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5 Strategies for Facilitating Sharing of Research Materials and Data In the biological and biomedical sciences, it is essential that research materials and data be shared if progress is to be achieved. The discussions summarized here described strategies for leveraging time and resources to meet this crucial need. While not all of these strategies are specifically geared to the development of drugs for rare and neglected diseases, they were presented with the idea that they could potentially be employed with that focus. FINDING AND BARGAINING FOR RESEARCH MATERIALS AND DATA1 Dr. Mowatt explained that the sharing process is relatively simple: request, negotiate, and receive. Successful execution of a complex research project often requires that multiple parties share materials and informa- tion. The acquisition of these “ingredients” can be challenging, resulting in an iterative process during which difficulties are likely to be encoun- tered. Mowatt described two barriers to sharing of research materials and data—finding and bargaining for them—and ways in which those barriers can be overcome. 1 This section is based on the presentation of Michael Mowatt, Ph.D., Director, Office of Technology Development, National Institute of Allergy and Infectious Diseases, National Institutes of Health. 

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 FACILITATING SHARING OF RESEARCH MATERIALS AND DATA Finding Materials and Data Determining where to look and whom to contact for research materials or data may seem simple, but this often is not the case. Certainly it is easiest to find something when all resources of potential interest are located in the same place. One approach to collecting resources is through the develop- ment of repositories, whether for reagents and materials or for data. Repositories have a number of characteristics that facilitate the exchange of materials and data. In general, they are set up to be searchable. Once cre- ated, a repository can alleviate the technical, logistical, and administrative burdens associated with sharing, such as propagating vectors, aliquoting materials, managing paperwork for shipping, and completing the material transfer agreement (MTA). Most repositories require users to register to make a withdrawal, and this registration usually serves as the standard- ized agreement under which withdrawals are made. Users understand the terms associated with transfers to them or to the repository and the use of those materials before they make a request or a donation. Another benefit of repositories is that the distribution and use of materials can easily be tracked, and their impact on research can be assessed. The National Insti- tutes of Health (NIH) has supported a number of successful repositories, such as the NIH AIDS Research and Reference Reagent Program, the Malaria Research and Reference Reagent Resource Center (MR4), and the Biodefense and Emerging Infections Research Resources Repository (BEI Resources) (see Table 5-1). Another model for sharing is a virtual repository, consisting of an electronic material-transfer system functioning in some ways similarly to eBay or the marketplace on Amazon.com. The repository contains informa- tion about available materials and facilitates the transactions necessary to acquire those materials, but the materials themselves are not maintained TABLE 5-1 Examples of Repositories of Materials and Data Supported by the National Institutes of Health AIDS Reagent Program* MR4 BEI Resources Year of inception 1988 1998 2003 Unique materials contributed >8,500 >1,200 >10,000 Requests in 2007 >15,000 1,600 6,700 Countries of requesters 65 66 30 Registrants >3,800 650 677 NOTES: Data are for 2008. BEI Resources = Biodefense and Emerging Infections Research Resources Repository; MR4 = Malaria Research and Reference Reagent Resource Center. *The AIDS Reagent Program is described further in Cohen, 2008. SOURCE: Mowatt, 2008.

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 BREAKTHROUGH BUSINESS MODELS by the repository. Like a standard repository, this mechanism provides an infrastructure for finding materials, as well as for negotiating and for track- ing impact. The materials are then distributed by the owner. An example is the Biological Materials Transfer Agreement Project of Science Commons, which is striving to make materials easier to find on the web and easier to obtain. Bargaining Bargaining relates to negotiation of the terms and conditions of the transfer of materials or data, which generally involves an MTA. As dis- cussed earlier, the publication of research results is a priority for all research institutions, and the dissemination or use of research results should be addressed when an MTA is negotiated. Intellectual property issues, such as who retains the rights to inventions developed during an investigator’s use of shared materials, may be covered by an MTA. Another concern is the liability of the provider as a result of the use of the materials by the requester. Contention in negotiations often derives from the provider’s and recip- ient’s differing perceptions of the value of the material, whether it be a tool, a drug, or a reagent needed to conduct research. There can be dis- agreement on the proposed use of the shared material (e.g., for discovery, preclinical, or clinical research). Conflicting interests and obligations also occur because the cultures and priorities of academia and industry, while overlapping, are quite distinct. Negotiation of MTAs can be very labor-intensive. Given the diverse nature of the materials the parties may want to share, these agreements contain many nonstandard terms. As a result, the recipient organization must review each agreement meticulously. This process typically involves the technology transfer office of a university or the business development office of a company, as well as legal counsel and the researchers. As with negotiations in any venue, the process often entails cycles of offers and rejections or counteroffers, making the process resource-intensive and itera- tive and leading to high transaction costs. This time and these resources are consumed at the expense of other opportunities. The bargaining process could be facilitated through the use of standard- ized agreements, which would theoretically eliminate the need to conduct de novo legal reviews of MTAs and transfer agreements. An example is the Uniform Biological Material Transfer Agreement (UBMTA), developed and implemented by NIH and others in 1995. This master agreement embodies a set of terms that 331 organizations to date have agreed to as those under which material transfers will be made. The UBMTA itself is lengthy and

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 FACILITATING SHARING OF RESEARCH MATERIALS AND DATA detailed, but to simplify the transactions that utilize it, the terms of the transfer are referenced in a one-page implementing letter signed by repre- sentatives of the receiving and providing organizations. The UBMTA and implementing letter have streamlined the transfer of research materials, and the fact that so many institutions have accepted its terms is a good indicator that those terms are broadly acceptable. But the large number of signatories does not reflect the frequency with which the UBMTA is used, and in the experience of the National Institute of Allergy and Infectious Diseases, its use is not common. Its principal users have been nonprofit and public organizations. As a follow-up to the launch of the UBMTA, in 1999 NIH published guidelines for disseminating research resources developed with NIH fund- ing. These guidelines articulate the expectation that recipients of NIH funding will use a Simple Letter Agreement for exchanges of unpatented research tools. The Simple Letter Agreement is used more frequently than the UBMTA, but there is still a need to negotiate nonstandard agreements, sometimes with universities, but most commonly with industry. Another approach to streamline the exchange of essential research materials and information to accelerate research has been implemented by the Collaboration for AIDS Vaccine Discovery (CAVD), a program of the Bill and Melinda Gates Foundation consisting of a network of centers and consortia. Participants in the program are expected to agree to and comply with certain principles for the sharing of materials and data, as well as to use a master MTA and a confidential disclosure agreement for exchanges of materials and information among the various CAVD awardees and collaborators. THE ALzHEIMER’S DISEASE NEuROIMAGING INITIATIvE (ADNI): A PuBLIC–PRIvATE PARTNERSHIP2 The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a public– private partnership that grew out of a need for validated biomarkers for clinical trials targeting Alzheimer’s disease (Box 5-1). Current Alzheimer’s trials use clinical or cognitive outcome measures that have a slow rate of change over time and therefore cannot easily be used to determine the dis- ease-modifying effects of treatments. In addition, such trials usually require large sample sizes and are time-intensive and costly. Dr. Ryan said the hope is that using imaging and biochemical biomarkers will improve the speed and efficiency of clinical trials of therapies for Alzheimer’s disease. 2 This section is based on the presentation of Laurie Ryan, Ph.D., Program Director, Alzheim- er’s Disease Clinical Trials, Division of Neuroscience, National Institute on Aging, National Institutes of Health.

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 BREAKTHROUGH BUSINESS MODELS BOX 5-1 Examples of Data Sharing Models for Biomedical Research THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIvE (ADNI) ADNI is a 5-year longitudinal, multisite observational study designed to collect clinical and imaging data, and assess these data for rates of change in cognition, function, brain structure and function, and biomarkers so as to identify the best markers for following disease progression and monitoring treatment response. The study (which began in 2005) includes 200 subjects with Alzheimer’s disease, 400 subjects with mild cognitive impairment, and 200 elderly controls across 57 performance sites. ADNI comprises several core groups: an administrative core; a clinical core based at the University of California at San Diego (UCSD); a neuroimaging core (magnetic resonance imaging [MRI] and positron-emission technology [PET]) and an informatics core, housed at the University of California at Los Angeles (UCLA) in the Laboratory of Neuroimaging (LONI); a biomarker core; a neuropathology core; a statistics core; and an industry scientific advisory board (ISAB). • The LONI image data archive facilitates deidentification and pooling of image data from multiple institutions, making the data available to all authorized investigators. The clinical and biomarker database is housed at UCSD and linked to LONI. • A key feature of ADNI is rapid public access to all raw and processed data. New data are quarantined for a maximum of 30 days for quality control review prior to posting. • An ADNI data-use agreement is a prerequisite for obtaining data, and a user table lists everyone who is accessing ADNI data. All qualified investigators have equal access; ADNI study investigators do not have priority access. There is also a data-sharing and publication committee. • Biological sample sharing is facilitated by a resource allocation review commit- ADNI is a longitudinal, multisite observational study. Its primary goal is to collect data and biological samples to establish a brain imaging, biomarker, and clinical database that will enable identification of the best markers for following disease progression and monitoring treatment response. The study is also focused on determining the optimum methods for acquiring, process- ing, and distributing images and biomarkers in conjunction with clinical and cognitive data in a multisite context, and on validating the imaging and biomarker data through correlation with the clinical and cognitive data. A key feature of ADNI is rapid public access to all data.

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 FACILITATING SHARING OF RESEARCH MATERIALS AND DATA tee. Requests are reviewed for significance, scientific quality, lack of duplication among projects, and a commitment to sharing by the investigators. The deci- sion to allocate biological samples rests with the National Institute on Aging. http://www.adni-info.org, http://www.loni.ucla.edu/ADNI/ GENETIC ALLIANCE BIOBANk Launched in 2004 by seven genetic disease advocacy organizations, the Genetic Alliance Biobank is modeled after the PXE International Blood and Tissue Bank, which was established in 1995. The primary goal is to revolutionize access to resources and data and to enable translation of research into diagnostics, drugs, and services that support individualized decision making. The BioBank is a repository for clinical data and biological samples, owned by advocacy organizations, housing medical records, DNA/RNA, self-reported patient information, cell lines, tissue, and organs. The degree of open access to each collection is determined by the managing organization. The BioBank: • centralizes the standardized collection and archiving of both clinical data and biological samples; • maintains the integrity of each advocacy organization’s collections and data; • enables institutional review board (IRB)-approved investigator research; • ensures appropriate use of data and samples; • enables ethical recontact and follow-up for phenotype/genotype correlations and natural history and longitudinal studies; • allows for regular communications with key constituents; and • facilitates stewardship and benefit sharing among advocacy organizations. http://biobank.org Design and Launch of the ADNI Study ADNI was launched in 2002 with informational and advisory meet- ings, followed by the formation of four working groups to address mag- netic resonance imaging (MRI), positron-emission tomography (PET), study design, and biological measures. In July 2003, a meeting was held with industry representatives, advocacy groups, the Food and Drug Adminis- tration (FDA), and the Foundation for the NIH, and in October 2003, a request for applications was issued. By the end of 2004, funding had been awarded, and recruitment for the study began in September 2005. As noted, a goal of ADNI is to identify markers of disease progression,

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 BREAKTHROUGH BUSINESS MODELS primarily at the transition between normal cognition and Alzheimer’s dis- ease. The study was designed to include 400 subjects with mild cognitive impairment—200 with Alzheimer’s disease and 200 as controls. Currently, 822 subjects are enrolled in 57 sites. All studies are to be completed by summer 2010, with most analyses completed by the end of 2010. Through- out the trial, at various time points from zero to 36 months, standard cognitive and clinical measures are taken. In addition, biological samples are collected, and pathological markers of Alzheimer’s disease are analyzed. The study comprises several core groups: an administrative core; a clinical core that is based at the University of California at San Diego (UCSD); a neuroimaging core, including MRI and PET; an informatics core, which is housed at the University of California at Los Angeles (UCLA) in the Labo- ratory of Neuroimaging (LONI); a biomarker core; a neuropathology core; a statistics core; and an industry scientific advisory board (ISAB). ADNI Funding and Operation ADNI is funded through a cooperative agreement at $12 million per year for 5 years. However, total funding currently exceeds $60 million, with $40 million in NIH funds and nearly $25 million raised by the Foundation for the NIH from 17 organizations, 15 companies, and 2 nonprofit organi- zations. All industry sponsors have representation on the ADNI ISAB and steering committee. Funding has also been provided for a number of addi- tional ancillary studies. One of these studies is aimed at identifying analytical methods for cerebrospinal fluid (CSF) analysis. Amyloid imaging is funded with a supplement of $2.6 million, sponsored by the Alzheimer’s Association and GE Healthcare. Blood is also being collected for genome-wide genotyp- ing and genetic analysis, and this promises to be one of the most robust and extensive Alzheimer’s disease genotyping databases available. Key Features of the ADNI Model for Open Sharing of Data and Samples ADNI is truly a public–private partnership. Common, specific goals were clearly defined at the outset, and resources, both financial and intel- lectual, are being pooled. The heart of ADNI is open sharing of data and samples, which includes: rapid public access to all raw and processed data; • a central repository for all quality-assured MRI and PET images • through LONI; a clinical database, housed at UCSD and linked to LONI; • databases that are in the public domain and available to all quali- • fied investigators;

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 FACILITATING SHARING OF RESEARCH MATERIALS AND DATA no special access privileges (i.e., ADNI investigators do not have • priority access, and data become public nearly in real time, imme- diately following quality assurance); a data-sharing and publication committee, an ADNI data-use • agreement that is a prerequisite for obtaining the data, and a user table that lists everyone who is accessing ADNI data; and biological sample sharing, facilitated by a resource allocation • review committee that assesses applications for significance, sci- entific quality, lack of duplication among projects, a commitment to sharing by the investigators, and the investigator and environ- ment (following the assessment, the decision to allocate biological samples rests with the National Institute on Aging). The Global Reach of ADNI Data ADNI data are being utilized worldwide, well beyond what was expected. In the 22 months after the first application for data use was approved, there were more than 270,000 image downloads by 265 investi- gators, and clinical data were downloaded by 203 investigators. Figure 5-1 shows the downloads by country. Not surprisingly, the most downloads have been by researchers in the United States, with the United Kingdom and Canada also being very active. But Ryan noted that it was surprising to observe nearly 8,000 downloads from China and to see interest and down- load activity from such countries as Turkey and India. The sources of the applications received by the ADNI database are shown in Figure 5-2. Most are academic sites, but use by the pharmaceutical industry has increased 400 percent in the last year. Another interesting outcome is that the ADNI methodology has sparked similar efforts in Japan, Australia, and Europe, and the hope is that data can someday be compared across these interna- tional efforts. ADNI is meeting or exceeding all expectations, and there are many opportunities for analysis and publication and for studies using ADNI data as controls or for comparison. ADNI hopes to establish the optimum methods for multisite Alzheimer’s clinical trials and to identify imaging and biomarker techniques that have high rates of change, small standard deviations, high power, and correlation with the clinical measures. These imaging and biomarker techniques will be used in Phase II and III studies and validated in treatment settings. ADNI results may allow for the use of prior information in the design and analysis of trials, potentially increas- ing statistical power, and it is hoped that FDA will give greater weight to ADNI-evaluated imaging and biomarkers. The ultimate goal of ADNI is to facilitate the development of effective disease-modifying therapies for the

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0 FIGuRE 5-1 Worldwide use of ADNI data. More than 270,000 image downloads by 265 investigators occurred in the 22 months following the database’s inception, and clinical data were downloaded by 203 investigators. SOURCE: Ryan, 2008. Figure 5-1, R01292 grayscale, landscape bitmapped fixed image

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 FACILITATING SHARING OF RESEARCH MATERIALS AND DATA 135 90 45 0 University/Research Pharmaceutical Biotech Manufacturing 2008 Government 2007 Scanner FIGuRE 5-2 Sources of applications for use of the ADNI database. While most are academic institutions, use by the pharmaceutical industry increased 400 percent from 2007 to 2008. SOURCE: Ryan, 2008. Figure 5-2, R01292 grayscale treatment of Alzheimer’s disease, the delay of disease progression, or the fully editable prevention of the disease. GENETIC ALLIANCE BIOBANK3 Genetic Alliance was founded 22 years ago by a social worker as a place for disease advocacy groups to support one another (Box 5-1). More recently, the organization has matured to promote an environment of openness aimed at transforming health through genetics. The Alliance brings together diverse stakeholders to establish novel partnerships in advo- cacy, integrating individual, family, and community perspectives to improve health systems. By revolutionizing access to genetic information, the Alli- ance hopes to enable the translation of biomedical research into health services and to facilitate better individual decision making. 3 This section is based on the presentation of Sharon Terry, M.A., President and CEO, Ge- netic Alliance, and founding Executive Director of PXE International.

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 BREAKTHROUGH BUSINESS MODELS Genesis of the BioBank4 In 1994, Terry’s children were diagnosed with a rare disease called pseudoxanthoma elasticum (PXE). Within 2 months of the diagnosis, Terry, a college chaplain, and her husband, a fire protection engineer, had read everything that had been written on PXE—about 400 articles—and real- ized that there was no coordinated plan to address the disease. They took action by founding PXE International and the PXE International Blood and Tissue Bank. The foundation-owned and -managed bank was the first of its kind and served as the model for the Genetic Alliance BioBank, which was founded in 2003. Key Characteristics of the BioBank The vision of the Genetic Alliance BioBank is to revolutionize access to the information and resources needed to enable the translation of research into diagnostics, drugs, and services that support individualized decision making. The needs to be met are quite clear, and Genetic Alliance seeks to address those needs by providing the following: access to well-annotated samples; • the ability to obtain consent and reconsent from study participants • dynamically; longitudinal clinical data collection; • a clinical health information registry; • medical record collection; • interoperability with electronic medical records/personal health • records; archival exchange with the database of Genotype and Phenotype • (dbGaP), which is part of the NIH system for genotype/phenotype correlations; and compliance with good manufacturing practices. • The Genetic Alliance BioBank is a cooperative model that provides infrastructure for clinical records and images; research questionnaires; and biological materials such as DNA, tissue samples, and cell lines. A web- based interactive system enables the collection of self-reported data from patients. The BioBank is owned by advocacy organizations, and the dis- ease-specific organizations manage their own collection and facilitate the distribution of information and materials. The BioBank currently contains 4 For additional information about PXE International and the creation of the Genetic Alliance Biobank, see Terry et al., 2007.

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 FACILITATING SHARING OF RESEARCH MATERIALS AND DATA about 10,000 physical samples—encompassing all types of tissue, blood, and cell lines, including whole-body harvest—and about 20,000 clinical records for seven diseases. Some of the collections are virtual, meaning they are recorded in this system but housed elsewhere. Structurally, the BioBank creates a firewall between researchers and many of burdensome administrative tasks associated with working with patients (see Figure 5-3). The BioBank provides scientists with all the information they need with respect to samples, clinical data, and medi- cal records, as well as standardized MTAs and publishing rights. Because the organizations themselves maintain control, they are able to broker with their researchers regarding the most productive use of these rare samples. Another important element is that the BioBank has its own insti- tutional review board, so transactional issues are standardized, saving time and energy. Additionally, the BioBank is able to recontact patients and to conduct longitudinal studies that would not be possible in other situations. The system also gives back to participants by providing them with information that results from the studies. This is a public trust, and PXE International, Inc. Research Participants Enterprise • Centralization and Coordination Firewall • IRBs and Study Management • Informed Consent Process • Blood and Tissue Bank • Genotype/Phenotype Database • Coded Patient IDs • Coordination of Labs • Reporting and Re contacting - • Shared Information and • Longitudinal Follow -up Technology Transfer • Patient Education and Updates FIGuRE 5-3 PXE International, Inc., BioBank model. The Genetic Alliance Bio- Bank, modeled after the PXE International model, creates a firewall between researchers and many of the costly and time-consuming administrative tasks as- sociated with working with patients. NOTE: IRB = institutional review board. New 5-3 SOURCE: Terry, 2008.

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 BREAKTHROUGH BUSINESS MODELS advocates are included in all steps of the design so that processes such as informed consent, cohort accrual, and participant retention are simplified and improved. The primary interest of Genetic Alliance constituents is to ensure that the experimental treatments used in the clinical trials are effective. Con- stituents are willing to assume additional safety risks if a treatment is effective—an approach to drug development that reflects the unique needs of people living with a rare disease. Ultimately, a new, flexible paradigm is needed that: • is forward looking and takes into account the rapid changes in research and industry; • is well coordinated across federal agencies and companies; • has safe harbors for high risk, encourages publishing of negative results, and allows companies to take risks without fear of being penalized as they might be under the current regulatory regime; • is transparent and open; and • is characterized by more common registries and more shared data. In addition, intellectual property issues must be addressed to enable win–win situations. And sharing failures is critical to save others from wasting resources. In conclusion, Terry stressed the need for bold leader- ship to dissolve old boundaries and accelerate the adoption of this new paradigm.