The National Cancer Institute (NCI) has played an active role in the development of drugs for cancer treatment for over 40 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. (http://dtp.nci.nih.gov/)

1. What role does the 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.
   
   
   

2. How long has NCI had a drug development program?
   
   NCI has had some form of 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. Compounds in the early decades were screened in leukemic mice, and in l975 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 5, has been operational since l990.
   
   
   

3. 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.
   
   
   

4. 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, which collaborates with agencies throughout the world to collect thousands of plant and marine organisms for the tumor screen.
   
   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.
   
   
   

5. 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. Approximately 2,500 compounds are ested on a yearly basis. 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. 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 1 millimeter in diameter and 2 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 substantial 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).

   
   
   

6. What groups of people are responsible for decisions at the various stages of development?
   
   

   • Access and Information Group, an interdisciplinary group of scientists from DTP, makes recommendations for the initial tumor screen. This committee makes sure that each compound tested has a biological rationale and novel chemical structure.

   • Screening Data and Review Committee, a group of biologists and chemists from DTP, reviews the screening data from the tumor cell lines and recommends which candidate drugs should be tested in animals.

   • Biological Evaluation Committee (BEC), an interdisciplinary group of 15 to 25 extramural scientists, meets monthly to evaluate tumor screening and hollow fiber data. The BEC makes recommendations to halt or proceed with testing.

   • Drug Development Group (DDG), an interdisciplinary group of 15 to 25 NCI clinicians and scientists, meets monthly to evaluate all the in vivo data from compounds that are under serious consideration for testing in humans. This group decides whether or not to recommend a drug for human 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 animals 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 200 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 1,200 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 (http://ctep.cancer.gov/resources/coop2.html) are composed of academic institutions and cancer treatment centers throughout the United States, Canada, and Europe, and are made up of more than 1,500 institutions and 8,000 physicians that contribute patients to clinical trials.
    
    The NCI Cancer Centers Program (http://cancercenters.cancer.gov) comprises more than 50 NCI-designated cancer centers throughout the country. Many cancer centers conduct NCI-approved protocols and have web sites that provide information about ongoing trials at their facilities.
    
    The Community Clinical Oncology Program (CCOP) (http://www3.cancer.gov/prevention/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 330 participating hospitals and 2,300 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 25,000 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. (http://www.cancer.gov/clinical_trials/ )
    
    
    

12. What happens after Phase III trials?
    
    At the conclusion of the 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?
    
    It takes about 15 years on average for an experimental cancer drug to travel from the lab to patients. Preclinical testing takes about six and a half years and phase I, II, and III clinical trials about seven years to complete. The time between filing the results of the completed clinical trials with FDA (NDA) and the drug's approval by FDA is about six months to two years. At this point, doctors can prescribe the drug.
    
    
    

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 the success ratio for drug development?
    
    From 1990 through October 1998:
    
    

    • 70,702 compounds were selected for screening by Access and Information Group;

    • 6,452 of those showed potential activity 1,546 of those were chosen by the Biological Evaluation Committee for testing in mice;

    • 79 of those were effective in killing or slowing the growth of human tumor cells, and

    • 10 were approved by the DDG for human testing after further toxicity studies in animals.

    So about one to two out of every 10,000 drugs screened in human tumor lines is tested in human trials. Typically, only 20 percent of those tested in early human trials (phase I) are finally approved by FDA for commercial use.
    
    
    

16. What is unique about the screening program at NCI?
    
    The NCI focuses on scientific merit and uniqueness. In particular, NCI scientists are looking for drugs with novel mechanisms of action.
    
    
    

17. 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.
    
    Other examples include:
    
    

    • Alkylating Agents: BCNU, Carboplatin, DTIC

    • Anti-metabolite: Ara-C, Pentostatin

    • Synthetics: Hydroxyurea, Mitoxantrone, Topotecan

    
    
    

18. What are some of the new directions for NCI's drug development program?
    
    

    • This year sees the initiation of the Molecular Targets Drug Discovery Program which provides support to take advantage of new knowledge in cancer-related molecular targets and pathways. Forty research groups are currently supported by this program. (http://dtp.nci.nih.gov/branches/gcob/gcob_web9.html)

    • NCI's drug portfolio has expanded to included a variety of new molecular and cellular therapeutic targets and approaches, including: angiogenesis inhibitors, tumor vaccines, antibodies, immunotoxins, and antisense oligonucleotides.

    • Rather than testing only to see whether drugs are effective against particular tumors, the screening program is testing whether drugs are effective against specific gene mutations in tumors. For example, researchers are screening yeast mutant cell lines (which have been engineered to have only single gene mutations) with the vast NCI drug repository to see if certain drugs are effective against specific mutations.

    • RAID (Rapid Access to Intervention Development) is a new program (8/98) designed to speed up the pre-clinical testing for promising drugs. The RAID program is intended to target academic laboratories that have novel candidate compounds, but lack specific resources or expertise. By applying for aid on specific drug development tasks, academic researchers across the country can have access to NCI's resources. Some tasks that are supported by RAID include: developing a formulation of a drug that is suitable for humans, scaling up the production of a drug to the level needed for human trials, and conducting stability and toxicology tests on a candidate drug. (http://dtp.nci.nih.gov/docs/raid/raid%5Fpp%5Fold.html)

    
    
    
    

19. 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:
    
    

    Antibodies to VEGF integrins	O6 Benzylguanine: alters DNA repair
    OSI-774 (OSI Pharmaceuticals) and Iressa (Astra Zeneca): inhibitors of growth factor signaling	Flavopiridol (Aventis) and UCN-01 (Kyowa Hakko Kogyo): cell cycle
    CAI: anti-metastasis and anti-angiogenesis	Rapamycin analogs (Wyeth-Ayerst): cell cycle function
    Rebeccamycin: topoisomerase inhibitor	Halichondrin analogs (Eisai Co.): inhibits tubulin formation
    Pyrrolobenzodiazepine: alters DNA function	KRN5500: mechanism uncertain
    FR901228: binds to multi-drug resistance gene product

    
    
    
    

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

    • Chapter 11,"New Targets for Cancer Chemotherapy" by Susan G. Arbuck, Janet Dancey, James M. Pluda, Louise Grochow, Anthony J. Murgo, Percy Ivy, John Wright, Barbara Blaylock, Laura E. Via and Edward A. Sausville, M.D., Ph.D., from Cancer Chemotherapy and Biological Response Modifiers Annual 19, edited by G. Giaccone, R. Schilsky and P. Sondel. Elsevier Science B.V., 2001.

    • "Evolving Approaches to Cancer Drug Discovery and Development at the National Cancer Institute" by E. A. Sausville and E. Feigal in Annals of Oncology, No.10, September, 1999, 1287-1291.

    • "Molecules for the Millennium: How Will They Look? New Drug Discovery Year 2000" by E. A. Sausville and J.I. Johnson in British Journal of Cancer, Vol. 83, No.11, August, 2000, 1401-1404.

    
    

    Web sites:
    
    

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

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

    • For cancer clinical trials: http://www.cancer.gov/clinical_trials/

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