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Fact Sheet

  • Reviewed: 06/06/2006

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Drug Discovery at the National Cancer Institute

Key Points

  • NCI has played an active role in the development of drugs for cancer treatment for over 50 years. This is reflected in the fact that approximately one half of the chemotherapeutic drugs currently used by oncologists for cancer treatment were discovered and/or developed at NCI.
  • NCI’s Developmental Therapeutics Program (DTP) has over 400,000 drugs in its repository that have gone through some kind of screening process. About 80,000 compounds have been screened since 1990, using the current screening system.
  • Compounds can enter at any stage of the development process―with either very little or extensive prior testing.
  • NCI supports about 1,500 clinical trials through a variety of programs. Some are conducted by NCI researchers at the National Institutes of Health in Bethesda, Md., while others take place at cancer centers, hospitals, and community practices around the country.
  1. How has NCI contributed to the development of drugs for cancer treatment?

    NCI has played an active role in the development of drugs for cancer treatment for 50 years. This is reflected in the fact that approximately one half of the chemotherapeutic drugs currently used by oncologists for cancer treatment were discovered and/or developed at NCI. The Developmental Therapeutics Program (DTP) promotes all aspects of drug discovery and development before testing in humans (preclinical development), and is a part of the Division of Cancer Treatment and Diagnosis (DCTD). NCI also funds an extensive clinical (human) trials network to ensure that promising agents are tested in humans. NCI’s Cancer Therapy Evaluation Program (CTEP), also a part of DCTD, administers clinical drug development. This fact sheet focuses primarily on preclinical development within DTP.

  2. What role does DTP play in drug development at NCI?

    DTP participates in all stages of pre-clinical drug discovery and development. At the initial stage, DTP actively solicits scientists for candidate drugs. A drug is first screened in a variety of human tumor cell lines growing in tissue culture dishes to test for its ability to prevent the growth of specific kinds of tumor cells. If the drug shows promise, extensive testing in animals will determine whether it is effective and safe enough for testing in humans.

  3. How long has NCI had a drug development program?

    NCI has had a screening program to test experimental cancer drugs since 1937, but it was not until 1955 that a formal organization (called the Cancer Chemotherapy National Service Center) was formed to integrate laboratory resources with clinical facilities. In the early decades, compounds were screened in leukemic mice, and in 1975, a program to screen mice bearing transplanted human tumors was introduced. Over time, the system has evolved into one that combines both in vitro (cancer cells grown in a dish in the laboratory) with in vivo (animal) testing. The current system, described in detail in question 6, has been operational since 1990.

  4. How many drugs has NCI tested?

    DTP has over 400,000 drugs in its repository that have gone through some kind of screening process at NCI. About 80,000 compounds have been screened since 1990, using the current screening system.

  5. Where do these drugs come from? How can they be characterized?

    NCI actively solicits drugs from government laboratories, research institutes, academic institutions, and companies throughout the world. DTP scientists systematically scan the latest literature for novel compounds and request samples of promising drugs.

    Another source of novel compounds comes from the Natural Products Branch, a part of DTP that collaborates with agencies throughout the world to collect thousands of plant and marine organisms for the tumor screen. To expedite drug discovery, NCI is providing sample sets of more than 140,000 synthetic chemicals, 80,000 natural products extracted from plants and marine organisms, and other biological materials to investigators who might have discovered potential cancer-associated molecular targets.

    Although many drugs are voluntarily submitted, a substantial fraction screened are solicited by NCI. Of all the drugs screened by NCI, about 40 percent come from industry. The remainder comes primarily from academic collaborators.

  6. What are the specific stages of testing in DTP once a drug has been chosen to be evaluated?

    • Preliminary in vitro screening: New drugs are first evaluated in a pre-screen consisting of three human tumor cell lines. Cells are exposed to each drug at a single concentration for 48 hours. If growth of one or more cell lines is inhibited, the drug is automatically evaluated against the full panel of 60 human tumors.
    • In vitro screen in human tumors: Each drug is exposed to 60 human tumor cell lines, including lung, colon, melanoma, prostate, ovarian, breast, and kidney cancers at five different doses for 48 hours. If the drug is unique in some way―kills preferentially one or more of the tumor cell lines, has a unique mechanism of action, or can kill tumors at a very small concentration―testing will proceed to the next stage. Approximately 2,500 compounds are tested on a yearly basis. About 2 percent of those screened will be recommended for the next stage of testing in mice.
    • In vivo testing using hollow-fiber technique: Small hollow fibers (tubes one millimeter in diameter and two centimeters long made of a plastic, polyvinylidene fluoride), containing cells from human tumors are inserted underneath the skin and in the body cavity of the mouse. Each candidate drug is administered at two dosages and is tested against 12 target tumor cells in different hollow fibers. A total of about 150–200 compounds/year is screened by this method. Compounds that retard the growth of the cells are recommended for the next level of testing. The average length of this test is about four days.
    • In vivo testing using xenografts: Human tumors are injected directly below the skin of mice. Candidate drugs which have shown evidence of activity in the hollow fibers may be selected for testing in xenografts. The drugs are administered to the mice at various dosages, and those compounds that kill or slow down the growth of specific tumors with minimal toxicity to the animal will proceed to the next stage of testing. The average length of this test is about 30 days.
    • Pharmacology, formulation, and toxicology studies: Drugs that reach this stage of development are under serious consideration for testing in humans so that substantial resources may eventually be committed to their development. There are two levels of development at this stage.
    • At the first level of development, scientists determine the basic pharmacology of the compound in animals to see where the drug is metabolized. The best chemical formulation for administering the drug, how much of the drug to give, how often and whether the drug should be taken orally or by injection is also established.
    • If a drug progresses to the next level, NCI commits resources, approximately $250,000 to $500,000, to further development. A large-scale production plan for the compound may be developed if needed. In addition, toxicology evaluations are done in two species of animals using the same material under consideration for human trials. If the drug has no serious problems, scientists recommend the initial dose, route and schedule for patients in early trials (phase I clinical trials).

  7. What is the usual procedure for a company or academic laboratory to enter into the process of NCI's drug development program?

    Compounds can enter at any stage of the development process―with either very little or extensive prior testing. A laboratory may only want its compound screened in tumor lines. Alternatively, a compound may have been already tested outside the NCI in tumor cell lines, requiring only animal evaluation. Some compounds have been tested in animals outside the NCI and are brought before the DDG for approval to test in humans.

  8. What happens after the final testing in animals?

    Once a drug is approved by the DDG, the next step is to file an Investigational New Drug Application (IND) with the Food and Drug Administration (FDA) to allow testing in people. The IND describes the chemical structure of the compound, how it is thought to work in the body, any toxic effects found in the animal studies, how the compound is produced, and where and how the human trials will be conducted. The IND may be submitted by NCI, a company or an academic lab.

    CTEP is responsible for submitting INDs for NCI as well as drugs in which NCI is involved in a CRADA (Cooperative Research and Development Agreement) or CTA (Clinical Trials Agreement) with a company or supplier. NCI currently holds nearly 129 INDs; many of these represent cooperative drug development efforts with industry.

  9. What happens after the drug is approved by the FDA for testing in humans?

    The sponsor of the IND prepares a plan, or protocol, outlining the institutions and number of people that will take part in the study, the eligibility requirements, the medical tests and interventions they will receive, and how often. The protocol must be approved by NCI (or the organization sponsoring the study) and the Institutional Review Board (IRB) at each hospital or study site. This board, which includes consumers, clergy, and health professionals, reviews the protocol to ensure that the research will not expose patients to extreme or unethical risks.

    Once the centers and institutions have been selected and protocols approved, phase I and phase II trials are conducted with a limited number of people to determine the safety, dosage, effectiveness, and the side effects of a drug. If these preliminary trials indicate that the drug is well-tolerated and shows some efficacy, phase III trials are initiated. In phase III trials, hundreds of people around the country are assigned at random to receive either the new treatment, the standard treatment, or if no standard treatment is effective, a placebo.

  10. What groups carry out NCI-supported clinical trials?

    NCI supports about 1,500 clinical trials through a variety of programs. Some are conducted by NCI researchers at the National Institutes of Health in Bethesda, Md., while others take place at cancer centers, hospitals, and community practices around the country.

    The Clinical Trials Cooperative Groups are composed of academic institutions and cancer treatment centers throughout the United States, Canada, and Europe, and are made up of more than 1,700 institutions that are responsible for placing more than 22,000 new patients into cancer treatment trials each year.

    The NCI Cancer Centers Program comprises 61 NCI-designated cancer centers throughout the country. Many cancer centers conduct NCI-approved protocols and have websites that provide information about ongoing trials at their facilities.

    The Community Clinical Oncology Program Network (CCOP) provides support to community physicians and local hospitals which are not a part of the Cooperative Groups so they can participate in NCI-supported clinical trials. By affiliating with either an NCI-supported clinical cooperative group or cancer center, the 390 participating hospitals and 2,320 participating physicians in CCOP, can enter patients into NCI-sponsored trials.

  11. How many cancer patients participate in NCI-sponsored clinical trials?

    Each year about 27,000 new patients enter into NCI-sponsored clinical trials. About 20,000 participate in Cooperative Groups, 5,000 in the CCOPs, and 2,500 in trials conducted at NIH in Bethesda, Md. This represents about 3 percent of adult cancer patients and about 60 percent of children who are diagnosed with cancer each year. Children under age 20 account for about 1 percent of all cancer cases.

  12. What happens after Phase III trials?

    At the conclusion of phase III trials, the results are reported at meetings and in peer-reviewed journals. If the treatment is proven safe and effective in phase III trials, the drug company sponsor of the drug files a New Drug Application (NDA) with FDA. The average time for FDA approval is six months to a year. Once approved by FDA, the drug becomes available for physicians to prescribe for patients.

  13. About how long does the entire drug approval process take?

    There is a growing recognition that a major factor contributing to the bottleneck in drug development is the time-consuming and less than optimal processes for preclinical and clinical testing of drugs. The Pharmaceutical Research and Manufacturers of America (PhRMA) estimates that on average the industry must spend $0.8–$1.7 billion and 12–15 years of research and development to bring a product to market. This leaves only 2–5 years of patent life and market exclusivity before generic competition results in lower prices and profits. With such a limited time to recoup its investment, industry is forced to charge increasingly higher prices.

  14. Does NCI have mechanisms for ensuring privacy of the test results when working with private industry?

    Yes, in order to encourage collaborations with private industry, procedures were developed for confidential handling of proprietary chemicals, called the Discreet Screening Agreement. All screening data are returned to the supplier.

  15. What is unique about the screening program at NCI?

    NCI focuses on scientific merit and uniqueness. In particular, NCI scientists are looking for drugs with novel mechanisms of action.

  16. What are some success stories? What drugs developed by DTP at NCI are now in commercial use?

    Half of the FDA-approved anticancer drugs were sponsored by NCI. For example, cisplatin for treating testicular, ovarian, and lung cancer, and paclitaxel (Taxol) and fludarabine phosphate for treating several cancers and lymphoma, respectively are examples where NCI involvement in early stage of development resulted in products which eventually were licensed to commercial organizations and reached the market.

    Tamoxifen, Herceptin, Gleevec, Erbitux are examples of successful FDA approved drugs. For a complete list of drugs, go to the Cancer Drug Information list.

    Other examples include:

  17. What are some promising drugs under consideration now?

    NCI is supporting the development of drugs that target many biochemical pathways in the cell―genes involved in apoptosis, cell cycle control and cell signaling, angiogenesis, tumor invasion, and metastasis, DNA synthesis and immune functions. Some of the promising agents and their biochemical pathways that are in early clinical development at NCI include:

  18. What are other sources of information about drug development at NCI?

    For DTP: http://dtp.nci.nih.gov/

    For CTEP: http://ctep.cancer.gov/

    For cancer clinical trials: http://www.cancer.gov/clinicaltrials/

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