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Making Better Drugs for Children with Cancer
Pages 1-35

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From page 1...
... The near absence of research in pediatric cancer drug discovery threatens to halt the progress in childhood cancer treatment achieved during the past four decades. The achievements of the past 40 years are testament to the efforts of pediatric oncologists, radiation oncologists, and surgeons nationally and internationally who systematically evaluated the anticancer drugs developed during this period, largely for cancers in adults, for use in children.
From page 2...
... Over the past few years, differences at the molecular level have been documented for all the major childhood cancers, and herein lies the promise: the molecular abnormalities represent a place to start searching for drug "targets." Cutting-edge science notwithstanding, market forces are not sufficient to drive the process and bring to the bedside new drugs for children with cancer. Because so much of the technical capacity for drug discovery and development for pediatric cancers already exists -- much of it supported by the National Institutes of Health (NIH)
From page 3...
... The National Cancer Institute (NCI) has begun to facilitate this by funding the first consolidated preclinical testing program for pediatric cancers, so that the necessary steps before the first use in children are completed as quickly as possible.
From page 4...
... . If the discovery and development of new agents for childhood cancers were to capitalize on today's science -- which in large measure it does not -- there is every reason to believe that cure rates could be improved for all pediatric cancers, including those for which current longterm survival is very low, such as brain tumors.
From page 5...
... A key point is that the financial market for childhood cancer drugs is very small -- below the dollar value needed to interest profit-making drug and biotechnology companies. Even incentives such as orphan drug provisions and the recent "pediatric incentive" offered for testing products in children cannot tip the balance sufficiently.
From page 6...
... (p13;q25) tumor parts Abnormalities cell tumor soft of round family Molecular small myxoid sarcoma 1 melanoma fibrosarcoma rhabdomyosarcoma sarcoma cell liposarcoma TABLE Cancer Disease Alveolar Ewing's Malignant Desmoplastic Extraskeletal chondrosarcoma Synovial Myxoid Congenital
From page 7...
... 7 <150 <2,500 <160 <370 <300 <450 <900 2002. mutations SHP December Meis1)
From page 8...
... . Bone and Joint Other 189 deaths 444 deaths 8% 20% Brain and Other Nervous System Soft Tissue 520 deaths 147 deaths 23% 7% Non-Hodgkin's Hodgkin's Lymphoma Lymphoma 101 deaths 31 deaths 5% 1% Kidney and Renal Leukemia Pelvis 728 deaths 66 deaths 33% 3% FIGURE 2 Childhood cancer deaths in the United States, 2001, Ages 0­19.
From page 9...
... THE EXISTING CAPACITY FOR DEVELOPING NEW AGENTS SPECIFICALLY FOR CHILDHOOD CANCERS Considerable basic research on childhood cancers has resulted in the identification of molecular abnormalities unique to those cancers (Table 1)
From page 10...
... However, there are no major R&D programs in either industry or the government devoted to developing new drugs for childhood cancers. As already explained, even with incentives such as orphan drug provisions, the market for pediatric cancer drugs is too small for pharmaceutical companies to recoup their investments in developing new products, and full-scale drug development is not considered a government function.
From page 11...
... . Even though no comprehensive R&D program exists to develop drugs for childhood cancers, the components that would constitute such a pipeline do exist -- in universities, in academic medical centers, within pharmaceutical and biotechnology companies, and to a surprising degree, within NCI (and other parts of NIH)
From page 12...
... DTP and CTEP both have in-house activities as well as grants and contracts with outside organizations. The activities relevant to developing pediatric cancer drugs are mentioned here.
From page 13...
... Drug Discovery Screening Services The In Vitro Cell Line Screening Project accepts both natural and synthetic compounds from scientists in the academic and industrial communities worldwide, and tests them for anticancer activity against 59 human tumor cell lines. Compounds for testing are selected by the NCI Drug Synthesis and Chemistry Branch, based on the degree of novelty of the structure of the molecule and any associated biological information provided by the supplier.
From page 14...
... 14 4 Dosage limited) Administration, (but dosage Indication Pediatric and or Yes Yes No No No Yes No Yes Yes No sarcoma, HL tumors HL testicular cell ALL, germ hepatocellular tumors neuro- CNS NHL, Ewing's germ osteosarcoma, carcinomas, tumor, 3 NHL LL, osteosarcoma, melanoma cell retinoblastoma Cancers Uses sarcoma, APL LL neuroblastoma, ALL, tumor, AML, Wilms' germ neoplasms, Pediatric NHL, ALL, HL, Osteosarcoma, blastoma, Osteosarcoma, neuroblastoma, Osteosarcoma, ALL, AML, Wilms' rhabdomyosarcoma, carcinoma, neuroblastoma, neoplasms, NHL, NHL, neuroblastoma, Ewing's cell hepatoblastomas, carcinomas Childhood of effusions tumors, cancers of (various)
From page 15...
... Drug Institute tumors, lung testicular ALL chemical information, and ,2005 cell cancers cancers, Cancer dosage Food Testicular small-cell Germ cancer ALL/AML Many ALL Childhood AML APL Many pediatric HL=Hodgkin's LL=Lymphoblastic NCE=New NHL=Non-Hodgkin's or the Reference by National Desk and indication 1/1/82 1/1/82 1/1/82 1/1/82 identified (2001) Physicians' drug pediatric 2/22/96 1992 Before Before Before 1992 Before 1995 3/7/84 leukemia leukemia on of Poplack leukemia system listed based the and mention nervous on myeloid lymphoblastic promyelocytic status Pizzo some based on least Date Approval Based At 1 2 3 4 Etoposide Ifosfamide mercaptopurine Methotrexate Prednisone Teniposide Thioguanine Tretinoin Vincristine ALL=Acute AML=Acute APL=Acute CNS=Central Application.
From page 16...
... Some activities supported include the development of high-throughput screening assays, computer modeling, recombinant target protein production and characterization, and chemical analog generation. Drug Development Resources Drug discovery produces promising compounds that still require "development" into a drug that can be used by patients.
From page 17...
... Access to Drug Development Resources: RAID Rapid Access to Intervention Development (RAID) is a program to bridge the gap between drug discovery in the university laboratory and a new drug for use in the clinic.
From page 18...
... is part of NCI's Cancer Therapy Evaluation Program, one of about a dozen cooperative groups that together cover all types of cancer and all therapeutic interventions. COG is the unified children's cancer cooperative group formed by the merger of four cooperative groups that had been independently conducting pediatric cancer trials.
From page 19...
... have made substantial investments in the basic science of childhood cancers, with the work being carried out mainly in academic laboratories. Through this basic research, the molecular abnormalities of many pediatric cancers have been identified, at least some of which may represent valid drug targets.
From page 20...
... Drug Testing Preclinical Testing The need for a preclinical testing program to identify promising drug candidates for pediatric cancers was recognized in the Best Pharmaceuticals for Children Act of 2002. It states (Section 15[c]
From page 21...
... Scientific opportunity and technical capabilities are not lacking, but they have not been put into service for this purpose. What appears to be missing in order to realize the potential for new childhood cancer drugs is an organized focus on childhood cancers to coordinate the pieces and drive a process toward shortening the developmental time line and multiplying the numbers of possible new agents.
From page 22...
... Some (e.g., Global Alliance for TB Drug Development) have a large number of founding part ners, and others (e.g., Cystic Fibrosis Foundation Therapeutics Inc.)
From page 23...
... The Medicines for Malaria Venture The Medicines for Malaria Venture (MMV) was established because the pharma ceutical industry has largely disengaged from antimalarial drug discovery and de velopment, for economic reasons.
From page 24...
... These do not appear to be insurmountable problems, but they will have to be faced by any group taking up this cause. DELAYS IN TESTING APPROVED AGENTS IN CHILDREN Even if a pipeline for new pediatric cancer drugs is established, drugs developed for adult cancers will likely continue to be a source of new treatments for children.
From page 25...
... Irinotecan, a relatively new cytotoxic drug used primarily for colorectal cancer, is an example of a drug developed for adult malignancies that was tested against a variety of pediatric cancers in children who had not responded to other drugs, only after the drug was approved by the FDA for use in adults. The first Phase I trial results in adults were published in Japan in 1991, followed by Phase I trial results in the United States published in 1993.
From page 26...
... Completing Pediatric Clinical Trials More Quickly There are limited ways to shorten the time it takes to conduct clinical trials to determine whether a drug is of benefit to patients. In the future, there may be validated surrogate end points that could cut the time to assessing clinical benefit, but these do not yet exist for pediatric cancers.
From page 27...
... . (There are, of course, adult cancers that are as rare as childhood cancers, and the problems of developing and testing new agents for them may be equally daunting.)
From page 28...
... The well known examples do not involve cancer drugs, but the lack of labeling applies across all drug categories. Deaths caused by the antibiotic chloramphenicol (Powell and Nahata, 1982)
From page 29...
... Clinical experience in adults is of limited relevance to use in children, on whom the drugs will be used for different types of cancer, in regimens with different drugs than used in adults. But the decision to test a drug for cancer in children becomes part of the larger issue of prioritizing clinical trials in pediatric cancers, which is critical because of the small numbers of children eligible to participate.
From page 30...
... The 1998 Pediatric Final Rule and the Pediatric Research Equity Act of 2003 The 1998 Pediatric Final Rule,4 which took effect in April 1999, "mandates pediatric studies if an application for a claim is under review and the proposed indication is for a disease that exists in both adults and children." This gave the FDA discretion to mandate specific pediatric studies and stated further that the "applicant also may be required to develop a pediatric formulation for a drug product that represents a meaningful therapeutic benefit to such patients over existing therapies." Companies could request waivers if the mandated studies were highly impractical or if there was evidence that the product would be ineffective or unsafe for children. The 1998 Rule also had provisions for testing drugs already on the market, with the FDA bearing responsibility to demonstrate a need for testing.
From page 31...
... Pediatric Subcommittee of the FDA Oncologic Drugs Advisory Committee Since 2000, the FDA has held public meetings of a new Pediatric Subcommittee of the Oncologic Drugs Advisory Committee to discuss broad principles that would underlie the agency's application of the Pediatric Rule to oncology drugs, including the question of equivalence of adult and pediatric diseases. Congress subsequently established this Subcommittee in law in the Best Pharmaceuticals for Children Act in January 2002, broadening membership to include representatives of NCI, patient advocates, and the pharmaceutical industry.
From page 32...
... The pediatric incentive has been extended through 2007 by incorporation into the BPCA. The Pediatric Incentive has had a modest effect on pediatric cancer drugs.
From page 33...
... eTamoxifen has no pediatric cancer indication. It was studied in female patients aged 2 to 10 years with McCune-Albright Syndrome and precocious puberty.
From page 34...
... Advocacy groups, government, academic institutions, and the pharmaceutical and biotechnology industries should collaborate to establish a not-for-profit "public­private partnership" to fund and direct drug development for agents uniquely targeting pediatric cancers. Arrangements could be made, for example, for industry to relinquish intellectual property rights (or otherwise reduce barriers)
From page 35...
... NCI, pediatric oncology researchers, and other interested parties should continue to explore ways to test compounds in development for adult cancers in preclinical and early clinical trials as soon, and as quickly, as possible. Specifically: · The evolving NCI preclinical testing program should be fully supported and eventually expanded because it will play a key role in providing the evidence needed to begin early-stage clinical trials of new agents in children.


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