Division of Anti-Viral Products (DAVP) Pre-IND Letter of Instruction

• Chemistry Manufacturing and Controls
• Pharmacology/Toxicology
• Microbiology (Virology)
• Proposed Animal Studies
• Clinical Development Plan
• Additional Resources
• Contact Us

Thank you for your inquiry regarding the Division of Antiviral Products (DAVP)  Pre-IND Consultation Program. This program allows communication between a sponsor or investigator of a candidate drug and DAVP early in the development of new therapeutics before sufficient data have been accumulated for an IND submission. The list of products that DAVP reviews includes drugs directed at:

• HIV and AIDS (including antiretroviral therapy and Prevention of HIV transmission by topical microbicides)
• Hepatitis (HBV and HCV)
• Herpesviruses
• Emerging viral infections (including but not limited to respiratory viruses, zoonoses, and potential biologic threat agents)
• Other non-life-threatening and life-threatening viral infections

We believe early consultation with DAVP can be valuable in the development of promising new drugs, by allowing identification of optimal strategies for efficient data collection. We encourage you to initiate discussions with us early in the drug development process, so that you will have the opportunity to consider our recommendations in planning your nonclinical and clinical development programs.

So that we may give you the best assistance, we suggest that you provide us with as much information as possible about your new drug and your plans for its development. We recommend that you submit the following information, together with a list of specific questions related to the type and amount of data necessary to support submission of an IND that you wish us to address. However, if components of this information are not yet available but there are development questions to be addressed, we recommend that you contact DAVP to discuss a partial submission that may be the first in a series of Pre-IND interactions.

DAVP Pre-IND interactions should be considered as preliminary communications based on early development information, and will generally take the form of a teleconference. (Face-to-face meetings will be granted on a case-by-case basis.) In most cases, written preliminary comments will be issued prior to the teleconference/meeting. Additions or modifications to these communications may arise, as additional information becomes available, during follow-up Pre-IND interactions or when an IND is established.

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 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 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 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.

You may find it useful to consult 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, Nov 1995.

Your Pre-IND submission should contain a description of your planned program of 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 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 (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 microbiology studies proposed to support introduction of the drug into clinical studies. These studies should provide evidence of preclinical activity 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 toxicity studies.

Specific areas that should be addressed include mechanism(s) of action, antiviral activity in cell culture and/or animal models, cytotoxicity (to assess the selectivity index in antiviral activity assays, and also to assess potential drug toxicity relevant to human tissues and cell-cycle phases), susceptibility of appropriate clinical isolates (including recent specimens and varying subtypes, quasispecies, or clades where applicable), potential for development of drug resistance, cross-resistance with any approved drugs sharing the target or mechanism of the candidate drug, and in vitro combination activity relationships with approved drugs. 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 performance characteristics. Finally, a plan for evaluation of resistance emergence in clinical studies should be described.

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.

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. 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.

Such 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, but 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

Although most sponsors utilizing our Pre-IND consultation program request advice regarding nonclinical 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 initial clinical development (i.e., phase 1 or 2 studies), as the latter will impact on the selection and design of nonclinical studies. To allow us to place your nonclinical program in perspective, we recommend that you include the following information in your Pre-IND submission:

1. The proposed rationale for use of your new drug in infected patients or to prevent infection in uninfected subjects
2. The anticipated conditions of use, including intended patient population(s) and plans for combination therapy, if any
3. Available information on 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 studies planned
5. A synopsis of the proposed clinical study protocol or protocols you plan to submit in an 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 DAVP’s Getting Started Page. 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.

Contact Us

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. Please direct any comments to the appropriate division referenced on the CDER Pre-IND Consultation Contact List (PDF - 36KB).