The NIH Roadmap: Inviting Drug Abuse and Addiction Researchers to Contribute to the Clinical Research Enterprise

Symposium held at Bethesda North Marriott Hotel and Conference Center, Bethesda, MD, October 24, 2005: 8:45-4:45 p.m.

View the Videocast - http://videocast.nih.gov/ram/nida102405.ram RealPlayer required

Presenters

• Timothy Condon, Ph.D., Deputy Director, National Institute on Drug Addiction (NIDA)
• Barbara Alving, M.D., MACP, Acting Director, National Center for Research Resources
• Amy Patterson, M.D., NIH/Office of the Director
• James Kiley, Ph.D., National Heart, Lung, and Blood Institute
• Ken Buetow, Ph.D., National Cancer Institute
• Deborah Adler, Ph.D., National Institute of Arthritis and Musculoskeletal and Skin Diseases
• Robert Star, M.D., National Institute of Diabetes and Digestive and Kidney Diseases
• Gregory Farber, Ph.D., National Center for Research Resources
• Robert Califf, M.D., Duke University Medical Center

Welcome and Introduction

Dr. Timothy Condon, Deputy Director, NIDA, and chair of this meeting, provided an overview of the strategy, opportunities, and funding for the NIH Roadmap for Medical Research. He explained that the NIDA is participating in the NIH Roadmap through NIDA staff involvement in the conceptualization, management and implementation of initiatives. Dr. Condon stated that the 'New Pathways to Discovery' initiative provides multiple opportunities for NIDA scientists to conduct innovative research. He underscored that 'Research Teams of the Future' initiative is breaking new ground though the high-risk researchers (Pioneer Awards), interdisciplinary research, and public-private partnerships. Dr. Condon added that during the past 2 years of the NIH Roadmap, 43 Roadmap grantees were successfully funded and are conducting research that is related to NIDA's mission. He concluded by asking participants to explore ways that the Roadmap dovetails with their current research, especially within the Roadmap initiative addressed in the symposium under "Re-engineering the Clinical Research Enterprise."

NIDA's Roadmap web site is: http://www.nida.nih.gov/about/roadmap/index.html

Institutional Clinical and Translational Science Awards (CTSA): Building an Academic Home

Dr. Barbara Alving, Acting Director of the National Center for Research Resources (NCRR), explained that NIH Director, Dr. Zerhouni, envisioned the Roadmap Initiative as a transforming approach to implement biomedical discoveries made in the last 10 years and develop new prevention strategies and treatments, lowering barriers between disciplines and catalyzing change. The NCRR has the mission of changing the current status of how clinical and translational research is conducted, breaking down silos and barriers, and changing conventional research practice.

The CTSA mechanism is one way to support the transformation of clinical science. This award program provides a home for clinical and translational science that will connect traditionally disparate elements, including trial design and clinical research ethics, advance degree-granting programs, participant and community involvement, regulatory support, biostatistics, clinical resources, and biomedical informatics. Two CTSA funding opportunities exist:

• RM-06-002: Institutional Clinical and Translational Science Award RFA and
• RM-06-001: Planning Grant RFA for Institutional CTSAs.

Eligibility for these awards is open to:

• Domestic institutions, universities, academic health centers, or other organizations conducting clinical and translational research;
• Graduate schools (participation by multiple schools is encouraged);
• Partnerships with independent and other research institutions.

Applicants can only submit or be part of a single application and must show evidence of significant institutional commitment. In addition, the PI should have direct involvement in the daily activities of the project and should be an established clinician scientist who reports to an official with broad trans-institutional authority. Foreign institutions are excluded.

The primary objective of the CTSAs is to speed discovery to improved patient care. To this end, the program is expected to:

• Develop a distinct discipline for clinical and translational science at U.S. institutions;
• Provide opportunities and resources for original research on novel methods;
• Develop translational technologies and a knowledge base for the full spectrum of clinical and translational science;
• Synergize partnerships with industry, foundations, and community physicians; and
• Train the interdisciplinary teams that will conduct the clinical and translational research of the future.

CTSA awardees may receive up to $6 million in total costs per year for their CTSA grant, for awards of 5 years (with a 5-year extension potential). In FY 2006, there is approximately $30 million to support 4-7 awards, with a plan to expand to 60 awards (costing up to $500 million) by 2012. Funds come from the NIH Roadmap for Medical Research and existing NIH programs.

CTSA and Planning Grant RFAs were published earlier this month. Letters of intent are due February 17, 2006 and applications are due March 27, 2006. Applications will be reviewed the summer of 2006 and grants will be funded in September 2006.

Discussion

• The NCRR is especially interested in supporting graduate programs in clinical and translational sciences.
• Dr. Alving stressed the importance of the flexibility and nonprescriptive aspects of the CTSAs.

Clinical Research Policy Analysis and Coordination Program (CRpac): Harmonization of Clinical Research Policy

Dr. Amy Patterson, NIH/Office of the Director, described the NIH Clinical Research Policy Analysis and Coordination Program (CRpac, also known as "Harmonization"), which is part of the NIH Roadmap's initiative to "reengineer the clinical research enterprise." Dr. Patterson explained the necessity of addressing conflicting signals among and within agencies before harmonization is possible. To this end, CRpac was established to "promote clear, effective, and coordinated policies and regulations for the conduct and oversight of clinical research."

CRpac is a standing NIH program within the Office of Science Policy that works with sibling agencies and research communities to catalyze the coordination of Federal policies related to clinical research, to maintain the integrity and enhance Federal and institutional oversight, and to facilitate compliance with clinical research policies and requirements.

Dr. Patterson explained that the NIH's involvement in policy development may be uncharacteristic, but in this circumstance, NIH has both an interest in (as an end user) and expertise that is critical to developing workable regulations. In addition, as stewards of public funds, NIH is obligated to find ways to standardize its own requirements. In the end, Dr. Patterson suggested, this effort should enhance the ethics and safety of clinical trials it supports. Examples along the research continuum where the CRpac has been working to improve clinical research include:

• In clinical trial design, CRpac has planned a conference (cosponsored by FDA, OHRP, AHRQ, CMS, DoD, DVA, and NIH) to explore issues related to usual care arms in clinical research, with an anticipated outcome of Guidelines for the Design and Conduct of Trials.
• Related to enrollment, CRpac is exploring various approaches to informed consent and sharing of best practices and has issued guidance on informed consent for gene transfer research that may be a model for other disciplines.
• Monitoring issues related to operating DSMBs are being addressed with a review of best practices and clarification of roles and responsibilities of DSMBs. The next step will be sponsorship of a workshop series on this topic.
• CRpac has also established a Federal Adverse Event Task Force (FAET) to address issues related to reporting and, in conjunction with the Secretary's Advisory Committee on Human Research Protection, is working to describe models for AE reporting and develop Points to Consider to guide investigators. The FAET is also proposing means to promote harmonized and streamlined Federal requirements for reporting AEs; this is being done through a series of work groups and focus groups within the government and researchers in the community.
• To improve the analytical processes of clinical trial data, the CRpac is developing publications describing models of IRB review, encouraging investigators to utilize centralized IRBs as well as local IRBs, facilitated central IRBs, and IRB reciprocity when appropriate. A workshop to explore these models will be held November 2005 and Points to Consider will be developed and a national conference will be held to help investigators determine which model is best.

CRpac is a work in progress designed to be a resource to researchers and input from the research community is needed, especially as efforts are broadened in 2006.

Discussion

• Central IRBs have been invaluable and efficient to some researchers, offering efficiency and consistency. However, some sites do not want to use central IRBs because of liability and regulations. In some cases, the reciprocal or joint review may be appropriate. CRpac is working on liability problems in many forms.

NIH Roadmap: Clinical Research Networks Update

Dr. James Kiley, Director of the National Electronics Clinical Trials and Research Network (NECTAR), described this effort of the NIH to integrate clinical research networks, which was instituted under the NIH Roadmap Program.

Dr. Kiley described the standard model of research that has been used to move research from the bench to the bedside. He explained that while the traditional model is segmented and one-directional, in fact all of these segments (e.g., laboratory, translational, clinical, population, and public health) need to intersect so that each element can inform and drive research. To facilitate this new way of looking at research, two feasibility projects, funded in 2004, were funded by the Re-engineering the Clinical Enterprise:

• Feasibility Study of Integrating and Expanding Clinical Research Networks
• Inventory and Evaluation of Clinical Research Networks (IECRN)

These projects form the base of the National Electronics Clinical Trials and Research Network (NECTAR) and the results will be used to assure that existing networks may expand and link to ensure that patients, physicians, and scientists form true "communities of research." The goals of these projects are overlapping, focusing on sharing best practices, harmonizing with industry, and establishing a web portal for primary care doctors to have access to research and to recruit patients into clinical trials. These projects will also help to assess the ability of existing networks to use informatics. Some uses include:

• Flexible infrastructure to manage clinical research "business transactions,"
• Electronic toolbox to link multiple ICUs to extend critical care research to practice,
• Tools to transfer complex genomic data from electronic medical records into a network database for research, and
• Tools to harmonize methods derived from industry, academic and community-based practice sites.

The long-range goal for the feasibility projects is to develop networks based on common infrastructure elements, e.g., informatics, governance, common language, and training, in both academic and clinical care settings.

The major goals of the IECRN are to:

• Develop a full inventory of clinical research networks,
• Prepare detailed description of existing practices and selection of candidate best practices, and
• Conduct a national leadership forum to discuss findings and best practices.

The IECRN Website will be operational in the next 9 months to allow users to see what exists in terms of networks around the world. To date, 250-300 clinical research networks (CRNs) have been inventoried and surveys have been sent to 264 CRNs. This list will be culled down to 30-40 best CRNs.

On May 31 and June 1, 2006, a public National Leadership Forum will be held to engage CRN leaders in building a common framework for dialogue on the NIH Roadmap Initiative, support cross-network exchange in the CRN community, and provide a springboard to ongoing dissemination of information and practice models to the CRN community. More information can be found at http://nihroadmap.nih.gov/publicmeetings.asp.

Discussion

• Dr. Tai stressed that this is an opportunity for the CTN to learn from other networks that have been operating for many years.

An Example: The Cancer Biomedical Informatics Grid (caBIG)

Dr. Ken Buetow, from the Cancer Biomedical Informatics Grid (caBIG), National Cancer Institute, shared the experience of NCI in developing a network. In addition to synthesizing technology with infrastructure, the caBIG has an incredible capacity for generating biomedical information. With the amount of data that are generated, integration is critical to achieve promise of molecular medicine. The NCI has a goal to develop a virtual web of interconnected data, individuals, and organizations to redefine how research is conducted, how care is provided, and how patients/participants interact with the biomedical research enterprise.

The goals of caBIG are to:

• Build a widely distributed infrastructure,
• Share vocabulary and data elements,
• Collect interoperable applications to a common standard, and
• Make raw cancer research data available for mining and integration.

The primary principles of caBIG are to be open source, open access, open development, and federated. In addition to brining together patient care and/or trials, technologies, animal models, and use of compounds, they are also interested in developing the research community so that any researcher can access any of the data. Lastly, they hope to bring together cancer institutes to access each other's data. The action plan for caBIG includes: 1) establishing a pilot network of NCI Cancer Centers, 2) expanding the collection of participants, and 3) establishing a consortium development process.

Currently, caBIG has over 80 organizations, including NCI Centers, government agencies and Institutes, industry, international groups - with over 700 active participants. There are four domains: 1) Clinical Trial Management Systems, 2) Integrated Cancer Research, 3) Tissue Banks and Pathology Tools, and 4) In-vivo imaging. There are two Cross-Cutting Workspaces: 1) Vocabularies and Common Data Elements and 2) Architecture. In addition Strategic Level Planning Groups have been established in the following areas: 1) Data Sharing and Intellectual Capital, 2) Training (boot camps, seminars, workshops, on-line tutorials), and 3) caBIG Strategic Planning.

Dr. Buetow also discussed the Cancer Common Ontologic Representation Environment (caCORE), a system of information integration and cross-discipline reasoning, including common data elements and a controlled vocabulary and biomedical objects. Through caCORE, there is agreement to use the same models for the information that needs to be collected. In addition, in order to assure that the standards supporting the infrastructure are used properly, a series of toolkits are being developed to help others make use of the applications that are part of caCORE.

Dr. Buetow described the Clinical Research IT infrastructure and how the components of clinical research are put together, with data available throughout the continuum to patients, researchers, and physicians. Some pieces of the infrastructure include:

• Participant registration,
• Data collection instruments,
• Clinical Research Information Exchange (CRIX) - to track and share data, including a caIMAGE Repository and caTISSUE ,
• caARRAY, to analyze the data or project in a biological process context, and
• A pathway database (in development).

There are other aspects of this program as well, such as the Cancer Molecular Analysis Project, which allows molecular biologist or clinical researcher to use to show why one might want to participate. This can be used to identify potential sites for adverse events, to identify over- and under-expressed genes, related clinical trials, etc.

For more information about becoming involved with caBIG, participants were directed to http://caBIG.nci.nih.gov; and http://cmap.nci.nih.gov.

Discussion

• The budget for this project is $20 million/year.
• NIDA can be a partner to this project and researchers can participate in a piece of it. For example, micro array repositories can be developed for NIDA, or the system can be used for CRFs, medical histories, etc.
• The area of behavioral mechanisms needs to be addressed for translational and etiological perspectives. NCI has a portfolio of behavioral research that they would like to bridge.
• It is possible to download any of the programs that have been developed using public funds (some of the programming comes from commercial software, however).

Dynamic Assessment of Patient-Reported Chronic Disease Outcomes: The PROMIS Initiative

Dr. Deborah Ader provided background on the PROMIS (Patient-Reported Outcomes MIS) Initiative, which is aimed to contribute to the re-engineering the clinical research enterprise by creating highly valid and reliable item banks and associated computerized adaptive testing that will be widely adopted to improve the assessment of self-reported symptoms and other heath-related quality of life domains across a wide range of chronic diseases. PROMIS integrates methods from cognitive, qualitative, and health survey research to:

• Conceptualize and operationalize the domains and issues affecting patients;
• Build valid, comprehendible PRO assessments tools for a wide variety of patients; and
• Ensure interpretable and meaningful results for researchers, clinicians, and patients.

To support PROMIS, an RFA has been issued to develop and test a large bank of items measuring Patient-Reported Outcomes (PROs), create Computerized Adaptive Testing (CAT) for efficient assessment of PROs across a range of chronic diseases; and create a publicly available, adaptable and sustainable system allowing clinical researchers access to a common item repository and CAT. This system will allow scores to be "cross-walked" between instruments intended to measure the same construct. It is also possible to use this technique to develop multiple instruments measuring the same domain with different item sets.

The PROMIS Network includes cooperative agreements across the country (six sites and one statistical center). The Project Team is led by Dr. Ader and members from various Institutes, with Science Officers that form the PROMIS Steering Committee. First year activities included development of the Developmental Domain Framework, a Qualitative Item Review (QIR), and archival data analysis. Currently, they are completing the Framework and QIR, conducting focus groups, conducting cognitive interviewing and finalizing the item pool. They will begin testing this year. The goals for the first 5 years of the PROMIS initiative are to complete feasibility testing and planning of ongoing partnerships in 2009. Opportunities in substance abuse include:

• Advise on content for relevant domains;
• Evaluate PROMIS tools in clinical trials; and
• Participate in the national effort.

In addition to input on research, they would also like clinical input into the item banks and assessments.

More information is available on http://www.nihPROMIS.org. Further suggestions and dialogue can be directed to Dr. Ader, via e-mail to aderd@mail.nih.gov.

Discussion

• There is great promise and excitement in the possibility of shorter assessments for drug abuse patients.
• Participants shared the following domains that would be useful in assessing patients with drug addiction: impulsivity; drug-seeking behavior; social health domains such as financial need, housing, etc.; pain; fatigue; medical problems related to drug abuse such as osteoporosis in older patients; and cognitive thinking (particularly with methamphetamine patients).
• Although the primary audience is researchers there is hope that this will have clinical applications.
• As beta-testing begins (in 2009), researchers might be able to apply to NIDA for grant funding or for supplements. A specific mechanism has not yet been developed. This will be available at no cost or minimal cost when it is fully developed.

Clinical Research Training and Career Development Programs

Dr. Robert Star, NIDDK, described the Clinical Research Training and Career Development Programs available through the Roadmap Initiative. He explained that this Program was developed to address the barriers that are keeping students from pursuing careers in clinical research. Some barriers include:

• Difficulties in recruiting or retaining clinical researchers;
• Fragmented training;
• Difficult career pathways, which compete with the demands of clinical care;
• Regulatory burden and overhead costs;
• A bias against clinical proposals in multiple settings including academic health centers;
• The difficulty of conducting clinical research with a dearth of common core knowledge.

Dr. Star described changes in the model by which clinical researchers are being prepared for their careers. The focus is on the clinical trial process, clinical pharmacology, behavioral science, statistics, and clinical researchers using common core knowledge, which is the discipline of clinical research. In addition, lone investigators are being replaced by clinical research teams, which include a variety of disciplines and expertise. These teams need to know how to work together and management skills are needed. Thus, it is clear that the entire career pathway must be considered, new training models are needed, and the trans-NIH/community process needs to be involved.

The NIH Training/Career programs, including pre- and post-doc and R01 grants, T32 training and K12 Career programs, K23 and 23 Awards, and Curriculum Awards, can operates as fragmented, isolated programs. The Goals of the Reengineering Clinical Research Enterprise Workforce are to develop a national cadre of well trained clinical investigators and team members and to integrate clinical research training and career development programs across an institution. Some elements include:

• The National Clinical Research Associates, which allows clinicians to enroll patients in clinical trials and provide feedback and trial design input.
• The Predoctoral Clinical Research Training Program (T32), which includes courses for all students in a, summer experiences, and intensive year-long pull-out programs (Masters, MD-DDS/PhD). Currently, 10 sites are funded for this program.
• Multidisciplinary Clinical Research Career Development Programs (K12), which allows 20 Post-Doctoral/Junior Faculty Scholars per site, for multidisciplinary courses in the discipline of clinical research and survival skills (with tuition for advanced degrees). Currently, 12 sites are funded.

Dr. Star pointed out that there are 54 scholars currently funded under this program. NIDA is currently not represented among the grantees. The CTSA, which serves as an academic home, should work with all the NIDA training programs and encouraged NIDA to invite researchers to utilize the CTSA to provide the infrastructure for training.

Discussion

• The NIH needs to hold grantees to the spirit of the grant. The governance structure is set up as a consortium with multiple levels of governance to minimize unbalanced levels of power.
• Support for mentors is critical.
• The hope is to fund institutes that will fund additional slots in areas of extreme shortage.
• The part-time opportunity offered by the National Clinical Research Associates is extremely well suited to NIDA researchers.
• Hurdles of medical students includes salary, too many medical students have tremendous debt. The NIH payment program can help in debt reduction. This needs to be better advertised.

Exploratory Centers for Interdisciplinary Research

Dr. Gregory Farber, NCIR, spoke about the Exploratory Centers for Interdisciplinary Research (P20), funded through the Research Teams of the Future (part of the NIH Roadmap). He explained the rationale for supporting interdisciplinary research, noting that many questions in disease treatment have been answered and that the remaining difficult and critical questions require interdisciplinary research.

Dr. Farber described the Exploratory Centers as focused on the development of common language and approaches. There was funding in the first year for 21 Centers. Centers represent in a wide range of areas - both scientifically and geographically. Sites received support of $400,000 per year for 3 years. Information on the sites can be found at http://www.ncrr.nih.gov/ncrrprog/roadmap/ecirdirectory.asp.

The next phase will be open to all applicants and will fund 8-10 Interdisciplinary Research Consortia with approximately $3 million in direct costs. About 200 applications are expected; therefore there will be a 2-stage review process (prŽcis before full proposals) starting in May 2006. Invitations for full proposals will be due October 2006. Quasi-independent awards will be made from all members of the team (including competitive supplements, RO1s, instrument awards, training award, etc.).

The second round of notices on Interdisciplinary Research Consortia should be released in December or early January and will include:

• NOT-RM-06-001: Notices for Précis
• NOT-RM-06-002: Notice for Central Cooperative Agreement for Full Application
• NOT-RM-06-003 to 007: Notices for the Various Mechanisms Available in a Full Application

For those who are interested, it was suggested that participants e-mail Dr. Farber to be added to the mailing list and attend the interdisciplinary research and technical assistance workshop February 9-10 - http://www.niddk.nih.gov/fund/other/roadmap2006/index.htm.

Discussion

• Most grantees involve more than two disciplines. Most are housed in a single institution, but this is not a requirement.
• The P20 mechanism was chosen to allow members to develop their team to develop an approach to the research problem. In year 2, a pilot program is conducted.
• The NIH reviewers focused on interdisciplinary research, the nature of the problem to be addressed (should be an important problem that had resistant to single or multi-disciplinary research), whether this was a new form of interdisciplinary research, and the proposed expertise.

Overcoming Translational Blocks: A Role for the Roadmap

Dr. Robert Califf, Director of the Duke Clinical Research Institute (DCRI), talked about the field's perspective on the NIH Roadmap and how drug abuse researchers can best be involved with the activities of the Roadmap. He explained the importance of "delivering the goods," citing the following:

• A recent analysis indicates that NIH funding is declining as money goes to biodefense research. Pharmaceutical firms fund an increasingly larger amount.
• Declines in mortality rates; since 1950, scientific advances have made a greater impact than environmental events such as improvements in nutrition and clean water.
• Life expectancy in the United States is comparable to Cuba, behind UK, Canada, and Japan and ahead of China Cambodia, and Angola. This raises questions about the impact of spending on health care. Infant mortality statistics follow similar patterns.
• The Roadmap provides an opportunity to do the most important research, which goes from bench to bedside and translation from clinical trials into practice.

A functional interpretation of translational blocks requires new concepts of how interventions work (biological, behavioral, social) and testing notions in a way that facilitates improvement in health states. He asked the question: what are NIDA and NIDA grantees doing to facilitate movement in these two arenas? His suggestions for NIDA researchers included:

• Clearly distinguish notion development from translation into practice;
• Develop common nomenclature and data standards;
• Develop professional momentum for practice based on evidence;
• Do adequate randomized trials to generate irrefutable evidence of the benefit (or harm) of proposed interventions;
• Use biology and behavioral theory to develop ideas ("notions"), but measure the big 3 outcomes to determine how to treat patients (and influence payers) - live longer, feel better, avoid unpleasant experiences - for less money; and
• Find opportunities to conduct research across clinical interests - e.g., one-third of cardiac patients have substance abuse issues.

Dr. Califf suggested that the old system separates research from clinical practice, passing results to practitioners to "figure it out." The new system is based on theory tested in practice using definable "packets" or "therapeutics" with practitioners measuring and refining. Clinical research, he stated, is a cycle, with the goal is to do clinical trials and outcome studies that lead to guidelines that lead to performance indicators - then you can measure performance with constant feedback.

Dr. Califf identified the following elements of quality medical care: safe, effective, timely, patient-centered, efficient, and equitable. Errors in medical care include failure of a planned action to be completed as intended, use of a wrong plan to achieve an aim, and accumulation of errors resulting in accidents. He suggested that if you don't know the balance of risk and benefit of a therapy on outcomes, by definition you don't know if you've made an error. Thus, critical elements of process include appropriateness of care and a reasonable chance of nontrivial benefit, agreed to by a professional standard.

Dr. Califf shared the following principles of clinical research:

• Because treatment effects are usually modest, he suggested that for much research the planned sample size should be multiplied y 10 or even 100 in order to produce unarguable results.
• Involvement of practitioners is important.
• Implementing known treatments with definitive data to back them up improves outcomes.

Dr. Califf then reviewed the Aims set out by the Roadmap and progress in each of these areas in cardiovascular disease research, in tuberculosis clinical research, and in the Child and Adolescent Psychiatry Treatment Network. He concluded with several areas where he thought drug abuse researchers and the CTN might also focus their attention:

• Developing common controlled terminology and data standards; and
• Developing a system of "notion" development - with packets of intervention.

Discussion

• The Roadmap does not include a goal of changing clinician behavior. Dr. Tai suggested that the CTN is ahead of the curve on this one, with its mission to take research to the bedside and the community. Dr. Condon urged participants to "not be silent" on this issue.
• The industrial strength model does not work as well with outcomes such as substance abuse. Because surrogate markers and bio-markers don't work, it is important that there be emphasis on measuring outcomes.
• The NIH is needed to conduct research that will promote treatments that do not necessarily make profits.
• In industrial strength research, there is also the hope that the results will advance practices.