Productive pre-IND interactions with FDA are important to the success of any drug development program, including infectious disease product development. The Pre-IND Consultation Program through the Office of Infectious Disease (OID), one of 27 review divisions within the Office of New Drugs, provides opportunities for makers of infectious disease products to engage with FDA by facilitating early communications between the Division of Antivirals or the Division of Anti-Infectives within OID and sponsors/investigators of potential new therapeutics – these products include drugs and therapeutic biologics for the treatment of bacterial, fungal, and viral infections (including SARS-CoV-2 infection). Early interactions allow for valuable FDA input prior to the accumulation of sufficient data for an IND submission, and allow the sponsor to solicit FDA feedback regarding the initial drug/biologic development plans, nonclinical IND-enabling study data needed to support moving the drug/biologic into clinical testing, and many other issues. In addition to these pre-IND interactions, FDA provides guidance documents regarding the development of therapeutics for some specific infectious diseases (see FDA Guidance for Industry: Chronic-Hepatitis-B-Virus-Infection-Developing-Drugs-for-Treatment; FDA Guidance for Industry: Chronic-Hepatitis-C-Virus-Infection—Developing-Direct-Acting-Antiviral-Drugs-for-Treatment-Guidance-for-Industry; and FDA Guidance for Industry: Vaccinia Virus – Developing Drugs to Mitigate Complications from Smallpox Vaccination). Here, we specifically discuss antiviral products at the pre-IND stage, and unique considerations for these products.

As with any development program, CMC, pharmacology, and toxicology programs* are necessary to move forward with an IND for antiviral products. Antiviral products additionally require nonclinical virology data to support the initial submission of an IND. Prior to the initiation of Phase 1 clinical studies, FDA recommends conducting nonclinical virology studies, including mechanism of action (MOA), antiviral activity in vitro, effects of serum protein binding on antiviral activity, and cytotoxicity and therapeutic indexes. These are discussed in more detail below.

MOA Studies

MOA studies should demonstrate the investigational product’s ability to specifically inhibit viral replication or other virus-specific function, establish the site of the product’s action, and demonstrate the specificity for the viral target over cellular or host proteins. These studies provide useful data for predicting toxicities, and can also inform the design of studies for the assessment of the development of resistance. Understanding the MOA can help with the identification and subsequent characterization of resistance mutations in the viral genome, and subsequent characterization of such mutations can, in turn, provide in vivo validation of the MOA studies. There are additional considerations surrounding MOA studies for immunomodulatory antiviral products (such as interferons), as they can have unintended effects on viral replication and/or other adverse effects resulting from their impact on the immune system; sponsors are encouraged to consult the division for advice on the development of immunomodulatory products for the treatment of viral diseases, as well as products with other non-viral host targets.

Quantification of Antiviral Activity

Antiviral activity of an investigational product should be shown to be specific and should be quantified in vitro prior to initiation of Phase 1 trials. These assessments, using primary human target cells preferably, should be performed against a broad range of viral isolates (including different clades, subtypes, or genotypes), including mutant viruses that are resistant to products with a similar MOA. Antiviral effects should be demonstrated at concentrations that are achievable in vivo with acceptable risk-benefit, as further supported by cytotoxicity assessments that show low levels of cytotoxicity at the effective concentration. The impact of serum proteins on antiviral activity should also be evaluated, as highly protein-bound products may have reduced activity in vivo. For human viruses for which no adequate cell culture or animal models exist (e.g., hepatitis B and hepatitis C), inhibition of an essential viral function or activity against related viruses may be used to indicate potential activity. In cases where no suitably predictive in vitro cell culture or replicon systems exist, measurement of viral titers after treatment in animal model systems can be used to assess antiviral activity.

Cytotoxicity and Therapeutic Indexes

Cytotoxicity assessments should be conducted prior to Phase 1 studies in order to determine that an antiviral product has an acceptable risk-benefit profile. These studies should establish that an investigational product exhibits antiviral activity at concentrations that are achievable in vivo without inducing toxic cellular effects. A high therapeutic index, defined as the relative effectiveness of the antiviral to inhibit viral replication compared to induction of cell death, is preferable. Cytotoxicity studies should be conducted in both stationary and dividing cells from multiple relevant human cell types and tissues. Additional cytotoxicity assessments on the growth of human bone marrow progenitor cells are typically required for antiviral products having myelosuppressive effects. In addition, for antiviral products that are potential inhibitors of cellular DNA polymerases, IC₅₀ values against cellular polymerases should be determined, and specificity for the viral target over cellular polymerases should be demonstrated. Finally, sponsors may need to examine effects of their antiviral on human pol γ activity and on mitochondrial toxicity.

Additional Considerations

In addition to the nonclinical studies discussed above, which should be completed prior to initiation of Phase 1 clinical studies, additional nonclinical studies deserve consideration for the development of an antiviral product. These include 2 types of in vitro drug combination activity studies if applicable: 1) one for assessing the investigational product in combination with approved antiviral products for the same target and same indication and 2) one assessing in vitro antiviral activity of the investigational antiviral product with an antiviral product for a different indication for co-infected patients. Evaluating the in vitro selection of resistant viruses to the antiviral product, the phenotypic and genotypic characterization of resistant viruses, and cross-resistance should be done prior to initiation of clinical studies in patients infected with the particular virus. Comprehensive resistance testing should be undertaken during all phases of product development consistent with the way the product will be used in clinical practice, as resistance and cross-resistance data are key for product development plans and protocol design. Sponsors are encouraged to develop and submit a plan for monitoring the development of resistant viruses in clinical studies before initiation of clinical studies in virus-infected patients. This resistance monitoring plan should be included with the overall clinical development plan in the IND. Additionally, it is recommended that sponsors include plans for genotypic and phenotypic baseline studies and resistance substudies in the IND. Additional details regarding virology studies, including how and when they should be performed, are provided in FDA Guidance for Industry: Antiviral Product Development – Conducting and Submitting Virology Studies to the Agency.

*If species specificity, immunogenicity, and other considerations render toxicology models irrelevant, sponsors are encouraged to contact FDA to discuss toxicology testing.

Charity Duran, PhD, RAC, Integrated Product Development Associate, works with companies at all stages of development to support their regulatory submissions. She has over a decade of experience in scientific and regulatory writing. Her experience includes the development and production of documents supporting regulatory submissions (modules of NDAs and INDs), the preparation of briefing packages to support regulatory meetings, and the development of clinical study documents, including clinical study protocols and clinical study reports.