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Division of Antivirals (DAV) Information for Pre-IND Submissions

Submission of a pre-Investigational New Drug (Pre-IND) prior to an IND allows for early communication between a sponsor [or investigator] of a candidate drug early in the development of new therapeutics before sufficient data have been accumulated for an IND submission. DAV regulates and reviews IND applications and marketing applications for drug products and therapeutic biologics (monoclonal antibodies and therapeutic proteins) intended for the prevention or treatment of infections caused by viruses (e.g., influenza, hepatitis, respiratory syncytial virus (RSV), human immunodeficiency virus 1 [HIV-1], and adenovirus).

If the CDER review Division is unknown, please contact the Division of Drug Information (DDI) at 301-796-3400 or 855-543-3784, 301-431-6353 (fax) or druginfo@fda.hhs.gov or DDI.eIND@fda.hhs.gov.

Considerations for Preparing a Pre-IND Submission

Early consultation with DAV can be valuable in the development of promising new drugs, by allowing identification of optimal strategies for efficient data collection. We encourage engagement with the Division while the drug development process is in the early stages to allow adequate time to consider the Division’s recommendations as product quality, nonclinical, and clinical aspects of development programs are being planned. To best assist you, we suggest that you submit as much information as possible about your new drug and your plans for its development in your Pre-IND submission.

Pre-IND interactions should be considered as preliminary communications based on early development information. Additions or modifications to these communications may arise as additional information becomes available.

For additional information on meetings with the FDA, including how and where to submit a Pre-IND meeting request, please review the guidance for industry entitled, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products (PDF - 336KB).”

In addition to general information about the product and development program, and as outlined in the Formal Meetings Guidance (see link above), the following information would be helpful to include in the submission:

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 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 still under development 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 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 and detailed information. For additional information, refer to the Guidance for Industry – Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products and INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information

Pharmacology/Toxicology

Toxicity and pharmacological testing are intended to determine the quantitative and qualitative aspects of a drug's biological effects. Toxicity testing is a stepwise process that allows 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 range of pharmacological activities. The initiation, completion, and submission of supporting nonclinical toxicity studies should be integrated with the appropriate phases of clinical development. Although most drugs under development for treatment of viral infections 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.

For additional information, refer to the following:

Guidance for Industry – Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products and ICH Guidances:

Your Pre-IND submission should contain a detailed description of your planned program for toxicity and pharmacological testing. The results of any studies completed to date 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 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.

Virology

The following two components should be included in the Pre-IND submission of the preclinical microbiology development plan.

The first component should be a research plan describing all specific virology studies proposed to support introduction of the drug into clinical studies. These studies should provide evidence of preclinical activity and mechanism of action that will establish a rationale for use of the drug in infected individuals, as well as provide information about the potential risks of use in humans that will complement the results of animal toxicology studies.

Specific areas that should be addressed include mechanism(s) of action, antiviral activity in cell culture and animal models, cytotoxicity (to determine the selectivity index in antiviral activity assays, and also to assess potential drug toxicity across human tissues and cell-cycle phases), susceptibility of appropriate clinical isolates (including recent specimens and varying genotypes, subtypes, or clades where applicable), potential for development of drug resistance, cross-resistance with any approved drugs sharing the target or mechanism of the investigational drug, and in vitro combination antiviral activity relationships with approved drugs. When feasible, structural studies of the drug bound to the target should be performed to identify direct contact and close proximity (<5 Å) residues and naturally occurring polymorphisms at these positions.  In the case of immunomodulatory drugs, the potential for unintended adverse effects (including activation of viral replication) resulting from the drug's actions on the immune system should be assessed. For some immunomodulatory compounds, information on drug effects in appropriate animal models may provide the only method for pre-clinical evaluation of activity to support subsequent clinical study design, but cell culture studies may still be important to show whether viral replication is enhanced or whether the proposed product alters the antiviral activity of approved drugs. It is preferred that you select and use FDA approved assays in proposed clinical studies. For investigational assays, you should include information on the assay’s performance characteristics. Finally, a plan for evaluation of resistance emergence in clinical studies should be provided.

The second component of the submission should be a summary of any data already developed to support drug activity; complete raw data should not be submitted for Pre-IND evaluation but will be required to be included in all IND submissions. Sponsors typically have characterized the mechanism of action at the time of Pre-IND submission.

For additional information, refer to the Guidance for Industry - Antiviral Product Development--Conducting and Submitting Virology Studies to the Agency.

Proposed Animal Studies

For some rare or emerging infections, studies of activity in animal models with varying levels of resemblance to human disease may constitute a particularly important part of the development plan. The challenge virus used in animal studies should have representative susceptibility, i.e. greater than or equal to the median susceptibility of geographically and temporally distinct isolates.  In addition to any animal data available at the time of Pre-IND contact, sponsors are urged to submit plans and proposals for any additional animal studies they may be considering together with the rationale for use of the proposed models and study designs, so that the selection, design, conduct, and utilization of animal studies can be a topic of interdisciplinary discussion and advice during Pre-IND interactions.

Prospective discussion of animal studies is especially crucial if the sponsor is considering possible use of the Animal Rule (21 CFR 314 Subpart I) for principal evidence of therapeutic antiviral effects.  These discussions may also be important for other development situations in which animal data may contribute significantly to evaluating the product, and for the most efficient collection of supporting data for safety as well as treatment effect.

Clinical Development Plan

We encourage sponsors to submit information about their plans for initial clinical development (i.e., phase 1 or 2 studies), as this information may impact the selection and design of nonclinical studies. We recommend that you include the following information in your Pre-IND submission:

  1. The rationale for the use of the investigational drug in your proposed population
  2. The anticipated conditions of use, including intended patient population(s) and plans for combination therapy, if any
  3. All available information, including all available safety and activity data, from any previous human experience with your product or closely related products
  4. A summary of the proposed initial clinical development program, including basic design and approximate size and duration of any planned clinical trials
  5. A synopsis of the proposed clinical study protocol or protocols you plan to submit in an IND. This may be a synopsis 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), safety monitoring and proposed endpoints

How To Submit:

Please submit the Pre-IND meeting request electronically via:

CDER NextGen Portal

Or via mail:

Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
Attention: Division of Antivirals
5901-B Ammendale Road
Beltsville, MD 20705-1266

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