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Development of new strategies for targeted drug
development.

Development of new strategies for vaccine development.

Changes in approaches to clinical trials and access to experimental therapeutics.

DRUG DEVELOPMENT

The discovery and development of safe and efficacious therapeutic modalities for the treatment, control and prevention of HIV infection and HIV-associated OIs and malignancies represent an urgent public health priority. malignancies represent the major causative agent resulting in mortality of AIDS patients.

OIs and

The NIH has established extensive intramural and extramural programs for the discovery and pre-clinical development of new agents for AIDS with academic centers and pharmaceutical establishments. Identification of each of these programs and a brief summary of their activities is outlined below:

Developmental Therapeutics Program, Division of Cancer Treatment, NCI has contract resources for drug development with the capability for:

Screening up to 27,000 compounds a year in a cell culture assay (40,000 compounds screened since 1987, with approximately 1 percent showing antiHIV activity).

Providing developmental capacity for identified drugs including scale-up drug synthesis, drug dose formulation, pharmacology and toxicology for IND application.

Developmental Therapeutics Branch, Division of AIDS,
NIAID has established three major programs:

National Cooperative Drug Discovery Group-HIV.

National Cooperative Drug Discovery Group-OI.

Animal models for testing efficacy of drugs and combination therapies.

NIGMS' Targeted Antiviral Program provides extramural NIH investigations using sophisticated techniques including:

Nuclear Magnetic Resonance (NMR)

X-ray crystallography

Computer modeling

Biophysical studies of proteins

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The intramural AIDS Targeted Antiviral Program, Office of the Director, has developed a facility with highly sophisticated technologies. This facility is currently being utilized by 12 ICDs on 48 separate research programs. The program supports resources for:

The Protein Expression Laboratory

Computer modelling

Synthesis of new compounds

Screening

Animal models

X-ray crystallography

Major Accomplishments of these programs include:

O Discovery and development of AZT, ddI, ddC, d4T and
rsCD4.

CLINICAL TRIALS

The NIH has the primary responsibility for the national clinical trials efforts for the evaluation of potential therapies for the treatment of HIV infection and its sequelae. The NIH, through its intramural and extramural programs, has developed a multifaceted approach for the evaluation of antiretroviral and anti-01 drugs. OIs represent the common cause of morbidity and mortality of AIDS patients.

The objective of the NIH-funded clinical trials is to investigate new drugs valuable to the treatment for patients with HIV infection and HIV-associated opportunistic infections and malignancies. This represents an urgent public health priority. The goal is to develop innovative and effective new procedures for the diagnosis, prevention, and treatment of immunologically related diseases.

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12 adult ACTUS also have pediatric components

Drugs evaluated for entry in NIH-funded clinical trials as of 1991: approximately 200 agents.

Patients enrolled in NIH-funded clinical trials as of 1991: over 13,000.

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Pediatric patients enrolled in NIH-funded clinical
trials as of 1991: over 1,400.

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Pediatric NIH-funded clinical trials as of 1991: 20.

Approximately 33 percent of the ACTG protocols are evaluating anti-01 therapies, which have an enrollment of 2,800 patients.

CPCRA has two active OI protocols and is developing 4 additional OI studies.

Recent initiatives relative to increasing underrepresented populations in the clinical trials effort include:

establishment of a committee in the ACTG and CPCRA to focus on specific needs of women; development of women-specific endpoints; supplements to increase recruitment of

underrepresented populations; expansion of pediatric clinical trials as part of the $22.6 million increase by Congress with an additional $7.8 million increase in basic research on pediatric HIV disease; and collaboration with HRSA in the development of a pilot project under the Ryan White Comprehensive AIDS Resources Emergency ACT of 1990 (C.A.R.E.), Title IV legislation providing for increasing access to experimental therapeutics and primary health care by the provision of ancillary services to HIV infected pediatric patients and their families.

Major Accomplishments in the NIH-funded clinical trials:

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Establishment of a national clinical trials network in
both academic medical centers and universities, the
AIDS Clinical Trials Group (ACTG) and a community based
program, the Community Programs for Clinical Research
on AIDS (CPCRA) capable of testing new anti-HIV and
agents for the treatment of opportunistic infections.

AZT effectively slows disease progression in HIV-
infected individuals.

Extension of the use of AZT for individuals with early and asymptomatic infections including HIV-infected children down to 3 months of age.

IV gamma globulin (IVIG) effectively reduces the number of Ols in children with CD4+ counts >200.

Aerosolized pentamidine effectively used for
prophylaxis of PCP.

ddI phase I clinical trials funded through NCI have demonstrated that survival has been significantly prolonged, with the actuarial 2-year survival reaching 80 percent even in patients with advanced stages of AIDS.

Phase II/III studies of ddI are ongoing in
collaboration with the ACTG.

ddI has been made available through expanded access programs for AZT-intolerant patients with CD4 counts less than 200/mm as well as for patients who have failed AZT therapy and whose disease is progressive despite AZT therapy.

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Fluconazole has been demonstrated to be effective for
Cryptococcal meningitis.

Foscarnet has been demonstrated to be effective for CMV retinitis.

Interferon-alpha has been shown to be effective in
reducing the rate of OIS in symptomatic patients.

VACCINE DEVELOPMENT

The development of safe and efficacious vaccines is a public health priority. Intensified efforts to decrease mortality from AIDS and AIDS-associated malignancies and ultimately to prevent HIV infection continues to emphasize the development of an FDA approved vaccine.

NIH-funded researchers continue to advance the understanding of the immune system that may be important in the development of potential vaccine candidates. The efforts include the collaboration of NCI, NIAID, Walter Reed Army Institute of Research, and industry.

The AIDS Vaccine Clinical Trials Network (AVCTN) sponsored by NIAID has established five AIDS Vaccine Evaluation Units that are designed for the evaluation of potential vaccines. Six vaccines are currently under investigation by the AVCTN.

Recent significant progress has been made in the development of potential vaccines for the prevention of AIDS including:

O Three potential AIDS vaccines currently in NIAIDsponsored Phase I clinical trials have been shown to elicit an immune response.

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Native or recombinant HIV subviral envelope (env) glycoproteins inoculated into chimpanzees induced both cellular and humoral immunity.

A whole virus SIV vaccine demonstrated protection in monkeys.

Inactivated whole virus HIV vaccine studies supported by NIH in chimpanzees persistently infected with HIV developed antibody responses and were cleared of viremia following virus challenge.

A synthetic peptide of the HIV-1 is under investigation in an NIH-sponsored study to determine its ability to prevent AIDS in individuals already infected with HIV.

Animal models are being developed for the evaluation of potential vaccine candidates including the SIV/macaque model for the comparative evaluation of vaccine approaches and adjuvants and the Severe Combined Immunodeficiency (SCID) mouse model for vaccine development.

INFORMATION SERVICES

Dissemination of information concerning ongoing research and research results is crucial to the management of patients with HIV infection.

The National Library of Medicine (NLM) currently sponsors three AIDS-related on-line databases on its MEDLARS network, AIDSLINE, AIDSDRUGS, and AIDSTRIALS:

AIDSLINE, an on-line computer file of more than 40,000 references to the published literature on AIDS, is updated weekly and is growing at the rate of about 800 new citations a month. NLM plans to continue to expand the coverage of AIDSLINE, not only with more source journals and meeting abstracts, but with other forms of information such as monographs and audiovisuals.

AIDSTRIALS and AIDSDRUGS were created in response to
the mandate of the Health Omnibus Programs Extension
Act of 1988, containing descriptions of clinical trials
being conducted to test the safety and efficacy of AIDS
therapeutics, and descriptions of the agents being
tested in the clinical trials, respectively.

In addition, the information has been disseminated through:

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The NIAID AIDS Clinical Trials Information Service
(ACTIS) which provides information on NIH- and
industry-sponsored clinical trials of new therapies to
HIV-infected people and health care workers, with
information on over 156 NIH-sponsored and 94 industry-
sponsored protocols from the FDA. Additionally, the
ACTIS maintains data records on specific drugs, their
mode of action and toxicity.

A series of 1990 AIDS technology transfer meetings, initiated to enhance the sharing of state-of-the-art information on treatment and management of symptomatic and asymptomatic patients. These programs will continue targeting areas that do not have a major medical research effort such as Puerto Rico and rural areas of the U.S.

An NIH-sponsored workshop held on January 15 to address
the issue of expedited dissemination of information
with immediate positive or negative public health
impact such as AIDS related clinical trials results.
Based upon the workshop discussion and with additional
input from physicians, patients, and other Federal
agencies, NIH policy and guidelines for information
dissemination will be developed.

FY 1992 PRESIDENT'S BUDGET

Question. Dr. Raub, does the President's budget include sufficient funds to support research project grants and center grants at their fully approved level? If not, what is the

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