality of life for patients disabled by spinal cord injury, stroke, or neurodegenerative disease. The device recently received FDA and institutional review board (IRB) approval to study brain control in individuals with paralysis. The ultimate aim is to close the gap for paralyzed patients between what they wish they could do and what they can do.

A powerful research collaboration with the Scripps Translational Science Institute, the West Wireless Health Institute, wireless device manufacturers, and the CTSA consortium is enabling researchers to conduct large-scale studies to discover how wireless devices, many the size of a small adhesive bandage, can be used to improve patient health and reduce health care costs.

NIH Clinical Center

The majority of NIH clinical research takes place at teaching hospitals around the country and overseas. Approximately 1,500 studies, however, take place at the NIH Clinical Center in Bethesda, Maryland at any given time. The NIH Clinical Center opened its doors in 1953, but the scope of NIH research expanded significantly with the opening of the Mark O. Hatfield Clinical Research Center in 2005. The Clinical Center is now one of the largest federal buildings in the Washington, D.C. metropolitan area.

The NIH Clinical Center is the nation’s largest hospital devoted entirely to clinical research. Each year, the Clinical Center serves more than 10,000 new patients and 6,000 inpatients and supports over 95,000 outpatient visits. In addition to the approximately 1,200 credentialed physicians, dentists, and post-doctoral researchers, it houses over 600 nurses and 450 other allied health professionals including pharmacists, dieticians, medical and imaging technologists, therapists, and medical records and supply staff. Since the hospital opened, it has hosted more than 400,000 clinical research participants. Because the Clinical Center is a research facility, only patients with the precise kinds or stages of illness under investigation are admitted for treatment. There are no labor and delivery services and no other services common to community hospitals. All patients must be referred by their physicians.

The Clinical Center, along with its active partners and research participants, contributed to milestone achievements such as the development of chemotherapy for cancer; the first use of an immunotoxin to treat a malignancy (hairy cell leukemia); identification of the genes that cause kidney cancer, leading to the development of six new, targeted treatments for advanced kidney cancer; demonstration that lithium helps depression; the first gene therapy; the first treatment of AIDS (with AZT); and the development of tests to detect AIDS/HIV and hepatitis viruses in blood, which led to a safer blood supply.

Along with NHGRI and ORDR, the Clinical Center hosts the Undiagnosed Diseases Program (UDP), through which individuals with longstanding medical conditions that elude diagnosis by physicians elsewhere can come for consultation. This trans-NIH program has two main goals, which are to provide answers to patients with mysterious conditions that have long eluded diagnosis and to advance medical knowledge about rare and common diseases.

Over 326 cases have been accepted into the program. After its first two years of work, the UDP is citing successes in patients whose cases have stumped specialists at leading medical institutions around the country.30 Furthermore, the UDP announced the program’s first discovery of a new disease, called ACDC, or arterial calcification due to deficiency of the protein CD73, in the New England Journal of Medicine. CD73 produces a small molecule, adenosine, that protects arteries from calcifying. A report on an additional new disorder is pending publication. Such discoveries could have implications for people with more common diseases and disorders.

In recognition of some of its achievements, the Clinical Center received the 2011 Lasker Public Service Award for creating a research hospital where doctors develop innovative therapies and explore new ways to diagnose, treat, and prevent a wide variety of diseases.

30 For more information, please see: https://www.nih.gov/news/health/oct2011/nhgri-06.htm.

Institute and Center Clinical Research Activities

Nearly all of the NIH ICs support a combination of resources, programs, and initiatives targeted toward strengthening clinical research, through either the enhancement of existing capacities or the engineering of new ones. Clinical testing of novel therapies for disorders is critically important to the development of new treatments for patients and is necessary for advancing new research discoveries into clinical practice. However, clinical trials require a significant amount of administrative, financial, and scientific resources, particularly during the start-up period when the infrastructure must be established and protocols approved. NINDS is expediting this process through the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), a new neurology clinical trials network that will offer shared infrastructure and expertise across neurology diseases. These centralized resources will include support for patient recruitment into trials, protocol-development assistance, and a central IRB, which are expected to expedite trial start-up time. The network will reduce delays in building infrastructure for each new trial, improve the speed of enrollment of trial participants, and enable better choices of therapies for Phase III trials.

NIH and NCI are working to develop policies to improve the complications that may arise from multiple institutional reviews of a single clinical protocol for multisite trials where reviews can be a barrier to the efficient and timely initiation of trials. For instance, NCI developed a central IRB initiative to improve access to NCI-sponsored Cooperative Group clinical trials by enabling local IRBs to approve clinical trials rapidly through the use of a facilitated review process, enhance the protection of study participants by providing consistent expert IRB review at the national level, and reduce the administrative burdens associated with IRB submission on local IRB staff and investigators. Moreover, the NIH Clinical Research Policy Analysis and Coordination program is a focal point for streamlining and optimizing policies and requirements concerning the conduct and oversight of clinical research.

NHLBI launched a major clinical trial to test a gene-based method of prescribing warfarin, a blood thinner that is widely used to prevent life-threatening blood clots. About 2 million Americans start taking warfarin each year, but the drug’s effect can vary significantly from one patient to another. Regular blood tests are needed to both establish an initial dose level and maintain the proper level as time goes on—for months and often for years. In early 2009, an international research consortium combined patients’ genetic and clinical data to produce a computer algorithm for initial dosing that appeared to be more accurate than dosing based on a patient’s clinical condition alone, and then increased or decreased the dose to achieve the optimal blood level. NHLBI launched the multicenter Clarification of Optimal Anticoagulation through Genetics (COAG) clinical trial 31 to compare the gene-based method with the current trial-and-error approach in a much wider pool of patients. COAG will enroll 1,200 patients of varying backgrounds at 12 sites and follow them for four years. Its outcome could improve protection against heart attacks and strokes for millions of Americans.

Widespread adoption of the electronic medical record (EMR) can potentially establish new frontiers for the use of genomics in medicine. The Electronic Medical Records and Genomics (eMERGE) Network, funded by NHGRI, aims to develop, disseminate, and apply research approaches that combine the use of large DNA collections (biorepositories) with EMR systems. In doing so, this should enable large-scale, high-throughput genomic methods for use in clinical research and ongoing clinical care. eMERGE is also studying the ethical, legal, and social issues involved in the use of EMRs for genomics research, such as privacy, confidentiality, and interactions with the public. The eMERGE Network successfully accomplished its Phase I (2007–2011) aims and has entered its Phase II (2011–2015). The key goal of eMERGE II is to explore the best avenues to incorporate genetic variants into EMRs for use in clinical care among diverse populations. To accomplish this, the Network expanded its member sites from five in Phase I to seven in Phase II to include racial/ethnic minorities and rural participants. The number of study participants increased from approximately 19,000 to approximately 33,000.

Maximizing human subject protection, while facilitating translational and applied clinical research, has become a critical challenge in the 21st century. To increase the efficiency and effectiveness of the clinical research enterprise, NIH is examining barriers to clinical research and striving to harmonize regulations and policies that pertain to its conduct and oversight. As the lead federal agency supporting clinical research, NIH has an obligation to promote the efficiency and effectiveness of the clinical research enterprise by facilitating compliance and oversight.

NCI is implementing changes to its Cooperative Groups Clinical Trials Program that will improve efficiency, oversight, and collaboration of trials, as recommended in an April 2010 Institute of Medicine report. These changes include consolidation of the adult clinical trials groups; standardization of clinical trials data management software for NCI-sponsored multi-site trials; acceleration of clinical trial activation through the implementation of a real-time, internet-based dashboard containing clinical trial information for all parties involved in the process; collaboration with FDA scientists in NCI's disease-specific scientific steering committees; standardization of language for clinical trial and intellectual property agreements; improving funding of studies and increasing incentives for patient and physician participation by increasing per case reimbursement rates; and developing a credentials registry for investigators and clinical trial sites.

NIH also has specific initiatives to restructure the clinical trials enterprise in the area of oncology. For example, the Standard Terms of Agreement for Research Trials are designed to help cut the time spent on contract negotiations between pharmaceutical/biotechnology companies and academic medical centers. In addition, NCI’s Clinical Trials Reporting Program is establishing a comprehensive database containing regularly updated information on all NCI-funded interventional clinical trials. Grantees are requested to enter specific information about each clinical trial into the database. This information will be used to coordinate research efforts to optimize the nation’s investment in cancer research.

Collecting and sharing clinical research data requires large investments in time and resources, yet currently there is no uniform way to help investigators implement NIH data-sharing policies for research on neurological disorders. In 2006, NINDS initiated an effort called Common Data Elements (CDEs)32 to address this issue for many different disease areas. NINDS has worked with disease-specific experts and other stakeholders as part of this effort to develop standards to facilitate data collection, analysis and sharing across the research community. To date, this effort has led to the development of a set of core data elements, and disease-specific elements for headache, spinal cord injury, stroke, epilepsy, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Friedrich’s ataxia, and multiple sclerosis, all of which are available on the website for use by investigators. A working group is currently developing data elements for several neuromuscular diseases, such as spinal muscle atrophy, Duchenne muscular dystrophy, traumatic brain injury, and myasthenia gravis.

Sometimes it is not clear which treatment or intervention is best for a patient in a given circumstance. NIH plays a critical and unique role for patients by sponsoring and funding research that compares different interventions or strategies to prevent, diagnose, treat, and monitor health conditions in real-world settings. Comparative effectiveness research (CER) improves health outcomes through the development and dissemination of evidence-based information to patients, clinicians and decision-makers about which interventions are most effective under certain circumstances. One recently published CER trial compared Lucentis, a drug developed by Genentech to treat wet age-related macular degeneration (AMD), and Avastin, a structurally related yet significantly less costly drug, also from Genentech, approved by the FDA for some cancers but commonly used “off-label” for AMD. The two-year NEI-funded study found the drugs were equally effective for improving visual acuity, providing doctors and patients more options for treating AMD. Given that most AMD patients are over 65, CATT findings have important implications for Medicare spending; the US Office of the Inspector General (OIG) issued a report in September 2011 stating that Medicare would have saved $1.4 billion in 2010 if all AMD patients had received Avastin.

One of the most visible means by which NIH reaches, engages, and informs the patient and medical health professional communities is through the congressionally mandated ClinicalTrials.gov Web site. To enhance enrollment and provide a mechanism for tracking the progress of clinical trials, the FDA Amendments Act of 2007 [FDAAA, P.L. 110-85] requires “responsible parties” (sponsors or designated principal investigators) to register certain “applicable clinical trials” of FDA-regulated drugs, biological products, and devices with ClinicalTrials.gov no later than 21 days after enrolling the first subject and to submit summary results information, including adverse-event information, no later than 12 months after the completion date of the trial if the drug, biological product, or device under study is approved, licensed, or cleared by FDA.

ClinicalTrials.gov provides patients, family members, health care professionals, and other members of the public easy access to information on clinical studies on a wide range of diseases and conditions. The information is provided and updated by the sponsor or principal investigator of the clinical study and the Web site is maintained by the NLM at NIH. It has been integral to the implementation of policies and other efforts to increase the transparency of clinical research. It serves as a unique, publicly accessible resource that enables users to: 1) search for clinical trials of drugs, biologics, devices and other interventions (e.g., by condition, intervention, or sponsor) and obtain summary information about the studies (e.g., purpose, design, and facility locations); 2) track the progress of a study from initiation to completion; and 3) obtain summary research results, whether or not they have been published. The unique identifier assigned by ClinicalTrials.gov to each registered trial has become a de facto standard for identifying clinical trials and is widely and routinely used in medical journal articles, MEDLINE citations, congressional documents, and press releases.

The existing ClinicalTrials.gov system was expanded by NIH to accept the registration and results information required to be submitted under FDAAA, making it the largest, most heavily used public research registry and results database in the world.

31 For more information, see http://coagstudy.org/. Exit Disclaimer
32 For more information, see https://www.commondataelements.ninds.nih.gov/#page=Default.

Inclusion of Women and Minorities in Clinical Research

The “efficacy-effectiveness” gap is a term used to show that interventions that show benefit in clinical trials don’t always perform as well in the population at large. One way of decreasing the “gap” includes taking steps to ensure the scientifically appropriate inclusion in a given study of research participants are representative of the population likely to use the product if it is approved. The NIH Revitalization Act of 1993 (Public Law 103-43) requires that all NIH-funded clinical research include women and members of minority groups. To meet these statutory requirements, all NIH-funded clinical research is subject to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research.33 In accordance with the inclusion policy, investigators are required to describe what populations will be included in the proposed study, justify the exclusion of specific groups, and provide planned enrollment data. Scientific Review Groups assess proposed clinical research studies, consider whether sufficient information is provided about planned enrollment, and determine whether the recruitment and retention strategy is realistic. Investigators are also required to report annually their cumulative enrollment data indicating the sex/gender, race and ethnicity of participants in each funded clinical research study. Inclusion enrollment data collected by each IC are compiled into the annual aggregate comprehensive report titled Monitoring Adherence to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research. 34 The 2011 report indicates that in FY 2010, women constituted 56.1 percent of the 23.3 million participants in clinical studies, and 32.1 percent of participants identified themselves as members of an underrepresented race and/or ethnicity.

Over the past two years, NIH has focused on analyzing and streamlining the data reporting process, reemphasizing the vital role of NIH staff in monitoring adherence to the NIH inclusion policy and management of grants, contracts, cooperative agreements, and intramural research projects involving human subjects. The role of peer reviewers and investigators in meeting policy requirements continues to be emphasized.

33 For the full report, see https://grants.nih.gov/grants/funding/women_min/women_min.htm.
34 For the full report, see https://orwh.od.nih.gov/research/inclusion/reports.asp.