Federal Agency Roles in Cancer Drug Development from Preclinical Research to New Drug Approval The National Cancer Institute and the Food and Drug Administration (2005) / Chapter Skim
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2 The National Cancer Institute
2 The National Cancer Institute
Pages 7-27
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From page 7... ...
, Congress appropriated funds to NCI for a national drug development effort, the NCI National Chemotherapy Program. Accordingly, the Cancer Chemotherapy National Service Center (CCNSC)
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, with the rest coming directly from the domestic or international pharmaceutical industry. Evolving Screening Approaches Preclinical models used by NCI to select new drugs for cancer clinical trials have evolved over time due to improved understanding of the biologic factors that affect the success of treatment, such as the relationship of tumor cell growth kinetics to drug responsiveness, to retrospective analyses of correlations between clinical and preclinical efficacy, and to the development of the NCI Drug Information System, a computer inventory of compound structure and activity in the mouse models, that limits the screening of analogues and directs the focus to novel structures (Schabel, 1969; Skipper et al., 1970.
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This approach identified new active agents that would have been missed by the mouse tumor models. However, many key disease events, such as metastasis, did not occur in the graft models raising concerns they might miss effective drugs and limiting their predictive utility.
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The screen uses 60 human tumor cell lines, representing leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney. Natural products collected in an NCI repository are also a major source of chemical entities screened (see Box 1)
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The premise of this technique is that advancing potential anticancer agents identified in an in vitro screen to preclinical development requires a demonstration of in vivo efficacy in one or more animal models (Hollingshead et al., 1995) , and hollow fiber screens appear to correlate well with clinical results (Johnson et al., 2001)
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The committee recommended that the 60 cell line screen be preceded by a 3 cell line screen to first identify lead antiproliferative agents. A subset of compounds identified in this manner could then be analyzed in the 60 cell line screen to gain insight into a compound's mechanisms of action.
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Correlations of compound activity are made with mechanisms of action for particular molecular targets and then used to generate hypotheses that relate to the potential targets, and the molecular targets of unknown drugs can be deciphered by analyzing their cell line screen data and comparing it with the activity of the agents in the database. These analyses and correlations have recently been enhanced through the use of publicly available data on gene expression patterns for thousands of expressed genes from NCI's collaboration with Brown and Botstein (Ross et al., 2000)
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In 2000, as a first step to refocus its efforts in this area, NCI announced the availability of Molecular Target Drug Discovery grants. Program announcements for this initiative stated that "Rather than depending on in vitro and in vivo screens for antiproliferative activity, investigators can now focus on new molecular targets and pathways essential for the development and maintenance of the cancer phenotype."3 The NCI announced that it was reorganizing its drug development programs from early drug discovery to the conduct of clinical trials in order to bring forward new types of agents based on strong rationales.
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The Human Tumor Gene Index identifies genes expressed during the development of human tumors. The Cancer Chromosome Aberration Project characterizes the chromosomal alterations that are associated with malignant transformation.
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The lack of adequate animal models has led to the development of transgenic mouse models to be used as preclinical assays to determine the likelihood of success for novel agents being considered for clinical studies. The Mouse Models of Human Cancers Consortium8 involves 20 groups of academic researchers who have created and are making available to researchers mice with defined genetic alterations that predispose the animals to certain types of cancer that could serve as a basis for testing new molecular targeting treatment and prevention strategies.
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Importantly, very few of these models have been validated as representative of human disease through molecular markers and response to current anticancer therapies. Human tumor grafts in mice have the advantage of human malignant cells of a wide variety of types and, in many cases, reliable tumor growth.
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An agent that survives higher hurdles during preclinical testing would presumably have a greater chance of clinical success, and guidelines for uniform data gathering and data analysis should allow improved selection of agents for clinical trials. Toxicologic Evaluation at NCI Once a compound of interest is identified, animal models are critical to assess preclinical toxicology.
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Compound samples accepted after DTP review can be screened for the academic originator using the NCI's three cell line, one day prescreen, and a follow-up of actives in the NCI 60 cell line screen. All output from a RAND project is returned to the originator of the project as synthesized or isolated materials, high-throughput screening or pharmacokinetic methods, informatics output, or in vivo screening results, among others.
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The Drug Development Group provides support for academic and corporate-derived compounds when NCI is responsible for conducting and monitoring the drug's clinical development. A number of promising agents have been developed through this program.
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These methods and reagents must, therefore, be suitable for in vivo use in animal models and in human beings. The first set of applications for this program was funded in early FY 2001.12 Sponsorship of Clinical Trials by NCI In 1955, the National Cancer Institute began to organize clinical trials of the first effective anticancer agents in leukemia patients.
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, emphasizing phase III studies, 11 for adult and the 12th, the Children's Oncology Group, for childhood cancer. Some groups (Children's Oncology Group)
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, or about 2 percent of the new cases and a much smaller percentage of all people living with cancer. Finally, while phase III trials are, with rare exceptions, required for final FDA new drug approval, most of the trials that in practice define the uses of a cancer drug take place after FDA approval, the importance and scope of such trials in cancer being far greater than for drugs for other conditions.
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Changing to Meet the Coming Needs If, as is anticipated, the number of new cancer drugs in development increases-possibly dramatically -- the NCI clinical trial network will be pressed to meet new challenges, including: greater involvement with pre-approval trials; more rapid development of protocols for post-approval trials; improving accrual rates; greater numbers of clinical questions likely to be generated by the larger numbers of agents (many of which should have known molecular targets) ; among others In addition to increasing enrollment in trials, efforts to select patients based on matching cancer molecular profiles with drug targets might identify the most appropriate patients for trials of particular agents.
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This complexity has bred inefficiencies and eroded the ability of the system to generate new ideas to reduce the cancer burden." The Review Group considered recruiting and retention of clinical scientists, recruiting of participants to clinical trials, improving clinical trials methodology, increasing collaboration and cooperation in clinical trials, and NCI's organizational framework and structure for implementation of clinical trials. The Group recommended that NCI should: increase funding for cooperative groups to fully recommended levels; reduce and limit data collection to study endpoints and patient safety and fund some large simple trials in common cancers to establish treatment differences; enforce uniformity of data collection; enlist advocates, industry, and the FDA to develop uniform standards and reporting requirements; provide cooperative groups and cancer centers with the means to access all relevant electronic databases and test the new NCI informatics system; and develop strategies to convince payers that clinical trials represent a better standard of care and ultimately result in decreased costs.
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Since then, NCI has established a Developmental Therapeutics Program to support the programs necessary to its pivotal role in the worldwide effort to develop new agents to treat cancer. The DTP supports the preclinical development of novel therapeutic modalities for cancer, the acquisition, synthesis, and definition of activity in both in vitro and in vivo models of cancer, and the advancement of active agents in preclinical models toward clinical evaluation.
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The challenge for the Institute is to continually reassess where its advantages lie, to consider its historical involvements in all phases of cancer drug development to focus on basic science and discovery of interesting molecules against novel targets, or on preclinical and clinical development of academic or industry agents in coordination with the FDA in deployment, or both -- and to create opportunities for moving forward. As of late 2004, NCI was considering a review to carry out just such a reassessment (Doroshow, J., personal communication to the National Cancer Policy Board, 2004)
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