Drug Development

Biological Resources Branch Preclinical Repository
http://web.ncifcrf.gov/research/brb/site/preclinRepo.asp

This repository, an NCI-sponsored facility, stores bulk cytokines, monoclonal antibodies, and cytokine standards under carefully controlled conditions. The repository provides a constant and uniform supply of high-quality reagents to nonprofit institutions and qualified commercial establishments at no charge. This facility obtains new materials by donation or at reduced cost by negotiating with companies and investors. To date, the Biological Resources Branch Preclinical Repository has distributed more than 40,000 samples, and the estimated value of materials shipped to investigators is about $100,000 per year.

Radiolabeled Materials Repository
http://dtp.nci.nih.gov/docs/misc/available_samples/radiolbllist2.html

For researchers who hold a valid radioactive materials license, there are roughly 90 radiolabeled drugs available from DTP’s Radiolabeled Materials Repository. Radio-labeled compounds are instrumental in noninvasive studies of biodistribution and in target pharmacokinetics of therapeutics.

Drug Formulation and Synthesis

DTP’s Pharmaceutical Resources Branch bears the responsibility of acquiring bulk materials for formulation and synthesis, formulating drugs and testing them, clinical dosage-form production, and stability testing of clinical dosage forms. This branch provides clinical researchers, both academic and institutional, with top-quality drugs for clinical trials and formulates drug compounds that are candidates for the Drug Development Group or the RAID program.

Drug Production: Biopharmaceutical Development Program
http://wwwbdp.ncifcrf.gov/

DTP’s Biological Resources Branch oversees the Biopharmaceutical Development Program (BDP), which provides biopharmaceutical development expertise and production capability to all NIH-supported investigators. The BDP produces a variety of clinical-grade biological agents from bacterial, yeast, and mammalian cells; natural products from various organisms; and DNA, RNA, and viral materials under current Good Manufacturing Practices for phase I/II human clinical trials or advanced preclinical animal testing.

Researchers have attempted to design cancer therapies to avoid toxicities associated with standard chemotherapeutic agents. BL22, one such targeted treatment, originated in an intramural NCI laboratory and was developed through DTP’s biologicals production facility.

The BDP was able to develop a complete, simple, and scalable clinical manufacturing process for immunotoxin production. A novel hydrophobic chromatography method was incorporated into the process to clearly separate the product, which elutes in a separate peak from the impurities. The new protocol almost tripled the yield of the final product and lowered the cost of production. This novel purification method has also been applied to other similar antibody-conjugated toxins, facilitating the manufacture of immunotoxin anticancer drugs in large scale.

BL22 showed promising results in a phase I trial: 11 of 16 patients with chemotherapy-resistant hairy cell leukemia have shown complete remission, lasting up to 18 months, mostly without major side effects. The drug is now in phase II clinical trials at NCI, involving patients with hairy cell leukemia. Commercialization efforts also are under way via a CRADA with Genecor, Inc.

The program’s labs, production suites, and offices are located on the NCI-Frederick campus and are currently operated under a contract with SAIC-Frederick.

Mouse Models of Human Cancers Consortium
http://mouse.ncifcrf.gov/

Until recently, the only factors available to measure anticancer activity in any model were inhibition of cell or tumor growth and the increased lifespan of the animal. Cancer-specific molecular targets were unknown, and investigators did not have the tools to measure the therapeutic effects or targets in biologic fluid or tissue. In addition, existing models did not predict well for clinical outcome. DTP is working with the Mouse Models of Human Cancers Consortium (MMHCC) to design studies examining the predictive value of genetically engineered mouse models.

The MMHCC was established in 1998 as a collaborative program to derive and characterize mouse models, to generate resources and information, and to use innovative approaches in preclinical and drug intervention studies. The MMHCC comprises 25 principal investigators whose research groups connect more than 50 institutions in the United States and abroad. More than 80 mouse strains are now available to cancer researchers.

The MMHCC also maintains the eMICE Website (http://emice.nci.nih.gov), which provides information on mouse models by disease site; information on the applications of mouse cancer models to translational research; links to other mouse-related resources, strain repositories, and databases; access to the MMHCC Mouse Repository Website, Cancer Models Database, and Cancer Images Database; and access to the caArray Database.

Mouse models that recapitulate steps in the genesis, progression, and clinical course of human cancers provide a valuable resource to cancer researchers, particularly in the field of drug discovery and development. The availability of these models via the MMHCC repository, which makes animal strains available to all members of the scientific community, is a key to discoveries that will lead to new approaches for cancer detection, diagnosis, therapy, and prevention.

The Type 1 Diabetes Rapid Access to Intervention Development Program
http://www.niddk.nih.gov/fund/diabetesspecialfunds/T1D-RAID

Five years of success for DTP’s RAID concept prompted the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to suggest a similar program for diabetes therapeutics. The Type 1 Diabetes Rapid Access to Intervention Development Program (T1D-RAID) is a cooperative program between DTP, which manages the technical resources, and NIDDK, which prioritizes and funds the projects. Like DTP’s parent program, RAID, T1D-RAID makes NCI resources for the preclinical development of drugs, natural products, and biologics available on a competitive basis. DTP support includes high-throughput screening, animal studies, drug formulation, pharmacology and toxicology studies, and bulk substance acquisition.

T1D-RAID, begun in 2003, is intended to remove the most common barriers novel diabetes therapeutics face before entering clinical trials.

This program is not a grant-making mechanism. T1D-RAID is open to extramural investigators from academic institutions, non-profit research institutions, and biotechnology and pharmaceutical companies. Requests are accepted twice a year, on November 1 and April 1. Each request is reviewed by a panel of extramural experts for the strength of the scientific hypothesis and scientific novelty as well as cost-benefit considerations.

NIH RAID Pilot Program
http://nihroadmap.nih.gov/raid

Contact:
NIH-RAID Pilot Program Office
301-594-4660, NIH-RAID@niddk.nih.gov

A new pilot program announced in December 2004— NIH Rapid Access to Intervention Development (NIH RAID)— opens the door to DTP’s drug-development expertise to the other Institutes and Centers. Intramural researchers outside of NCI now have access to DTP know-how in acquiring preclinical information in support of an IND application. They also will have DTP support with scale-up synthesis of the drug substance, dosage form development and manufacture, and development of analytical methods to characterize the drug substance/dosage form, assay the compound in tissues and body fluids, and carry out toxicological studies with correlative pharmacology and histopathology assessment.

Emphasis is on high-risk ideas or therapies for uncommon disorders that frequently do not attract private sector support at early stages of development. In these cases, government resources provide a means to acquire further information to assess the potential of these approaches and facilitate clinical evaluation.

The program accepts applications for these resources biannually. Two review cycles have been completed. Five Institutes are sponsoring or cosponsoring the four proposals accepted for implementation.

NIH RAID is part of NIH’s Roadmap Initiatives. Projects are jointly funded by the sponsoring institute and the Roadmap Office. The purpose of the Roadmap Initiatives is to identify major opportunities and gaps in biomedical research that no single Institute at NIH could tackle alone but that the agency as a whole must address to make the biggest impact on the progress of medical research.

NIH RAID is not a grant program. Successful projects will gain access to the government’s resources as well as assistance of the NIH in establishing and implementing a product development plan.