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U.S. Department of Health and Human Services

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Office of Antimicrobial Products (OAP) Pre-IND Letter of Instruction

Pre-Investigational New Drug (Pre-IND) Consultations for the Office of Antimicrobial Products (OAP) are designed to allow initiation of communication between sponsors and the FDA early in the development of drug products for the treatment of infections before sufficient data have been accumulated to warrant IND submission. We believe that such early consultation can be valuable in speeding the development of promising new drugs. It allows for the identification of optimal strategies for the rapid and efficient collection of data supporting their safety and efficacy. We encourage you to initiate discussions with us as early in the drug development process as possible. This will enable you to have the opportunity to consider our recommendations in planning your preclinical and clinical development programs.

General guidance documents that specify minimal standards for the development of antimicrobial compounds (Points to Consider) and insight on those elements considered important to the evaluation of clinical studies can be located through links located on this site (i.e., the OAP Pre-IND site). So that we may give you the best assistance, we suggest that you provide us with completed study summaries or scientific data summaries regarding your new drug and your plans for its subsequent development. Additionally, providing us with concise questions directed at the respective discipline would be advantageous in addressing specific developmental concerns. We recommend that you submit the following information:

Chemistry, Manufacturing and Controls

The chemistry, manufacturing and controls section of your Pre-IND submission should provide enough information to assure us that the identity, strength, quality, and purity of the new drug are adequately characterized to assess its safety and to allow interpretability of preclinical studies and clinical investigations. Your Pre-IND submission should include descriptions of the identity of the drug substance, components, and composition of the finished dosage form, name of the manufacturer(s), manufacturing processes, product specifications, analytical methodology, and, where available, stability of the drug substance and the finished dosage form.

We recognize that many aspects of an investigational product may be incompletely defined at an early stage and that refinement of methods, formulations, and specifications usually requires substantial research that will not be complete at the time of the Pre-IND consultation. We anticipate that, as drug development progresses and the scale of clinical studies expands, the sponsor will update this section with more definitive information.

Pharmacology/Toxicology

Toxicity and pharmacological testing are intended to determine the quantitative and qualitative aspects of any biological effects. Toxicity testing may be considered a stepwise process that allows for gradual and progressive refinement in the understanding of the interactions between a drug and physiological systems. In support of regulatory submissions, toxicity and pharmacological testing should include both general and specialized studies addressing the drug's safety and delineating the range of its pharmacological activities. The initiation, completion, and submission of supporting preclinical toxicity studies should be integrated with the appropriate phases of clinical development. Although most drugs under development are expected to undergo certain minimum toxicity and pharmacological studies, it is understood that the number, sequence, and variety of such studies will vary in relation to the anticipated toxicity, pharmacology, clinical application, and pace of drug development.

Your Pre-IND submission should contain a description of your program of toxicity and pharmacological testing with respect to the planned therapeutic use. The results of completed studies should also be submitted; although, it is not necessary to provide comprehensive reports for each study. Submission of a summary of each study completed, including information addressing conformance to current Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) requirements, will often allow us to make a preliminary assessment. We may then request additional data as needed to assist in our review.

Microbiology (Preclinical and Clinical)

With respect to the Microbiology Section of a Pre-IND submission for an anti-infective drug product, the following information will be necessary to permit proper evaluation of the drug under investigation. There are two general areas of concern that need to be addressed.

First, we request that you submit summary data already completed to support the potential use of the drug in future studies; complete raw data should not be submitted for Pre-IND evaluation but will be required and should be included in all future IND submissions.

Second, we request that a research plan, which describes all specific microbiology studies that are to be included in an IND to support introduction of the systemic drug into clinical settings, be provided. The research plan should describe studies that are designed to provide evidence of preclinical activity thus establishing the rationale for use of the drug in relevant clinical trials. The specific areas of clinical microbiology that should be addressed during drug development are described in the published guidelines titled General Guidelines for the Clinical Evaluation of Anti-Infective Drug Products1 and General Guidelines for Clinical Microbiology2.  Prior to the initiation of clinical trials, a specific amendment should be submitted to the discipline of microbiology that describes, in detail the rationale for the selection of the provisional in vitro antimicrobial susceptibility interpretive criteria that will be used to predict clinical efficacy.

Topical drug products, including antimicrobials and antiseptics should follow a similar course of product development as for systemic drugs but provisional in vitro antimicrobial susceptibility interpretative criteria are not applicable.

References:
1. Beam TR, Gilbert DN, and Kunin CM. General Guidelines for the Clinical Evaluation of Anti-Infective Drug Products. Clin Infect Dis 1992; 15(Suppl 1): S5-S32.
2. Thrupp LD, Cleeland R, Jones RN, Novick WJ, Reller B, Thornsbery C, and Washington A. General Guideline for Clinical Microbiology. Clin Infect Dis 1992;15(Suppl 1) :S339-S346.

Clinical Development Plan

Although most sponsors utilizing our Pre-IND Consultation Program request advice regarding preclinical development, we find that we can offer better guidance to those sponsors who are also able to provide us with information about their plans for clinical development, as this will impact on the selection and design of preclinical studies. To allow us to place your preclinical program in perspective, we recommend that you include the following information in your Pre-IND submission:

1. The rationale for the use of your new drug for the intended indication;

2. The anticipated conditions of use, including intended patient population and plans for combination therapy, if any,

3. A summary of your proposed clinical development program, including basic design and approximate size and duration of any studies planned; and

4. A synopsis of the clinical study that would be submitted as part of your IND. This may be a paragraph summarizing objectives, patient population, study design, approximate sample size, treatment regimen (including route of administration, dose level(s), if known, and frequency and duration of dosing), and activity endpoints.

Please submit your materials for our Pre-IND review to the address listed on the Pre-IND Getting Started Page. Please supply at least ten (10) copies of your Pre-IND submission and clearly indicate in your cover letter that the enclosed is a Pre-IND submission.

We will review your materials as quickly as possible, and will contact you regarding our comments. At that time we can determine how we can best assist you further.

Note: All OAP Pre-IND communications are considered informal under 21 CFR 10.90(b)(9) and represent the best judgment of the Office of Drug Evaluation IV at this time. The communications do not necessarily represent the formal position of the Center for Drug Evaluation and Research or the Food and Drug Administration, and does not bind or otherwise obligate the Center or Agency to the views expressed. Please direct any comments regarding OAP Pre-IND/Topical Microbicide Web Pages to ode4preind@cder.fda.gov.