The history of drug development and screening at the National Cancer Institute (NCI) spans over 70 years; the NCI has had a screening program to test experimental anticancer drugs since 1937. Over the ensuing decades, the NCI has had a profound impact on the development of cancer therapeutics. The NCI reports that approximately one-half of the chemotherapeutic drugs currently used by oncologists were discovered and/or developed at the NCI [1]. Some of the most prominent examples where the NCI was involved in early-stage development include cisplatin, paclitaxel, and fludarabine phosphate for treating solid tumors and hematological malignancies. In these cases, important technology was created or licensed by the NCI that enabled these drugs to reach the market. The NCI has also played a role in later-stage development activities; tamoxifen, trastuzumab, imatinib, and cetuximab provide examples of NCI contributions to obtaining FDA approval for cancer therapeutics.

It has been recognized for over a quarter century that the most difficult stage of drug development is translating basic mechanistic research and early-stage targeted compounds into therapeutics suitable for clinical development—this late preclinical/early clinical phase is commonly known as “the valley of death.” Only 11% of agents entering this stage of development eventually show clinical success, with only an 8% rate in oncology [2]. This poor success rate is attributable to a wide variety of factors, but the most significant (causing over 40% of failures) is adverse pharmacokinetics and bioavailability [2]. In addition to early-stage screening, over the past 25 years, NCI’s Division of Cancer Treatment and Diagnosis (DCTD) developed a variety of programs, including an expansive pharmacodynamics program, to move cancer therapeutics through late-stage preclinical and early-stage clinical development to address “the valley of death” in drug development.

Drug Screening Programs at the NCI

In 1955, the NCI formalized its screening program by establishing the Cancer Chemotherapy National Service Center’s (NSC) screening program [3]. The NSC program functioned until the mid-1980s, and most of the screening focused on the use of in vivo murine P1388 or L1210 leukemia cell lines [4]. These cell lines were chosen because hematologic murine tumors were inexpensive, stable, reproducible, and easily handled. Unfortunately, screening with rapidly growing leukemic cells biased the agent pool toward those compounds with activity against rapidly growing tumors and those with high growth fractions. This resulted in a relative lack of success in identifying agents with activity against common human solid tumors [5].

To address these limitations, in 1989 DCTD’s Developmental Therapeutics Program (DTP) moved from using hematologic murine tumors to an array of 60 cell lines derived from a wide variety of human solid tumors [6]. The “60-cell-line screen,” as it became known, remains the centerpiece of extramural DTP’s screening program; over 80,000 compounds have been screened since 1990, using the current screening system [1]. Data generated from 60-cell screens are analyzed via an algorithm known as COMPARE, a program that categorizes different groups of agents based on their patterns of cytotoxic activity [7]. The program is able to classify anticancer agents based solely on the cytotoxic pattern exhibited in the 60-cell-line screen [8]. The open screening program functions to this day; applicants may submit compounds for screening through DTP’s online screening application found on its website [9]. In recent years, the NCI has used the 60-cell-line screen as part of a multi-pronged approach to identify promising combinations of approved cancer therapeutics [10].

The Rapid Access to Intervention Development Program

In 1998, the NCI pioneered the Rapid Access to Intervention Development (RAID) Program as a partner to the Drug Development Group (DDG, see later discussion). The goal of this program was to use NCI contract support to provide critical early research to assist academic investigators in initiating clinical trials based on their own research. The investigator held an investigational new drug application (IND), while the NCI supplied early-stage resources, including IND-directed toxicology studies, pharmacologic assay development, clinical drug formulation, and good manufacturing practice (GMP)-quality agent for use in the investigators’ initial clinical trials. During its existence, the RAID Program approved 126 projects, through which 15 small molecules and 17 biologic agents later entered clinical trials [11].

In 2001, the NCI initiated a sister program to RAID—RAND (Rapid Access to NCI Discovery Resources)—to assist academic investigators with earlier stages of drug development. The RAND Program was intended to provide support for earlier drug discovery efforts than RAID, and offered resources to conduct high-throughput screening efforts, medicinal chemistry activities, and formulation studies. RAID and RAND were eventually phased out and their activities subsumed into the NCI Experimental Therapeutics (NExT) program. The impetus for these changes was recommendations by review committees that RAID and RAND would be more productive if the focus was shifted to the overall development of a therapeutic rather than as an assistance mechanism for individual investigators [12].

The Decision Network/Drug Development Group

“Internal” extramural drug development prior to the NExT Program was approved and conducted by the DDG (and prior to that, its earlier incarnation, the Decision Network). DDG projects differed from RAID projects in that the NCI held the IND and was the main sponsor of the clinical development of DDG agents. DDG resources spanned a wide range of development, from early-stage screening through initiation of Phase 1 clinical trials. The DDG served as a bridge between preclinical and clinical resources provided by the NCI and had several successes, including the work conducted on halichondrin B (see case studies).

Natural Products

The use of natural products as antitumor medications has a very long historical background [13]. In conjunction with the revision of the NCI’s screening program in the 1980s, the NCI began a concerted effort to collect natural products to test extracts in NCI 60-cell-line screen. Over the ensuing 30 years, the DCTD Natural Products Branch has collected more than 170,000 extracts from samples of more than 70,000 plants and 10,000 marine organisms. This was facilitated by the use of letters of collection with over 25 host countries. Letters of collection are a unique mechanism by which DCTD collects natural products in partnership with host countries. As part of the agreement to allow collection, any investigator who derives an invention from the natural product is required to offer rights back to the host country, with the terms varying from country to country. In some cases, this takes the form of a royalty, and in others it may take the form of agent development in the provider country. As of 2011, the NCI holds the most diverse natural products collection in the world and is currently in the process of reformatting the distributable collection into 384-well plates to facilitate high-throughput screening activities.

Cancer Therapy Evaluation Program: Sponsored Clinical Trials

In 1955, the NCI’s Clinical Trials Cooperative Group Program was established by Congress at a cost of $5 million. Over the ensuing half century, the program grew to become the largest sponsor of cancer clinical trials in the world. The program functions by funding networks of researchers who develop and conduct large multicenter trials. Trials are supported via contract and grant mechanisms to the cooperative groups. Funding for the groups is not linked to a specific trial; rather, the NCI funds the infrastructure, and the cooperative groups themselves generate trials compatible with their particular areas of interest and expertise.

The NCI Cancer Therapy Evaluation Program (CTEP) is the NCI program responsible for funding and oversight of the Clinical Trials Cooperative Group Program. Since the mid- to late-1990s, CTEP has stood as the largest sponsor of cancer-related clinical trials in the world. As of 2011, CTEP sponsors over 100 INDs, has approximately 11,000 registered investigators in over 3300 institutions, has over 1000 active clinical protocols that accrue over 33,000 patients, and has entered into over 80 collaborative agreements with both large and small pharmaceutical concerns for the development of experimental cancer therapies.

NCI’s Experimental Therapeutics Program

Over the 50 preceding years, the decision-making processes for the resources described earlier gradually became more and more complex. It was often difficult for the extramural community to gain access to or even acquire information about the many resources that the NCI had available for therapeutics development. As shown in Figure 10.1, resources were housed all over the institution and resided with multiple decision-making bodies, many of which did not coordinate their activities.

In 2009, the NCI launched the NExT Program. The primary impetus for the new program was to bring together the NCI’s disparate extramural development resources into a robust, balanced, goal-driven therapeutics pipeline. This pipeline focuses on developing a broad portfolio of molecularly targeted agents to pursue new and/or challenging pathways that have not been fully exploited by available cancer therapeutics. Combined, DCTD’s resources are capable of supporting a drug discovery and development continuum from initial discovery through clinical trial evaluation. Whereas in the past resources were awarded separately for different phases of development, now all the resources necessary for moving high-priority projects through the pipeline exist in a single structure, so access to the various components does not require additional research and negotiation by investigators.

It is important to emphasize that the NExT Program is not a grant-awarding mechanism, but rather an opportunity for investigators to partner with the NCI for drug discovery and development activities. Investigators gain access to resources rather than funding. In addition, by serving as scientific advisors to the project team, they enable the success of their individual projects and, collectively, the entire NExT Program.

Applications to the NExT Program are accepted three times per year through the NExT Program website (http://next.cancer.gov/) and are evaluated in a tiered review process (Figure 10.2). The review process follows standard National Institutes of Health (NIH) guidelines, except that even applications with exceptional science will not be accepted to the NExT Program without a clear path to the clinic or potential benefit to patients. Criteria for project approval include a concept associated with a compelling hypothesis that warrants clinical evaluation, a concept that will enable clinical evaluation of a new inadequately explored therapeutic approach, or a concept that is not likely to be explored in the absence of NExT Program assistance. Proposals are evaluated by a series of review committees, beginning with a special emphasis panel of external reviewers, each of whom has specific expertise in an aspect of drug discovery or development, such as immunotherapy or biologics; these reviewers come from academia, industry, and the government. After prioritization, highly regarded applications are assessed by internal review groups, who evaluate the projects for strategic fit within the NExT Program portfolio. Finally, a senior advisory committee approves the initial commitment of resources, and projects proceed on a milestone-driven basis. Projects may enter the NExT Program at any point; they are categorized as discovery (early-stage) or development (mid- to late-stage) upon entry into the pipeline. A Project Management Office, with the help of an information technology infrastructure, tracks project progress and data to ensure that both project team members and NCI leadership are kept informed of project activities and status.

Early Discovery

The primary discovery engine of the NExT Program is the Chemical Biology Consortium (CBC). The resourcing portion of the CBC consists of a collaborative network comprising 12 Specialized and Comprehensive Screening and Chemistry Centers selected based on their capabilities in high-throughput methods, bioinformatics, medicinal chemistry, and structural biology. Applicants who enter the early discovery program become participants, join the consortium, and join the project team that decides the direction and scope of the project. The goal of the CBC is for these groups to utilize their own expertise in conjunction with NCI’s internal and contract mechanisms to develop lead compounds, targets, and assays that can then be entered into NCI’s clinical development program. Integrated within the CBC are compound libraries for screening from both the CBC participants and the NCI; this can include the NCI’s repository of natural product extracts derived from terrestrial, marine, and microbial organisms.

Early Development Resources

Resources needed to facilitate discovery and late-stage preclinical development through first-in-human studies are provided by the DTP. These resources comprise activities that made up the former RAID Program, such as pharmacokinetics, pharmacodynamics, pharmacology, toxicology, and GMP scale-up for small molecules and biologics, as well as early-stage regulatory support. In addition, concurrent molecular imaging and/or pharmacodynamic assay development is provided by the NCI’s Cancer Imaging Program, National Clinical Target Validation Laboratory, Pharmacodynamic Assay Development and Implementation Section, and the Center for Cancer Research to allow early assessment of potential clinical biomarkers of drug effect. An important element of this support is providing validated assays as well as standardized specimen handling and testing procedures. Validated assays are particularly important for molecularly targeted drugs because they can demonstrate proof-of-concept that the drug is modulating its intended target in a patient’s tumor, ideally using nontoxic doses. For example, the NCI validated an immunoassay for use in the first phase 0 clinical trial in oncology of a therapeutic agent under the FDA’s Exploratory Investigational New Drug Guidance. This assay measured the activity of an inhibitor of the enzyme poly (ADP-ribose) polymerase (PARP) in patients’ blood and tumor biopsy samples [14]. Phase 0 trials have no therapeutic or diagnostic intent—their objective is to establish proof-of-concept of a new agent with minimal risk to participants—to inform decisions about whether the agent holds promise as an anticancer drug [15]. Based on the results from this trial, the NCI decided to continue clinical evaluation of the PARP inhibitor ABT-888 in combination with several different chemotherapeutic drugs to determine whether it potentiates their effects.

Late-Stage Development: The CTEP Clinical Trials Network

Clinical evaluation of NExT Program agents is supported by CTEP. Through CTEP, the NCI funds the largest cancer clinical trials network in the world, and the NExT Program provide agents suitable for testing to this network. The primary agents of interest for acceptance into the NExT Program at this stage are those requiring IND-directed toxicology data or agents already in Phase 1 or 2 clinical trials. In addition, CTEP maintains the collaborative aspect of the program wherein industry may submit agents in the late preclinical stage or early clinical stage for CTEP to further develop the clinical program in a niche area that is outside the pharmaceutical industry’s scope. As part of this stage of development, the NExT Program provides an array of support services, including regulatory support in the form of filing and maintaining an IND and developing a clinical protocol, while also funding the cooperative group studies. In addition to standard IND support, the NCI has been a pioneer in the development of exploratory IND studies, and can use its expertise to provide support for first-in-human Phase 0 studies [14].

Governance

The governance structure of the NExT Program is designed to streamline the decision process within and across projects. The NExT program has a similar application review structure to a grants program but provides nongrant resources to the development community, which require a different mechanism of approval and management. At the core is the project team, which is responsible for day-to-day project operational decisions within the constraints of the allocated resources. Balancing the allocation of the available resources between projects in the portfolio is the responsibility of an internal NExT Senior Advisory Committee (SAC). The SAC is responsible for decisions to initiate projects and allocate initial resources (beginning), to sustain resources throughout project progress based on project prioritization (maintenance), and to close projects by removing resources (close-out). The SAC makes decisions based on scientific input from and analysis of individual projects by the NExT Discovery and Development Committees, as well as on the availability and appropriateness of the resources required. The Discovery and Development Committees are composed of internal NCI staff with scientific expertise in the stage of development a project is assigned. The Discovery Committee provides oversight to discovery projects to ensure that all the scientific objectives have been met before triggering nomination of a clinical candidate. Once a clinical candidate has been nominated by the project team and approved by the Discovery Committee (or if the project entered the NExT Program at a later stage), project scientific review responsibility shifts to the NExT Development Committee.

To ensure a comprehensive scientific evaluation of each project, the internal NExT Committees are advised by a Special Emphasis Panel (SEP) composed of non-NCI staff who have specialized discovery or development expertise. The SEP is dynamic, consisting of members with both industrial and academic experience, and is intended to provide insight into the scientific direction of the NExT Program by bringing diverse perspectives to the conduct of a quarterly project prioritization of the NCI portfolio. SEP members include some of the most productive and experienced leading-edge researchers in the therapeutic development community. NCI relies on these members to share experience, provide guidance on appropriate targets and pathways, advise on medicinal chemistry, and provide strategic insight into what up and coming research is most appropriate for NExT development.

Overall oversight and accountability of the NExT Program is provided by the Senior Management Committee (SMC). The SMC consists of members of NCI’s Senior Leadership, including the NCI Director and Directors of DCTD and the Center for Cancer Research; Associate Directors of relevant programs, including DTP; and ad hoc expert government participants, as determined by the NCI Director. The SMC performs evaluative functions and provides guidance, final conflict resolution, and resources for the fiscal stability of the NExT Program. It also has final authority in establishing policies for the operations of the NExT Program.

In addition to the oversight bodies described earlier, the discovery engine of the NExT Program, the CBC, has a separate body whose purpose is to harness the collective expertise of CBC Centers and Participants. The CBC Steering Committee meets quarterly to provide suggestions for improving CBC operations. The CBC Steering Committee consists of participants, most notably principal investigators.

Technology Transfer Mechanisms Utilized by The NExT Program

When the NCI began designing the NExT Program in 2009, a substantial amount of effort was put into developing appropriate models for Technology Transfer. From an intellectual property (IP) standpoint, the goals of the program are straightforward:

1. To promote the discovery and development of novel anticancer agents and ensure they are developed, but retain the option to develop them in the NCI’s drug development pipeline.
   
2. To increase the rate and likelihood of novel cancer therapeutics becoming available to patients.
   
3. To bundle IP in such a manner as to encourage commercial development by an outside (nongovernment) party.

While the NCI has a significant investment in development activities, the government is neither equipped nor empowered to routinely enter into the business of producing and selling marketed drugs (but may do so under exceptional public health circumstances), so any framework had to include an effective mechanism for transferring commercial development to the private sector.

One of the overriding considerations in developing the NExT Program’s IP framework was how programmatic needs would interact with the NIH’s responsibilities under federal law. Whenever a recipient’s research work is funded either in whole or in part through NIH research grants, contracts, and cooperative agreements, that activity is subject to the requirements of Public Law 96-517, known as the Bayh–Dole Act of 1980 (hereinafter referred to as “Bayh–Dole”). Bayh–Dole was enacted in 1980 and is aimed at turning federally funded research and development into useful patented inventions to benefit American research institutions, industries, and consumers. In general, Bayh–Dole authorizes fund recipients to retain title to inventions resulting from their federally funded research and to license such inventions to commercial entities for development. This created challenges for the NExT Program because the majority of resources the NCI supplies under the program result directly from grants and contracts. Many collaborators, especially those with later-stage technologies, were concerned that the development of IP through the NExT Program would block their commercial development of that technology. Contractors and grantees would retain ownership of any inventions developed under the program, and collaborators feared that if an invention necessary to practice the technology were developed, it might be difficult to negotiate for the rights in the absence of a prearranged licensing option.

Another portion of the Bayh–Dole relevant to the NExT Program is 35 U.S.C. Sec. 202. This section grants to the federal government a “nonexclusive, nontransferable, irrevocable, paid-up license to practice or have practiced for or on behalf of the United States” any subject invention to which a government contractor has elected rights. This section allows the government to use any data or inventions generated by the NExT Program in any internal pipeline, ideally with the consent of the owner or licensee of a lead compound, but if necessary, without consent. This provision was integral to the development of the NExT Program’s IP structure because the NCI could utilize this license, especially in early-stage development, to continue work on a project even if diverse interests held IP that was generated as a product of a federal funding agreement.

Discovery to Early-Stage Development: The Chemical Biology Consortium

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