Governance and Business Models
| This module addresses options for National Biospecimen Network (NBN) governance and
business and operations plans, as would be needed for any new corporation (for-profit or
nonprofit), foundation, university, or consortium. It discusses governance models and associated
authority and oversight; business models and options for funding the NBN, including rules of
engagement, fees, and sources of funding; and initial organizational structures, including the
requirements for operating a new enterprise with standard operating procedures (SOPs), quality
assurance (QA), and communications plan. The governance and business models of
organizations with analogous missions also are reviewed. |
6.1 Introduction
The NBN is envisioned as a national scientific resource to support research on human
biospecimens and associated data. It is anticipated that the NBN will start as a demonstration
project and grow in size and scope as its user base increases to meet researchers’ needs.
Effectively governing and administering this enterprise will be an important challenge. The
National Dialogue on Cancer (NDC) Tissue Access Working Group (TAWG) recognized the
need for a sound governance structure and business plan to ensure that the goals of the NBN are
met.
The NBN governance and business models should include strategies that permit the NBN to
rapidly establish a firm foundation, and facilitate its growth into a self-sustaining organization.
The strategies must be sufficiently defined to be attainable, yet flexible enough to accommodate
the as yet undefined parameters of the NBN discussed elsewhere in this report.
The goals of this module are to:
- Identify an approach to continually incorporate best practices into NBN SOPs
- Propose options for a governance model
- Propose options for a business plan (define the market; explore costs and benefits and
sources of public and private funding; recommend incentives for engaging participants
and outline incentives needed to stock, maintain, and pay for the resource)
- Explore need for changes in existing rules and regulations, and/or new legislation
- Propose options for an operations plan, including an organizational model, SOPs for
prioritizing requests for sample withdrawal, and QA
6.2 Background
6.2.1 Key Issues
The first step in developing a business plan is to decide how the NBN will be organized. For
example, it could be a wholly new enterprise or a network of existing and/or new units where the
collection of activities and organizations use shared data standards and business rules to carry out
its purpose. If it is a network of existing and new organizations, it could be structured as a single
agency, or managed as a confederation governed by a central body, or as a loose confederation of
interested parties bound only by mutual agreements.
Once the organization and structure of the NBN is decided, the second step will be to design a
sound governance model. This structure could involve differing levels of NDC and National
Cancer Institute (NCI) participation, and would likely have a Board of Governors. The selection
criteria for Board membership, for-profit or not-for-profit status of the entity, and the need for
new rules, regulations, or legislation at the state or Federal level are all issues that must be
addressed during this step.
The third step in launching the NBN will be to clarify the business plan to consider the market
for biospecimens and associated data, anticipated costs, and potential revenue streams. Because
the NBN is expected to be a joint effort between the private and public sectors, mechanisms
should be identified to secure both private and public funding. In addition, user fees may cover
some of the expenses.
The fourth step is to define an operations plan that describes the working structure and functions
of the NBN. Networks are based on standards. The NBN will need to establish and enforce
standards for biospecimen collection, data handling, and perhaps complex biological analysis.
QA and systems for oversight will be vital to NBN activities. Specific issues include whether
processing, storage, and distribution of samples will be centralized, regionalized, or housed
locally; whether advanced analytic services will be provided and, if so, whether they will be
centralized or decentralized; and what systems will be in place to ensure equitable tissue
specimen distribution.
6.2.2 Existing Practices
It is helpful to review a broad array of existing governance and business models for a variety of
multi-institutional cooperative research endeavors. These models include biospecimen
repositories, research networks, and other research collaborations. They differ by organizational
structure, funding streams, and their integration with bioinformatics functions (including the
provision of advanced analytic capabilities). Some contain key centralized components, while
others offer greater decentralization of specific functions such as tissue collection, processing,
storage and dissemination. This section reviews the governance and business operations of a
variety of systems involving biological materials, roughly classified by their funding and
governance models, and then in alphabetical order (see Appendices N through T for more
detailed descriptions of some of these systems).
6.2.2.1 Nonprofit, Government-Funded Models
Cooperative Human Tissue Network
The Cooperative Human Tissue Network (CHTN) is supported by the NCI to provide biomedical
researchers with access to human tissues (see Appendix N). Since its establishment in 1987, the
CHTN has provided more than 500,000 high-quality tissue specimens from a variety of organs to
more than 1,000 investigators. The CHTN has an established, six-division infrastructure, with
good quality control (QC), timely collection of specimens, and established relationships among
surgeons and pathologists. Its primary focus thus far appears to be prospective (on-demand)
collection of biospecimens.
Experienced personnel from all six divisions of the CHTN participate in a coordinating
committee that formulates policies for the operation of the CHTN. The voting members of this
committee include the Principal Investigator and an additional member from each division. In
addition, the NCI has one voting member. The coordinating committee meets periodically to
assess the operation of the CHTN and to change or modify operating policies. A chairman and
secretary of the committee are elected yearly (www-chtn.ims.nci.nih.gov/purpose.html).
Early Detection and Research Network
NCI’s Early Detection and Research Network (EDRN) of cancer investigators focuses on the
development and testing of promising biomarkers or technologies aimed at the early detection of
cancer. It aims to collect biospecimens and to promote collaboration and rapid dissemination of
new information among academic and industrial leaders in molecular biology, molecular
genetics, clinical oncology, computer science, public health, and clinical applications.
Collaborators share resources for the development and testing of biomarkers, clinical and
epidemiologic studies, and data management. It is a “closed” network for the two-dozen
Principal Investigators, but collaborators may apply to participate in joint studies. It has been
reported that the EDRN has deployed a national infrastructure for sharing data and biospecimens
(www3.cancer.gov/prevention/cbrg/edrn).
Integrated Molecular Analysis of Genomes and Their Expression Consortium
The Integrated Molecular Analysis of Genomes and their Expression (IMAGE) Consortium was
initiated in 1993 by four academic groups who shared a common vision of how to achieve an
important goal in the study of the human genome. Specifically, the IMAGE Consortium shares
high-quality, arrayed cDNA libraries and places sequence, map, and expression data on the
clones in these arrays into the public domain. Using this information, unique clones then can be
rearrayed to form a “master array,” which ultimately may contain a representative cDNA from
each gene in the genome under study. The human and mouse genomes were the first to be
studied, and the collection now contains clones from rat, zebrafish, Xenopus, and rhesus
macaque, with additional species being added as resources permit. All clones are available free
of any royalties and may be used by anyone who ascribes to the guidelines, which specify
identifying the source as IMAGE, and free redistribution of clones, progeny, and any derivatives
thereof (image.llnl.gov).
United Kingdom National Cancer Tissue Resource
The UK has developed a comprehensive plan for the National Cancer Tissue Resource (NCTR)
to meet the demands of its research communities for biological samples linked to clinical
outcome information (Appendix O). The NCTR’s primary aim, similar to that proposed for the
United States, is to allow the routine collection, storage, processing, and distribution for research
of malignant tissue with case-linked normal tissue linked to standardized, site-specific
histopathological data and clinical outcome information. The UK National Cancer Research
Institute partners and other governmental departments initially will fund the planned NCTR. In
particular, the UK’s Department of Trade and Industry will provide funding for informatics
support. Eventually, private investment (as public-private partnerships) will be instituted in a
regulated manner.
It is envisioned that the NCTR will comprise five key components:
- Coordinating Unit, located within the Coordinating Center, to implement and operate the
NCTR.
- Tissue Acquisition Resource Centers (TARCs), created as a linked network, selected
through a tendering process, and contracted to adhere to SOPs for prospective collection
of biological samples and outcome clinical information (a fully operational NCTR will
incorporate up to six geographically distributed TARCs. It is anticipated that each TARC
will collect samples from up to 1,000 cases per year).
- Tissue-processing Resource Centers, created as a network, for production of DNA, RNA,
and tissue microarray, selected through a tendering process and contracted to adhere to
SOPs.
- The collection of samples from key established and future clinical trials, coordinated
through Clinical Trials Offices and the National Cancer Research Network.
- Bioinformatics Hub, a central information system that will link (1) tracking of collection,
processing, distribution, and analysis of samples to (2) histopathological datasets in line
with recommendations by The Royal College of Pathologists, to (3) clinical/outcome
information, to (4) results of research.
6.2.2.2 Nonprofit, No Government Funding
The Single Nucleotide Polymorphism Consortium
The Single Nucleotide Polymorphism (SNP) Consortium, a wholly privately funded
collaboration of more than 10 pharmaceutical, information, and technology companies, academic
centers, and the WellcomeTrust, is analogous to the data-sharing part of the NBN. The SNP
Consortium was formed in 1999 to find and map 300,000 common SNPs (see Appendix P).
Exceeding initial expectations, the Consortium has identified and mapped more than 1.8 million
human SNPs to date. The maps, which are still being updated and refined, are publicly available
to researchers worldwide.
The SNP Consortium has a 501(c)3 nonprofit governance core and is run by a Board of
Directors, with representatives from each funding partner. The Consortium has only one fulltime
employee; the remainder of the work is contracted out to technical experts identified by the
Board. Government involvement was deliberately avoided in order to expedite the SNP
discovery process.
6.2.2.3 For-Profit, Minimal or No Government Funding
The Ardais Corporation and First Genetic Trust are only two examples that could be described
under this model. Other examples, for which less detailed information was readily available
about governance structure, include Genomics Collaborative, Inc., a diagnostic and therapeutic
company providing access to DNA, serum, and tissue collected from patient populations around
the globe (www.genomicsinc.com); Asterand, which operates a human tissue bank to help
medical researchers discover new diagnostics and therapeutics for cancer and other diseases
(www.asterand.com); and IMPATH, a private company that has a database of over 1 million
patient profiles and outcomes data on over 2.3 million individuals (www.impath.com).
Ardais Corporation
Ardais Corporation is a privately held, 4-year-old, for-profit clinical genomics company that
markets its products and services to pharmaceutical and biotechnology companies, academics,
and government researchers (see Appendix Q). The company has invested $40 million
establishing the infrastructure, capability, and bioinformatics systems to enable the collection,
processing, and storage of tissue, assembling a library of tissue samples from four academic
medical centers across the country: Beth Israel Deaconess Medical Center in Boston, MA; Duke
University Medical Center in Durham, NC; Maine Medical Center in Portland, ME; and the
University of Chicago in Chicago, IL. Ardais deploys its SOPs and manages and supports the
collection process at each institution, with the goal of achieving consistently high standards for
maximum sample quality and annotation while protecting patient donor safety and privacy.
Ardais’ portfolio of clinical genomics resources includes formalin-fixed and frozen human tissue
samples and associated clinical information; standard or custom tissue microarrays for highthroughput
parallel analyses; and molecular derivatives, such as RNA, which are validated for
research use through a battery of qualification procedures. Ardais’ tissue samples and associated
clinical information are accessible through a bioinformatics system called the BIGR™
(Biomaterials and Information for Genomic Research) Library, which currently provides access
to over 170,000 human tissue samples collected under uniform, highly standardized conditions.
First Genetic Trust
First Genetic Trust is a business that develops information technology solutions to address data,
privacy, confidentiality, and ethical challenges in genomics and proteomics (Appendix R).
Although it does not distribute biospecimens, it is a relevant example for the NBN because it
provides an innovative platform to store and analyze genetic and clinical data. It has created an
information technology platform with three goals: (1) Enable large-scale genomic research and
eventually clinical genomic research; (2) work with pharmaceutical companies to speed the
development and use of new drugs; and (3) enable clinical adoption of genomics. Currently, First
Genetic Trust is involved in two sponsored research studies. The first is a large pharmaceutical
protocol in the United States and Europe, which has received very favorable responses from 19
institutional review boards (IRBs). The second is a breast and ovarian cancer research program at
the Memorial Sloan-Kettering Cancer Center, which enrolled its first patient in early 2003.
Activities with other pharmaceutical companies and universities (including Johns Hopkins) and
the International Genomic Consortium are in the formative stages.
Public access is the least-defined aspect of the system. Some data will be completely open, some
will be conditionally open, and some will require reconsent or further aggregation to be open.
Sponsors own the tissue and data, but the system will hold individual identifiers.
Histopathological image data are not currently available, but it is technologically feasible to
provide them. The design protocol can be written to automatically aggregate clinical updates and
secular outcomes.
6.2.2.4 Public/Private, Mixed Funding
The Clinical Cooperative Group Tissue Bank is one of the many NCI-supported human
specimen resources available.1 The National Surgical Adjuvent Breast and Bowel Project,
Cancer and Leukemia Group B, and others represent mixed funding banks. The NCI Cancer
Centers and perhaps the Specialized Programs of Research Excellence receive outside funding
that may go toward banking and specimen resource activities. The Children’s Oncology Group
(COG) provides yet another example that is described in more detail below because of its more
unique features.
Children’s Oncology Group
COG is an NCI-supported clinical trials cooperative program devoted exclusively to childhood
and adolescent cancer research. It was formed by the amalgamation of several groups, including
the Children’s Cancer Group, the Pediatric Oncology Group, the Intergroup Rhabdomyosarcoma
Study Group, and the National Wilms’ Tumor Study Group. COG develops and coordinates
cancer clinical trials conducted at the 238 member institutions, which include cancer centers of
all the major universities and teaching hospitals throughout the United States and Canada, as
well as at sites in Europe and Australia. There are 5,000 COG members.
All patients entering COG studies at member institutions are registered through a Web-based
remote data entry system, through which patient responses to therapy are centrally collected,
monitored, and analyzed. COG is managed under contract to NCI by the National Children’s
Cancer Foundation, which serves as the grantee and fundraising organization for COG; receives
and manages the COG grant from NCI; provides administrative, fiscal, personnel, grants and
contracts, and technical services to support the COG operations; and raises private funds for
COG research, as well as for its own advocacy and education activities.
British Columbia Cancer Agency/Genyous Life Sciences, Inc.
The Tumor Tissue Repository (TTR), a public sector initiative begun by the British Columbia
Cancer Agency in British Columbia, is a public/private model in Canada. The governance
structure is nonprofit, with a Board of Directors and operational units staffed by employees of
the TTR. Specimens will be obtained from the 4 million patients served by Canadian National
Health system in British Columbia, and primary funding will come from the Canadian health
system. Genyous Life Sciences, a commercial firm, provided funding to the TTR in return for
commercialization rights to these research findings for the first 5 years of operation. Genyous
does not have a seat on the TTR Board.
International Genomics Consortium
The International Genomics Consortium (IGC) is a private, nonprofit 501(c)3 medical research
organization, operating to ensure full public benefit of the Human Genome Project
(www.intgen.org/). IGC expression projects on human diseases will utilize a consortium model
of enhanced and accelerated tissue collection under standardized conditions to produce detailed
data on the molecular characterization of disease. The data will be available as a public,
standardized, regulatory compliant, readily accessible and searchable series of genomic
databases for use by the worldwide scientific community. The information from this unique
resource, which joins together the public and private sectors, was developed to stimulate research
on the underlying molecular mechanisms of diseases to accelerate development of diagnostic
tests, improved treatments, novel therapies, and disease prevention.
Infrastructure and executive management positions in IGC are funded through multiyear
committed support from public and private sources in Arizona. Funding of the expression
projects is derived through donations from members, which include pharmaceutical and biotech
companies, technology and informatics companies, foundations, governments, academic and
research institutions (providing in-kind support), and private donations.
IGC is governed by a board of directors that oversees an executive management team composed
of a chief executive officer (CEO), chief medical officer, chief financial officer, and chief
information officer. A scientific advisory committee speaks to the vision, operations, and
opportunity represented by IGC. Each of the different expression projects for human diseases is
advised by an executive steering committee (ESC) of members representing the funding sources
for the project. The ESC develops milestones for performance of IGC’s projects, formulates
metrics of deliverables, and advises operation of the execution of the projects. Subcommittees of
the ESC present recommendations on technology platforms, information technology, clinical
data, patient advisory affiliations, legal considerations, and public relations (see Appendix S).
United Network for Organ Sharing/Organ Procurement and Transplantation Network
The Organ Procurement and Transplantation Network (OPTN) is the unified transplant network
established by the U.S. Congress under the National Organ Transplant Act of 1984 to be
operated by a private, nonprofit organization under Federal contract (see Appendix T). Although
the requirements for collection of organs for transplantation are very different from those for
collection of diagnostic specimens for research, OPTN is included as an example of a
governance model that may be helpful in the development of the NBN. The United Network for
Organ Sharing (UNOS) was awarded the first OPTN contract in 1986 and continues to
administer the OPTN under contract with the Health Resources and Services Administration of
the U.S. Department of Health and Human Services.
The OPTN contract with UNOS is a cost-share contract. The contractor is responsible for 92
percent of the costs. Section 372 of the Public Health Service Act requires that the OPTN be
performed under contract by a private, nonprofit entity and limits appropriations to not more than
$2 million in any fiscal year. The contractor collects patient registration fees (a listing fee of
$450 in order to have each patient placed on the transplantation waiting list) to supplement the
cost of performing the OPTN contract requirements.
6.3 NBN Models and Recommendations
6.3.1 Proposed Funding and Governance Model
Reflecting the idea that the NBN would be able to accept funds from both public and private
sources, the Design Team proposed a funding and governance model with a not-for-profit
organization at the center of the nexus (see Figure 6-1). It is
recognized that a good portion of the
chain of trust discussed in 2. Management of Ethical and Legal Issues is embedded in
the
expectation that a nonpartisan and nonprofit-motivated organization have stewardship of the
NBN. Biospecimen donors and the public in general would expect that the NBN owe primary
allegiance not to stockholders, but to the pursuit of science and discovery. In addition to the
advantages of enhanced credibility, a nonprofit entity might also attract a wider choice of
possible leaders with experience and familiarity in the nonprofit world, tax preferences,
competitive advantage in obtaining government grants and cooperative agreements, lower
operating costs (since there is no profit incentive), and the ability to accept government and
private funds. This model also may make it easier to keep the data “precompetitive.” It is of
course possible and recommended that the 501(c)3 organization contract various business
functions to other organizations, for example to universities, research centers, or private
companies.
In addition to suggesting a not-for-profit core operations center, the Design Team recommended
the following model for NBN oversight (Figure 6-2):
| I. | Board of Governors | | — | The oversight authority |
| II. | NBN Operations Center | | — | The “home office” or headquarters |
| III. | The Business Units | | — | The operation arm (discussed after the business plan). |
Figure 6-1. Proposed NBN Funding Model
The Board of Governors would be either the NDC itself or (more likely) a 7- to 10-member
group formed by the NDC (and for which the NDC would have representation) to provide
oversight. The needed skills of Board members include a mix of strong science and business
experience. The Board would have to establish criteria for membership, draw up a charter and
bylaws, and decide whether the CEO would be a member. Members would include individuals
representing advocacy groups, major professional associations, and government agencies. After
completing its own organization, the next job for the Board would be to decide the funding
structure and the hiring of the CEO (and possibly other key officers).
The Operations Center would be the “home office” or headquarters for the NBN, under the
leadership of the CEO. It would consist of a relatively small staff of senior executives and
support staff, who would have overall responsibility for the NBN; and three in-house operational
units: QA, Bioinformatics and Data Management, and Communications.
The main task of the Operations Center would be to manage the operations of the NBN. It would
have basic management responsibilities, including strategic planning, budget, legal, and day-today
administration.
Figure 6-2. Possible Organizational Structure for the NBN
As discussed above, the Design Team recommended that the Operations Center be structured as
a nonprofit entity. The Foundation for the National Institutes of Health (FNIH) may be an option
to serve as an incubator for the NBN Operations Center. It could help with planning and promote
the integration of nonprofit and private-sector entities, or serve as an agent for the NBN in
accepting and distributing funding from Federal agencies and private donors. The FNIH has
served in a similar capacity for the Mouse Sequencing Consortium. Specific milestone needed to
trigger independence and how such a transition would be managed must be considered.
As an alternative, the NDC itself could play an organizing role. The real issue is whether or not
an entity has conflicting roles, be it for-profit, nonprofit, or academic. In general, there ought to
be a distance between the Operations Center and the business units, and between the Operations
Center and sites. Appropriate charter and bylaws would remove many of the potential problems.
Quality Assurance (QA) is a critical and central management function within the Operations
Center, devoted to ensuring that the NBN standards are set and documented; that business and
operations goals are well defined (e.g., customer satisfaction and costs); and that the systems for
meeting regulatory compliance such as those required by Health Insurance Portability and
Accountability Act, and compliance with other applicable Federal and state regulations, are in
place. QA should be distinguished from QC. QA is a set of processes to ensure quality. QC is the
application of those processes to specific activities to ensure the quality of the work product. QA
will functioin to work with business units to review and create all SOPs for all related business
units and affiliated sites.
The QA function is a critical NBN function. In that spirit, the QA functions should take into
account applicable best practices such as the Food and Drug Administration Good
Manufacturing/Laboratory Practices, other industry standards (College of American Pathologists
[CAP], International Society for Biological and Environmental Repositories [ISBER], National
Committee for Clinical Laboratory Standards [NCCLS], and other bodies) and document the
NBN practices. The business units would be subject to inspection/audit and, as part of their QC
functions, responsible for reporting required data to the QA Unit. The QA Unit would then
analyze the QC data to monitor compliance. The NBN is envisioned as a standards-based
organization with QA at its heart.2 The QA oversight should be collaborative, proactive, and
educative (and might have a research component for developing best practices and evaluating
pilot projects). It is not authoritarian and inspection oriented. Resolution of concerns will need to
be institutionalized and well documented. The QA Unit will have a staff of several highly trained
individuals who report directly to the CEO.
The NBN would make every effort to maximize the value and use of existing resources, provided
that they meet NBN standards. Moreover, depending on the research use, it may be possible to
have ranges for compliance (e.g., it may be sufficient to know the age of the donor within 2
years); or to have different categories of standards (e.g., tissue was frozen within 30 minutes or
can be paraffin embedded). The challenge will be to classify existing resources according to their
utility for different analytic techniques, from hematoxylin and eosin staining to DNA
microarrays.
The NBN Design Team recommends that QA be in-house because, like accounting, it is a central
activity; also, this area is susceptible to conflicts of interest, especially in a for-profit business
unit model. There was a strong consensus that the QA function is a vital corporate executive
responsibility that ought to be closely monitored by the CEO, should report to the CEO, and for
which the CEO should be held accountable.
Although there was some discussion that having the QA activity in-house may create the
appearance of a conflict of interest, as the QA function ultimately measures the quality of the
NBN Operations Center and its executives, this concern was outweighed by the importance of
having direct oversight by the CEO. QA activities should be regularly reported to the Board.
The NBN will be a standards- and performance-based organization that will need to develop and
enforce quality standards. The NBN would consult continually with other experienced
organizations knowledgeable in acquisition, processing, storage, and distribution of high-quality
biospecimens (e.g., CAP, ISBER, NCCLS, existing biospecimen resource providers) to
determine and update appropriate processes. It is recommended that the NBN be neither an
accrediting nor a certifying body, but call upon the experience of others in developing its
standards.
Bioinformatics and Data Management will have an Operations Center function and an
individual business unit function. Core staff, managed by a Chief Information Officer (or
equivalent), will have a central architectural role and also manage the Bioinformatics and Data
Management Business Unit. There will also be important bioinformatics activities needed for
business unit operations at every site. The core Operations Center Bioinformatics and Data
Management staff will coordinate these cross-cutting activities. The scope of the bioinformatics
activities at the operations center level will derive from needs (see 4. Bioinformatics and Data
Management) and must be carefully delineated to facilitate clear integration with the
Bioinformatics and Data Management Business Unit and the bioinformatics needs of other
business units.
Communications will have an Operations Center function and is also embedded within the
Patient Relations and Research Administration Business Units. Core staff, managed by a Chief
Communications officer (or equivalent), will have a central role in all communications internal
and external to the NBN. The primary purpose of elevating Communications to the operations
level is to ensure the appropriate coordination of a broad and comprehensive program of
communication throughout the NBN and its various units, with responsibilities encompassing
education and training, outreach, and public relations to ensure close coordination with
associated responsibilities of order processing, distribution, and shipping. It is important to
publicize the NBN to its key constituencies and to develop and maintain clear and effective
communication with all participants in the system (see 5. Communications).
Another extremely valuable function of Communications is to conduct an ongoing professional
market assessment of users, including at pharmaceutical and biotechnology company
researchers, to inform NBN design and engineering of evolving needs. This assessment could
include questions to determine the different types of tissues sought by researchers, inquiries
about what other resources are available (including those that might be NBN competitors), and
what advanced analysis services researchers desire. Regular feedback about user needs can help
to keep the NBN current and able to respond to emerging demands for more sophisticated
analyses.
6.3.2 Business Plan
6.3.2.1 Business Plan: Issues
The NBN is a major new initiative that requires a sound business plan, with a careful assessment
of costs and benefits. It is difficult to describe the NBN in classic business terms. The NBN has
two “products.” (1) The primary product is represented by the biospecimens and associated
patient data; and (2) information derived by users, such as expression microarray results or the
results of an in silico experiment, is the second. The “users” are researchers. The “producers”
may include the patients, surgeons, endoscopists, dermatologists, radiologists, pathologists, and
other clinicians. Finally, there is a long list of other interested parties (government, industry,
academe, other nonprofits, and the survivor community).
Willingness to Pay. The cost of accessing the NBN resource should not be prohibitively high.
The results of the NDC-NCI questionnaire administered at AACR showed that 85.3 percent of
respondents would be willing to pay between $20 to $100 per specimen for well-characterized
biospecimen samples with definitive associated patient clinical data. Additionally, a demand for
research data provided along with specimens was noted, as stated above. Approximately 69
percent of respondents were willing to pay between $100 to $500 per specimen for wellcharacterized
biospecimen samples with definitive associated patient data accompanied by
standardized gene expression by DNA microarray data. (It should be noted that this survey
targeted a convenience-based, nonrepresentative sample, but focused on the appropriate
audience. Complete results are provided in Appendix E.)
Costs. The estimated cost of a sample varies by how much information accompanies it. There
will also be economies of scale: A full freezer costs as much to operate as one that is one-quarter
full. Experience has shown that collecting human specimens for research can cost between $70
and $2,000 per specimen shipped, depending on the degree of annotation.
Determining the precise cost per specimen is difficult since there are many complexities. A
single case (patient specimen) can yield multiple research samples. Providing 250,000 samples at
$200 each would have an annual cost of roughly $50 million (exclusive of start-up costs). The
cost would of course scale if the marginal cost of specimens were greater than $200. By
comparison, approximately $40 million per year is allocated currently by the NIH to extramural
programs for “tissue banks.”3
Charge for Use. Some of the costs for annotation, storage, and distribution could be recaptured
through charges to researchers. Note that what is charged or paid by the user may be more or less
than cost. Charges could also be used to provide incentives for certain behaviors. For example,
researchers at academic institutions who provide specimens and data to the NBN could be
charged a lower amount for usage. Similarly, users who provide their research data might be
charged a lower fee than those who do not. Charges might be higher for more intensive users of
data, or for those who use harder-to-obtain or more desirable samples. Whether the charges to
industry and academia should be identical, cost-recovery considerations, and final pricing for
general and subsets of NBN biospecimens, remain to be determined.
Funding Mechanisms. The NBN is designed to be a national resource, supported by a mix of
public and private funding. It would be expected that the interested parties would be a mix of
Federal, state, commercial, and private (philanthropic) organizations. Some will contribute in
proportion to their perceived benefit, while others will provide funding purely to contribute to
the advancement of research. Pharmaceutical companies may find it advantageous to support a
national venture, either directly or via fees, as a way to share costs.
Incentives. To reap the enormous scientific benefits from the NBN, a sufficient number of tissue
donors and researchers who see value in the resource must actively participate in the endeavor.
Open communication and true partnerships with existing institutions are necessary to maximize
utility, overcome barriers, and change attitudes. To develop a sound business plan, it will be
critical that there be incentives to participation at multiple levels (see Table 6-1). Although it is
difficult to quantify the value of these benefits, it is still useful to articulate the incentives or
benefits that could accrue from the NBN.
Table 6-1. NBN Participants: Benefits and Incentives to Participation
| Type of Participant |
Benefits and Incentives to Participation |
| Government |
- Efficiencies for research and operations, especially via promoting
comparisons, economies of scale, and enforced QA/SOPs
- Fulfilling government mission of creating resource that private
sector may not be able to provide (may be question of scale and
specifics)
- If parts are “outsourced,” then it promotes efficient use of
government personnel for purely governmental functions, with NBN
Operations and business units handling administration
- Access to charitable monies for research
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Academics,
Research
Institutes |
- Efficiencies for research and operations, especially via economies of
scale and enforced QA/SOPs
- Access to previously “hidden” or simply unavailable resources
- If independent organization is created, then it provides a very open
process and may level competitive playing field
|
Pharmaceutical
Manufacturers/
Contract
Research
Organizations |
- Information for drug development, including improved information
about clinical and molecular effects of drugs (desired and undesired
effects)
- Possible decrease in approval time if they are using NBN “national
standards”
|
Device and
Information
Technology
Companies |
- New market for “national standards-based” products
- Vastly more reliable substrate for product development and testing
|
Biospecimen
Collection Sites |
- Priority access to biospecimens
- Institutional commitment to SOPs and QA developed by the NBN
- Improvement of pathology and bioinformatics infrastructure
- Fees
- Possible Centers for Medicare and Medicaid Services reimbursement
of selected NBN services (especially if Clinical Laboratories
Improvement Act-like standards put in place)
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| Donors |
- Sense of contributing to cure and prevention
- Possible improved understanding of personal, familial, or ethnic
group factors, especially long-term factors (but it must be
understood that risks of using unvalidated research results may
outweigh benefits)
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Suggestions to foster increased cooperation and collaboration include the use of clinical
cooperative groups to encourage the development of a culture of teamwork and cooperation
among institutions that might participate in the NBN; and the use of demonstration projects,
which can provide learning experiences, accelerate progress, and can be used to develop
standards and determine good tissue practices for the full system. Federal funders can also
encourage the use of data generated from demonstration projects to support grant proposals, and
the use of the NBN by NCI grantees. Biospecimen contributors could receive priority access to
tissues, or receive a number of samples for free in equal number to that which the institution
contributes. Enhancing the NBN with strategic linkages to other data-gathering repositories, such
as cancer registries, to enhance the database—or to clinical trials data—could further attract
users.
6.3.2.2 Business Plan: Recommendations
The NBN Design Team recommended that the initial business plan assume a combination of
direct government funding plus user fees. The government’s role in funding will likely be most
prominent at start-up, but it may be offset over time by user fees. As the NBN provides
precompetitive access to specimens and data and takes no intellectual property position relative
to findings from research using the specimens, users’ ability to retain intellectual property rights
should enhance participation. It is probably unrealistic to expect the NBN to be self-sustaining
for several years, if at all. Institutions and individuals that benefit from this system would be
expected to help support it financially, either directly or in-kind.
A detailed model that forecasts costs and charges will need to be developed. The model would
take into account the various products, producers, users, buyers, and payers. This model ought to
include fixed costs (governance, business infrastructure) and variable costs (the number of
samples and sites). Developing a pricing strategy would be a major objective of this study.
6.3.3 Operations Plan
Detailed operations pertaining to building and maintaining of the NBN are discussed in this
section.
6.3.3.1 Operations Plan: Issues
The operational issues include management of the NBN. Management covers activities related to
staff, budget, administration, policies and procedures (including accreditation), facilities, and the
scientific program itself. Key elements of the day-to-day operations include collection and
storage of specimens and operation of an information system; and resource administration,
including overseeing systems to allocate the specimens to researchers; compliance with
applicable laws and regulations; communications with researchers and other interested parties;
and QA. An organization of such complexity will require professional management and welldefined
SOPs. It is anticipated that there will be intense interest in NBN operations by various
organizations and agencies, such as government, academic, industry, and not-for-profit entities,
including those representing survivor or patient groups, and standards bodies.
6.3.3.2 Operations Plan Recommendations: The Business Units
A series of business units would be supported and coordinated by the NBN Operations Center.
Each business unit will focus on a particular part of the process, as discussed later. The business
unit is a functional entity (e.g., biospecimen and data acquisition), and should not to be confused
with a site (e.g., a community hospital). A business unit could have multiple sites, and one site
might be part of one or more business units. For example, a community hospital might be part of
the Biospecimen and Data Acquisition Business Unit and might also provide storage and
distribution capabilities. The business arrangements between the business unit and its sites are
mutually established and would not be managed by the NBN Operations Center. However, the
sites would be subject to QA oversight from the NBN Operations Center. Each business unit
would be responsible for developing local QC SOPs, and for reporting data to NBN Operations
to allow for network-wide and business unit-specific QC. The six proposed business units are
now described in more detail. The letting of contracts for individual business units should be
flexible in that multiple business units may be contracted to a single entity under one contract to
achieve synergy and consistency.
The Research Administration and Support Business Unit would administer the Biospecimen
Utilization Review Committee, help set scientific priorities for access to specimens, document
research results, and help define an ongoing scientific needs agenda for the NBN.4 It would
develop SOPs for each of these functions, coordinate support activities, work with standards
organizations, and serve as a common meeting ground for the activities of the other business
units. An important component of its work would be developing novel ways to track and allocate
specimens; comply with regulations; and communicate with researchers, IRBs, and other
interested parties. This business unit would have important communications responsibilities with
Principal Investigators, other partners, contractors, and sponsors. It also would be responsible for
understanding and meeting the needs of users.
The Specimen and Data Acquisition Business Unit would facilitate patient data collection by
identifying patients, administering consent, acquiring specimens of specified quality, collecting
clinical information, and performing a minimal set of analyses, as defined by SOPs (these
activities are further detailed in 3. Biospecimen and Data Collection and
Distribution.) There
could be multiple specimen acquisition organizations, and each might have multiple sites to
ensure that they meet the range of tissue types, quantities, and qualities required. This business
unit must have capabilities to collect associated pathology, demographic, social history, and
clinical data as well as biospecimens.
The Storage and Distribution/Basic Analysis Business Unit would be responsible for
specimen processing, storage, and retrieval, as detailed in 3. Biospecimen and Data
Collection and Distribution. Pathology review also could be based here, but it should be done in close
proximity to the collection site.5 Adherence to standards
and SOPs (both current and future) is important. This business unit might be partly or wholly decentralized, and
could be a single
entity or a consortium, as long as there is a single contracting entity. It could take advantage of
existing facilities, build new ones, or use a mixed model. It can thus utilize existing facilities at
universities or corporate or governmental laboratories. The challenge will be to develop fiscal
and scientific incentives to make NBN regional facilities attractive to researchers, including the
availability of precompetitive, highly standardized, well-annotated tissues with appropriate
associated data in a national database The big attraction for researchers would be access to a far
greater variety of biospecimens than could ever be acquired locally. Regionalization also would
facilitate QC of research services such as generating DNA and RNA microarrays. Figure 6-3 illustrates a possible NBN configuration.
An initial snapshot of the nationwide NBN might include:
- Two to five regions in the United States
- Five to 20 collection centers per region
- One initial processing, storage, and distribution center per region (specimens would be
distributed nationally from each region, and some specimens would be stored in other
than the home region repository for disaster avoidance purposes)
- One advanced analysis center for the nation
- A virtual bioinformatics grid encompassing the entire country.
Expansion of the NBN would involve the identification of additional collection sites in each
region, including Alaska and Hawaii. It is not anticipated that additional processing, storage, and
distribution centers, or additional advanced analysis centers, would be added as the NBN grows.
The Advanced Analysis Business Unit would be charged with providing advanced analytics
(e.g., gene expression microarrays, proteomics) to NBN users on a fee structure to be
determined. The goal is to provide standardized tests at competitive prices, and promote
comparability, to be specified by SOPs and monitored by sophisticated QA. It is not envisioned
that individual researchers would be required to use this service in preference to those provided
by other laboratories, including their own. In addition, this business unit would have a scientific
function of keeping abreast of new technologies and bringing them, as appropriate, to bear on the
NBN mission. This business unit may be a higher priority in later years. It is important to
conduct market analysis to determine demand prior to establishing this business unit.
The Bioinformatics and Data Management Business Unit will work closely with the
Operations Center’s Bioinformatics and Data Management staff to define the system
architecture, establish and maintain standards (and develop new ones as needed), and define
policies for data exchange between the business units and sites as outlined in 4.
Bioinformatics and Data Management. It would manage data flows throughout the entire “life cycle” of a
biospecimen and its associated information, from procurement, storage, distribution, and
analyses to possible reposting of research results. It is expected that eventually most data will
reside locally, with a central facility that will point to data, and thus provide users with access to
information about specimens. SOPs and QA will focus on software quality, system availability
and utility, security and backup, and data validation.
Figure 6-3. Hypothetical Model for NBN Biospecimen and Data Collection and Distribution
The funding and governance of the Bioinformatics system could be part and parcel of the overall
NBN governance structure or an independent entity that has a contractual relationship with the
NBN as a whole. As an independent entity, the NBN information system could be a commercial,
for-profit enterprise, a not-for-profit, or a governmental concern. Even if it is governmental or
not-for-profit, commercial firms could be contracted to do some or all of the work. For example,
the NBN entity could design the system architecture and hire a firm to create the data dictionary
or program the reports.
An alternative model is for the government to develop a base system and have another entity
perform maintenance, administration, and enhancements. Alternatively, the roles could be
reversed, in whole or in part. Finally, these arrangements could be changed after a set period
(e.g., 3 years).
The Patient Relations Business Unit will be responsible for communicating with healthcare
consumers to answer questions about the uses for their type of specimen, the results of research
studies, and their eligibility for studies. See 5. Communications for further discussion of its
functions. Donors will not have access to research results directly related to their specimen, but
only to a class of data (e.g., results of a particular study in women aged 50 to 69 with pancreatic
cancer). This topic is further discussed in 2. Management of Ethical and Legal Issues.
This business unit will handle other medical concerns directly relevant to the donor’s
participation in the NBN that their health providers would not be able to answer. It is likely that a
variety of communications modalities will need to be developed, including direct telephone
inquiry handling, referral to NBN constituent organizations (including the survivor
organizations), Web sites and listservs, brochures, newsletters, etc.
This business unit may play a role in promoting appropriate consent processes and measuring
overall satisfaction, and thus improving customer satisfaction, with the NBN. Marketing the
NBN, both conceptually and practically, will be an important function. This business unit is
likely to be a single entity with strong ties to many other organizations.
6.4 Summary of Key Findings and Recommendations
The NBN governance and business models must include strategies that permit the NBN to
rapidly establish a firm foundation and facilitate its growth into a self-sustaining organization.
The strategies must be sufficiently defined to be realizable, yet sufficiently flexible to meet the
likely evolution of research opportunities and needs of the NBN discussed elsewhere in this
report. It is unlikely that the NBN will be an entirely governmental project, in either management
or funding.
The key recommendations include:
- NBN governance should be organized at three levels to include a Board of Governors, the
NBN Operations Center, and its business units. The proposed business units would
include the following: Research Administration and Support; Biospecimen and Data
Acquisition; Storage and Distribution/Basic Analysis; Advanced Analysis;
Bioinformatics and Data Management; and Patient Relations.
- Any private or public entity—including existing businesses or research consortia and
tissue repositories—would be free to bid on business unit work (their own governance
structures permitting).
- Because funding sources are expected to a be a mix of public and private (charity and
fees), the overall funding structure must be able to accept funds from a variety of sources;
hence the NBN Operations Center should be a not-for-profit entity, possibly incubated in
the FNIH or within the NDC itself. Not-for-profit status of the NBN Operations Center
brings the added advantage of enhanced credibility and maximizing public trust.
- QA, Bioinformatics and Data Management, and Communications are core efforts that
will be critical and would be in the NBN Operations Center. Bioinformatics/Data
Management and Communications will also be represented in the business units.
- A sound business plan requires that there be incentives to participation at multiple levels.
Open communication and true partnerships with existing institutions are necessary to
maximize utility, overcome barriers, and facilitate participation.
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