Frequently Asked Questions: NCI and Biorepositories


 

Background on Biorepositories and their Role in Research

Why are biorepositories important?

Biorepositories are “libraries” in which biospecimens are stored, either for clinical or research purposes. These biospecimens are frequently annotated with information such as demographic or clinical data about the patient from whom the biospecimen was taken. Biorepositories are critical to enabling modern molecular-based research (including genomics, proteomics, molecular imaging, etc.) that will drive the development of a new generation of targeted diagnostics and therapies (i.e., personalized medicine) to improve clinical outcomes for patients.

What are biospecimens?

Biospecimens are biological materials (such as tissue, blood, plasma, and urine) and their derivatives (such as DNA, RNA and protein) that can be used for diagnosis and basic research. When cancer patients undergo procedures such as biopsies or surgery in which malignant tissue is removed for diagnostic or therapeutic purposes, it is often possible for a small amount of the excised specimen to be stored and later used for research. Many patients have given consent for their biospecimens to be applied to research, in the hope that the resulting knowledge might help other patients in future years. It is important to note that such biospecimens are being collected for research purposes, not for use in transplantation or other medical products.

How are biospecimens used in research?

Following the mapping of the Human Genome in 2000, biological research has moved into what is called the “genomic age.” This designation refers to the ability of scientists to study disease at the most basic “molecular” level, by identifying genes and their function, and understanding the role genetics plays in the origin and progression of disease. Other emerging fields of study include proteomics – the study of the full set of proteins encoded by the genome – and pharmacogenomics, which seeks to link the human genome to variation in patient response to pharmaceuticals.

In addition to molecular information, scientists are also analyzing a vast amount of clinical information from patient records and clinical trials. From this data, it is possible to identify patterns that provide a pathway to understanding disease sub-types, and potential strategies for diagnosing and treating disease in new and more effective ways.

Human biospecimens can provide a bridge between emerging molecular information and clinical information, by enabling researchers to study the molecular characteristics of actual human disease, and then correlating those patterns with what is known about the clinical progression of the disease. Specifically, human biospecimens can be used to:

  • Identify and validate drug targets (such as specific genes or gene products)
  • Identify disease mechanisms
  • Develop screening tests for “biomarkers” associated with certain sub-types of a disease
  • Group patients based on their genetic characteristics and likelihood of positive response, for testing of new drugs
  • Group patients based on the “biomarkers” of their disease to determine which treatment is appropriate

Are there examples of how well-characterized biospecimens can accelerate cancer research?

Yes. Two such examples are:

  • The development of trastuzumab (Herceptin ®) for the treatment of breast cancer illustrates the importance of access to well-characterized and preserved tissue samples. Human epidermal growth factor receptor 2 (EGRF-2) normally controls aspects of cell growth and division, but it was shown in tumor samples (from the NCI Cooperative Breast Cancer Tissue Resource) to be amplified in 20 to 30 percent of breast cancer cases. The development of an antibody to this receptor (Herceptin) as a therapeutic treatment might not have succeeded if it had been tested on the general breast cancer patient population. The biospecimens, however, pointed researchers toward a targeted, highly effective therapy for a sub-population of breast cancer patients.
  • Gleevec® was originally developed for the treatment of a form of leukemia by targeting the BCR-ABL protein. After conducting molecular profiling studies on biospecimens collected from different tumor types, scientists discovered that a mutant form of KIT, a protein related to BCR-ABL, is responsible for the progression of a rare but deadly type of cancer, gastrointestinal stromal tumors (GIST). This led to the hypothesis that Gleevec could be used to treat GIST, and subsequent clinical trials confirmed the effectiveness of this new indication for Gleevec.

NCI and Biorepositories

What are NCI’s activities with respect to biorepositories?

The National Cancer Institute (NCI), in recognition of the key role of biospecimens in cancer research, has led a pioneering effort over the past five years to standardize and enhance biorepositories. NCI sought input from leaders across the cancer research community, including basic scientists, clinical oncologists, private industry, patient advocacy groups, and the bioethics and patient protection community. Building on that collective knowledge, the NCI has led a coordinated effort to develop a common biorepository infrastructure that promotes resource sharing. This effort has already had numerous milestones, including:

  • Development of the National Biospecimen Network Blueprint (2003)
  • Analysis of NCI-Supported Biorepositories (2004)
  • Formation of a trans-NCI Biorepository Coordinating Committee (2004)
  • Establishment of the NCI Office of Biorepositories and Biospecimen Research (2005)
  • Hosting of the NCI’s first International Summit on Harmonization of Biorepositories (2005)
  • Issuance of Draft First-Generation Guidelines for NCI-Supported Biorepositories (2005)
  • Development of IT infrastructure and tools through the Cancer Biomedical Informatics Grid™ (caBIG™) to support collection, processing, archiving, and disseminating biospecimens suitable for genomics-based research (ongoing)

 Are there NCI-sponsored research projects that draw from biorepositories?

There are several NCI-sponsored research initiatives and projects that draw from biorepositories, and more are planned.

The Cancer Genome Atlas (TCGA) (see http://cancergenome.nih.gov/) is a joint NCI and National Human Genome Research Institute (NHGRI) initiative to broadly analyze the genomic profiles of cancer. A three-year pilot project is being launched in 2006. TCGA will rely on the establishment of a large, high-quality biorepository of tumor materials and the ability to process those materials into DNA and RNA.

The NCI Clinical Proteomic Technologies Initiative (see http://proteomics.cancer.gov/) is aimed at optimizing current proteomic technologies and developing new technologies, reagents, systems, and working consortia needed to significantly advance the field of cancer proteomics. This research requires protein lysates from tissue specimens and the Initiative encompasses the development of standard methods of protein extraction and processing, along with the development of analytical tools and informatics infrastructure.

What is the role of the NCI Biorepository Coordinating Committee?

Based on the findings of an NCI analysis of NCI-supported biorepositories, the National Cancer Advisory Board (NCAB) approved in November 2004 the formation of a trans-NCI committee, called the NCI Biorepository Coordinating Committee (BCC).

The mission of the BCC is to help develop a plan of action for improving the harmonization of policies and procedures for NCI-supported biorepositories. The BCC was charged with recommending harmonized policies and procedures for NCI-supported biorepositories to enable the highest quality research while ensuring ethical integrity of the process and fostering public trust. In the summer of 2005, the BCC organized two workshops to form recommendations on Biospecimen Access and Ethical, Legal, and Policy Issues; and on Best Practices and Recommendations for Establishing and Maintaining Biorepositories That Support Cancer Research. The NCI Office of Biorepositories and Biospecimen Research, on behalf of the BCC, then presented the Workshop recommendations to the National Cancer Advisory Board in September 2005 as the Draft First-Generation Guidelines for NCI-Supported Biorepositories (Biorepository Coordinating Committee (BCC)).

What sort of research is supported by these NCI-supported biorepository programs?

NCI-supported biorepository programs support basic, epidemiologic, translational, and clinical research. Biospecimen programs collect both frozen and formalin-fixed solid tissues, blood, and other liquids and their processing into molecular extracts, and provide for distribution of those biospecimens to support genomic and proteomic research.

What consideration has NCI given to ethical, legal, and policy issues related to biorepositories?

NCI is highly focused on ethical, legal, and policy issues related to biorepositories, particularly because biospecimens are frequently annotated with demographic and clinical information about patients.

It is extremely important to obtain appropriate informed consent from individuals who contribute their specimens, to protect their privacy, and to maintain the confidentiality of associated clinical data and information (Eiseman et al. 2003). Applying the highest possible ethical standards is necessary to ensure the support and participation of patients, physicians, researchers, and others in biorepository activities (NBN Blueprint 2003).

Over the past 10 years, NCI has participated in, and supported, many meetings and workshops that address the issues associated with collection of biospecimens from human subjects. Forums have included events convened by NCI, Food and Drug Administration (FDA), International Society for Biological and Environmental Repositories (ISBER), and Public Responsibility in Medicine and Research (PRIM&R).

In June 2005, NCI convened a landmark workshop that brought together leaders from the national and international academic communities, private sector, and government to provide recommendations for ethical policy guidelines that will govern the collection and use of human biological specimens and associated data in NCI-sponsored resources/repositories. The ongoing goal is to facilitate the collection and future use of specimens and associated data while protecting the subjects from whom the specimens and data are obtained. In December 2005, NCI posted the Draft First-Generation Guidelines for NCI-Supported Biorepositories to the website of the NCI Office of Biorepositories and Biospecimen Research (OBBR).
(See http://biospecimens.cancer.gov)

What is NCI doing to ensure that informed consent is part of the biorepository process?

The Draft First-Generation Guidelines for NCI-Supported Biorepositories (December 2005) note that NCI-supported biorepositories should use clear and specific informed consent language to ensure that people who contribute specimens and/or data for research purposes are fully informed that the research done with these specimens may help to develop products, tests, or discoveries, and that those products, tests, or discoveries may have commercial value and biospecimen contributors will not benefit financially from these discoveries.

According to the NCI, informed consent is not only a document signed by patients who participate in research studies; rather, it is an educational process between the investigator and the prospective subject (or the subject’s legally authorized representative) as a means to ensure respect for persons; mutual understanding of research procedures, risks, rights, and responsibilities; and continuous voluntary participation (NBN Blueprint, 2003).

What role does the Cancer Biomedical Informatics Grid (caBIG™) play in the area of biorepositories?

One of the most challenging areas in the field of biorepositories has been the absence of information technology tools and infrastructure to facilitate the appropriate collection, processing, archiving, and dissemination of biospecimens to the research community, not only within an individual medical institution but in a network across multiple institutions.

As part of its caBIG™ initiative, through the Tissue Banks and Pathology Tools Workspace, NCI is supporting the development of such informatics tools. Such tools include caTISSUE, a software application that will eventually address all aspects of donor enrollment and informed consent, collection and tracking of samples; the Clinical Annotation Engine, which will address annotation of biospecimens with molecular and clinical data; and caTIES, which will allow extraction of structured data from free text pathology reports. Together, these tools will improve the capability for researchers across the country to select and access appropriate samples for their research.

caBIG™ tools are also designed with security considerations to support patient privacy and data access restrictions, including those aspects covered by the “Common Rule” and HIPAA.

What is HIPAA?

HIPAA is the Health Insurance Portability and Accountability Act (see http://www.hipaa.org). The main requirements under HIPAA, originally designed in the early 1990s, are to provide for standardization of electronic data exchanged within health care transactions, specify security requirements for stored or exchanged protected health information, and to establish privacy regulations for protected health information. This last category imparts the many requirements upon the collection and transmission of the clinical annotations on biospecimens collected for research. HIPAA has a number of regulations designed to ease the burden on research.

What is the “Common Rule” (45-CFR-46)?

The “Common Rule” is the code of federal regulations governing patient protection for research conducted with Federal funds or sites supported with such funds, and as a result, the code effectively applies to every US academic medical center. The code delineates requirements for conducting ethically sound research using Federal funds, such as informed consent, Institutional Review Boards (IRBs), etc.

Is there a biorepository project underway for the Specialized Programs of Research Excellence (SPOREs)?

In September 2005, the NCI initiated a contract to work with the Prostate SPOREs to develop a common biorepository coordination system (BCS) and informatics infrastructure to support harmonized collection, processing, storage and dissemination of human biospecimens. Initially, the purpose of the Prostate SPORE NBN pilot was to determine the feasibility of establishing biorepositories to support post-genomic cancer research, and evaluate the impact of this controlled approach to biospecimen collection, storage, and distribution through a planned Inter-Prostate SPORE Biomarker Validation Study (IPBS). Ultimately, the goal of the NBN pilot was to foster the creation of infrastructure to annotate and integrate specimen banks, such as those of the SPOREs, to enhance the quality and availability of various biospecimens and associated data for the broader scientific community.

The pilot project was designed in 2 phases, beginning with a 3-month trial period followed by technical reviews in January and April 2006. Based on careful consideration of these reviews, the NCI determined that the model was not technically optimal, and would not result in a cost-effective solution. Therefore, the NCI decided not to proceed with Phase 2 of the project.

Although this contract will not continue, several valuable insights were gained from Phase 1 and the NCI is currently investigating alternative approaches to implementing the NBN concept. In addition, the investigators at the SPOREs are continuing work on harmonizing biorepository-related processes. Furthermore, the Prostate SPOREs still plan to work with NCI's caBIG™ network to explore adopting caTISSUE, a software tool designed to support the collection, processing, and dissemination of biospecimens.

National Biospecimen Network (NBN)

What is the National Biospecimen Network (NBN) and what is its purpose?

The NBN is a concept for a common biospecimen collection and biorepository infrastructure that promotes resource building and sharing for team science. Such an infrastructure would harness the potential of new technologies for cancer research, while ensuring that the privacy interests of biospecimen donors are preserved. The NBN would support a comprehensive framework of policies and technology to increase the number and quality of biospecimens available for research. It would include deployment of a robust, flexible, scalable, and secure bioinformatics system that supports the collection, processing, storage, annotation, and distribution of biospecimens and data using standard operating procedures based on best practices.

What is the NBN Blueprint?

The NBN Blueprint is a design plan that provides concrete recommendations for developing the NBN. The NBN Design Team developed the NBN Blueprint (September 2003) with the participation and cooperation of many stakeholders in the public and private cancer community, including researchers, clinicians, and patient advocates.

The Design Team engaged in site visits to state-of-the-art biospecimen banking facilities, conducted interviews with experts, and commissioned a RAND study to identify best practices in the design and operation of existing biospecimen repositories.

Why is a resource such as the NBN needed?

It was estimated (in 1999) that more than 300 million human tissue specimens from over 170 million cases have been acquired and stored in the United States, and continue to accumulate at a rate of 20 million per year. However, the procedures used for specimen preservation and data capture vary widely among existing biorepositories, and there have been no widely-accepted standards for them to follow.

Perhaps even more importantly, many of the traditional biobanks were developed in the past century primarily to serve the needs of pathologists in determining patient diagnoses. Biospecimens used for genomic and proteomic-based research must be collected differently to preserve their biological integrity and thereby ensure that researchers are able to measure genuine biological differences in tissue rather than sample-to-sample variability. Furthermore, current biorepositories are largely focused within small local research communities, and are not able to provide the sufficient numbers and types of biospecimen and data access across multiple researchers and geographies that are critical to the large-scale, team science characteristic of today’s research activities.

The NBN will create a shared, accessible, and searchable resource, providing information from its archived samples by enabling direct comparisons and analyses among independent studies, research institutions, and biorepositories. By encouraging extensive annotation of samples (linkage to clinical data on the disease state and background of the patient), and standardized procedures for acquisition, preservation and storage, this network will bridge the gap between the clinic and the research laboratory.

What is the role of patients in the NBN?

Patients have a critical role in the NBN, as they provide the biospecimens that will populate the repositories and databases. As such, the NBN has sought the input of patients, patient advocacy groups, and research advocacy groups in the design and continued operation of the network. Because patient participation is the keystone of the NBN, protection of medical information and accountability for its use is paramount.

Why is the NBN important for patients and people affected by cancer?

The NBN will enhance the ability of researchers to conduct large-scale genomic and proteomic analyses to accelerate drug discovery, identify new targets for disease intervention, improve the efficiency of clinical trials, and introduce a new paradigm of genomic medicine — treatment based on the patient’s genetic profile. For many years, research on human biospecimens has contributed to major scientific findings relating to the prevention, diagnosis, and treatment of cancer. However, the advent of genomic and proteomic technologies has expanded the critical need for — and potential of — human biospecimens to support new discoveries.

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