clinical centers with dedicated time to conduct its trials. In addition, TrialNet draws on a large affiliate network that includes several hundred physician practices across the country. It also uses a professional media group to draw attention to its research efforts. Most recently, the Jonas Brothers and Miss America have served as spokespersons for TrialNet studies. Also, an important attraction of TrialNet studies is the fact that the travel costs of clinical trial participants are paid for by the network. In addition, TrialNet is able to build on its connection with JDRF and ADA. JDRF’s website continues to be an important tool for referring patients to clinical trials.

Navigating the IRB Process

The reality of conducting clinical research today is that multicenter trials, with multiple local IRBs, are required to implement a trial capable of providing robust, informative answers. Greenbaum explained that TrialNet has put a great deal of effort into adapting to this situation. For one thing, it has adopted a proactive approach of providing explicit instructions to IRBs to help guide their decision-making process. For example, TrialNet protocols are drafted with specific language stating that it is permissible to study children in a particular trial and citing the guidelines and rules that apply. Greenbaum said IRBs appreciate the inclusion of this specific language in the protocol because it relieves them of the responsibility for making the decision as to which guidelines or rules apply in the case of a particular research study.

TrialNet also has a protocol template that includes a number of sections designed to facilitate the regulatory approval process. The sections range from substantial additions citing federal regulations regarding research in children to minor variations in the language of informed consent forms for patients. Greenbaum noted that in her experience, the key to creating a successful trial protocol (i.e., reducing the need for protocol amendments and deviations) is the inclusion of open wording. For example, a trial protocol might state that “no more” than a particular amount of serum or plasma will be drawn from each research subject in the trial. Because the amount of serum or plasma needed at a particular time in the study is likely to change, this wording allows for the necessary variation and eliminates the need to submit additional paperwork (i.e., a protocol deviation or resubmittal for a protocol revision). Preparing such carefully written protocols that include deliberate yet open wording has therefore helped TrialNet conduct more efficient clinical trials in terms of the recruitment and retention of patient subjects.



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 TRANSFORMINg ClINICAl RESEARCh IN ThE UNITEd STATES clinical centers with dedicated time to conduct its trials. In addition, Trial- Net draws on a large affiliate network that includes several hundred physi- cian practices across the country. It also uses a professional media group to draw attention to its research efforts. Most recently, the Jonas Brothers and Miss America have served as spokespersons for TrialNet studies. Also, an important attraction of TrialNet studies is the fact that the travel costs of clinical trial participants are paid for by the network. In addition, TrialNet is able to build on its connection with JDRF and ADA. JDRF’s website continues to be an important tool for referring patients to clinical trials. Navigating the IRB Process The reality of conducting clinical research today is that multicenter tri- als, with multiple local IRBs, are required to implement a trial capable of providing robust, informative answers. Greenbaum explained that TrialNet has put a great deal of effort into adapting to this situation. For one thing, it has adopted a proactive approach of providing explicit instructions to IRBs to help guide their decision-making process. For example, TrialNet protocols are drafted with specific language stating that it is permissible to study children in a particular trial and citing the guidelines and rules that apply. Greenbaum said IRBs appreciate the inclusion of this specific language in the protocol because it relieves them of the responsibility for making the decision as to which guidelines or rules apply in the case of a particular research study. TrialNet also has a protocol template that includes a number of sections designed to facilitate the regulatory approval process. The sections range from substantial additions citing federal regulations regarding research in children to minor variations in the language of informed consent forms for patients. Greenbaum noted that in her experience, the key to creating a suc- cessful trial protocol (i.e., reducing the need for protocol amendments and deviations) is the inclusion of open wording. For example, a trial protocol might state that “no more” than a particular amount of serum or plasma will be drawn from each research subject in the trial. Because the amount of serum or plasma needed at a particular time in the study is likely to change, this wording allows for the necessary variation and eliminates the need to submit additional paperwork (i.e., a protocol deviation or resubmittal for a protocol revision). Preparing such carefully written protocols that include deliberate yet open wording has therefore helped TrialNet conduct more efficient clinical trials in terms of the recruitment and retention of patient subjects.

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5 ClINICAl TRIAlS IN dIAbETES Informed Consent Although efforts have been made to streamline and improve the in- formed consent process, it remains a challenge for both investigators and patients. Greenbaum stated that the overlap between the confidentiality lan- guage of informed consent forms and federal requirements under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) makes draft- ing clear, readable consent documents somewhat difficult. Despite the grow- ing tendency in the field to emphasize obtaining the final patient signature on an informed consent document, TrialNet has tried to make informing and educating patients a priority instead of merely obtaining their signa- ture. TrialNet has developed patient participant handbooks and quizzes separate from the consent process to ensure that patients really understand what the trial involves. In addition, TrialNet requires that physicians be actively involved in the informed consent process for patients, a feature not commonly found in other study settings, according to Greenbaum. During the workshop discussion, Perry Cohen, a Parkinson’s patient advocate, noted that his organization, Parkinson Pipeline Project, has devel- oped a research participant bill of rights and responsibilities. The document lays out the features of clinical research that patients desire if they are to participate in a trial. The declaration includes patient requests and respon- sibilities related to informed consent issues, as well as rights to post study data (e.g., trial results and options for care after the trial ends).2 2 More information on the Parkinson Pipeline Project and the Declaration of Clinical Re- search Rights and Responsibilities for People with Parkinson’s can be found at http://www. pdpipeline.org/advocacy/rights.htm.

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8 Building a Robust Clinical Trials Infrastructure T he first day of the workshop focused on the organization of clinical trials and considered various approaches based on different types of diagnosis, study sponsor, and research entity, as well as other fac- tors. The case studies and discussions highlighted a wide range of concerns about how clinical trials are currently conducted and the potential decline in the nation’s capacity to conduct trials at a time when demand for them is increasing. The absolute number of meaningful inquiries that can be made into new products, services, and ways of delivering health care is limited by cost and the availability of qualified investigators and patients willing to participate. Thus, while the number of research questions is rapidly ex- panding, there are serious questions about the capacity of the U.S. clinical research enterprise to answer more than a fraction of them. Drawing on the insights and discussions from the first day of the work- shop, day two provided an opportunity for participants to consider current strategies and new approaches for conducting clinical trials in the United States. The need to develop a learning health care system that bridges the gap between clinical research and clinical practice was a key theme through- out the meeting. The goals of comparative effectiveness research (CER) are closely aligned with those of a learning health care system—in CER, clinical research is conducted in settings that are as similar as possible to those in which the intervention will be applied in practice (IOM, 2009d). Various forms of clinical research can support a learning health care sys- tem. Randomized controlled trials (RCTs) that take place in an academic setting remain the gold standard for clinical inquiry and will continue to be an important tool for future research. But new approaches, skills, and 

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 TRANSFORMINg ClINICAl RESEARCh IN ThE UNITEd STATES capacity will be needed to carry out the range of research necessary to meet the needs of a learning health care system. This chapter begins with an overview of some current efforts to improve clinical trials in the United States, as well as some international examples. The chapter then turns to the suggestions for improving clinical trials that resulted from the four disease-specific breakout session discussions. Finally, Janet Woodcock’s vision for a stable, continuously funded clinical research network in the United States is described. CURRENT EFFORTS TO IMPROVE CLINICAL TRIALS Any effort to effect large-scale improvements in the clinical research en- terprise must be informed by an examination of smaller-scale efforts already under way. While a number of individual institutions, companies, and non- profit organizations are engaged in streamlining the clinical trials process, the workshop focused on the efforts of the Clinical and Translational Science Awards (CTSA) program, particularly in the creation of templates for agree- ments used in the clinical trials process; the Clinical Trials Transformation Initiative (CTTI); the National Institutes of Health’s (NIH’s) Roadmap for Medical Research; and an overview of international efforts. Efforts of the Clinical and Translational Science Awards (CTSA) Program Barbara Alving, Director, National Center for Research Resources (NCRR) within NIH, described the CTSA program and its role in improving clinical trials in the United States. Launched in 2006 and directed by NCRR, the program makes grants to institutions that provide an academic home for clinical and translational science throughout the United States, working to ac- celerate the translation of laboratory discoveries into new treatments for pa- tients. The five strategic goals of the CTSA consortium of institutions are: 1. to build national clinical and translational research capacity; 2. to provide training and career development for clinical and trans- lational scientists; 3. to enhance consortium-wide collaborations; 4. to improve the health of communities and the nation; and 5. to advance T1 translational research to move basic laboratory discoveries and knowledge into clinical testing.1 1 T1 refers to the first stage of translational research, in which basic scientific discoveries are developed into new therapies, diagnostics, or preventive tools to be tested in humans. In the second stage of translational research (T2), clinical trial results are used to inform everyday clinical practice and health care decision making.

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 bUIldINg A RObUST ClINICAl TRIAlS INFRASTRUCTURE NJ = IDeA-Eligible State PR = CTSA State = IDeA- Eligible State and CTSA Member FIGURE 8-1 CTSAs include 46 institutions in 26 states. When the program is fully implemented in 2011, it will include approximately 60 institutions. NOTE: IDeA = Institutional Development Award. SOURCE: Alving, 2009. Reprinted from the National Center for Research Re- sources, NIH. Figure 8-1 R01728 Currently, 46 academic institutions make mathe CTSA consortium, bitmapped US up p covering 26 states (Figure 8-1). Alving noted that CTSAs are deployed so editable vector legend that their reach is effectively nationwide. In the western United States, the University of Washington works with a number of sites in Idaho, Montana, and Wyoming that do not have medical schools. The IDeA-eligible2 states are funded to create Centers of Biomedical Research Excellence. CTSA institutions are also engaged in public−private partnerships. For instance, the University of Rochester has created an Intellectual Property 2 Institutional Development Awards (IDeAs) are funded by NCRR/NIH to foster health- related research and enhance the competitiveness of investigators at institutions located in states in which the aggregate success rate for applications to NIH has historically been low. Additional information on the IDeA program can be found at http://www.ncrr.nih. gov/research_infrastructure/institutional_development_award/.

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0 TRANSFORMINg ClINICAl RESEARCh IN ThE UNITEd STATES Portal3 to aggregate and market technologies from CTSA institutions and NIH. Fifteen CTSA institutions are currently contributing information on their technologies to the site. Alving mentioned another Web-based tool, the CTSA Pharmaceutical Assets Portal,4 which links those with an interest in pharmaceutical products to investigators nationwide, as well as at NIH, who want to study the products. Alving listed the six areas in which the CTSA program is focusing sig- nificant effort to facilitate improvements in the clinical trial process: • developing data-driven approaches to process improvement; • reviewing steps involved in the initiation of clinical trials; • naming “Champions of Change” at academic health centers— individuals with the authority to effect changes; • educating academic health centers about uniform templates for clinical trial agreements (CTAs) (see below); • developing tools for enrollment of clinical trial participants; and • developing Web-based tools for management of clinical trial data. Alving noted that currently, the performance of CTSA institutions with respect to the length of time it takes for clinical trial contracts to be initi- ated is similar to that of non-CTSA academic institutions: both experience significant delays from the point at which a clinical trial protocol reaches an Institutional Review Board (IRB) office to the point at which initial ethical review is complete. While CTSA institutions vary greatly in terms of the time frames involved, Alving hopes that as a consortium, they can develop best practices to effect widespread improvement in these time frames across both CTSA and non-CTSA institutions. As a broad-based network of academic institutions dedicated to clini- cal and translational research, the CTSA consortium represents a number of key academic stakeholders engaged in clinical trials. Alving pointed out that while CTSA institutions enjoy the benefits of close collaboration with each other, some CTSA initiatives are available to all institutions, CTSA and non-CTSA alike. Alving stated that it takes anywhere from 4 to 7 months to negotiate a CTA between an academic institution and industry. She noted that, regard- less of the disease of focus in a clinical trial, a contracts office is responsible for negotiating the contract, and providing templates (disease-specific as well as general) for that office to choose from can facilitate the negotiation pro- 3 Additional information on the Intellectual Property Portal can be found at http://www. rochesterctsa.org/ip/. 4 Additional information on the CTSA Pharmaceutical Assets Portal can be found at http:// www.CTSApharmaportal.org/.

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1 bUIldINg A RObUST ClINICAl TRIAlS INFRASTRUCTURE cess. To streamline the lengthy negotiation process, the IOM Drug Forum commissioned the development of templates for both CTAs and material transfer agreements (MTAs).5 The templates, which are intended for wide- spread use, incorporate language considered acceptable to key stakeholders. Where companies and universities tend to have significant differences, the templates annotated the standard language to highlight and provide con- text for those differing positions. Alving described CTSA program efforts to disseminate the CTA and MTA templates to the CTSA consortium and to educate academic health centers on how they can be used effectively. The National Cancer Institute (NCI) also has created template agreements to facilitate contract negotiations. The NCI templates—Standard Terms of Agreement for Research Trial (START) Clauses—are based on the results of a survey of all NCI cancer centers. Alving also described the following programs supporting CTSA institu- tions and other clinical research programs: Research Electronic Data Capture (RedCap)6 gives research teams • an easy way to collect, disseminate, and protect the privacy of study data. It comprises two secure Web-based applications and provides software and support to partners (CTSA institutions, General Clinical Research Centers, Research Centers in Minor- ity Institutions, and other institutions) at no charge in exchange for participation in the consortium. Alving reported that 3,000 researchers currently use RedCap across 56 institutions and 22 countries. CTSApedia7 will be a comprehensive online resource for those • seeking courses in clinical and translational research. This resource will be available to both CTSA and non-CTSA institutions. • Researchmatch.org, launched in October 2009, is a Web-based patient recruitment registry connecting willing clinical trial volun- teers with researchers. It currently supports the CTSA consortium of institutions.8 5 TheCTA and MTA templates can be found at http://iom.edu/~/media/Files/Activity%20Files/ Research/DrugForum/April27-28/TemplateCTA%2042209.ashx and http://iom.edu/~/media/ Files/Activity%20Files/Research/DrugForum/April27-28/TemplateMTA%2042209.ashx. 6 Additional information on RedCap can be found at http://www.project-redcap.org/. 7 Additional information on CTSApedia can be found at http://www.ctspedia.org/do/view/ CTSpedia/WebHome. 8 Additional information on the Research Match Network can be found at https://www. researchmatch.org/partners/.