How Do You Know When You’re Ready to Submit an IND? Part 1

Key Considerations for Biotech Innovators‍

‍

Embarking on the journey toward your first clinical trial is an important milestone for any biotech company. In the U.S., before going into the clinic, a sponsor is required under 21 CFR 312 Subpart B to submit an Investigational New Drug Application (IND) to the U.S. Food and Drug Administration (FDA).  Determining the optimal timing for IND submission can be complex and requires strategic planning. Below, we delve into the core requirements for a successful IND submission, the strategic advantages of scheduling a pre-IND meeting, and how to prepare in a way that not only streamlines the review process but also reduces the risk of encountering a clinical hold.

1. Essential Information Needed to File an IND

If you are filing an initial IND for a Phase 1 study, FDA’s primary objective in reviewing the IND will be to assure the safety and rights of human subjects in your clinical trial.  Your IND must comprehensively present the required information and supporting data needed to enable this evaluation in a well-organized manner. Submitting incomplete or insufficient data can lead to a clinical hold, so ensuring you have all the requisite studies and documentation is paramount. Below are some examples:  

 Pharmacology and Toxicology (Nonclinical/Preclinical) Information

• Pharmacology: You need comprehensive information describing the pharmacological effects and mechanism(s) of action of the drug, including how the drug is absorbed and metabolized.  You will also need to show proof-of-concept of the potential therapeutic effect of your investigational product in animal models that closely mimic the human disease state. This type of study supports the safety and rights of subjects by demonstrating the potential therapeutic benefit to be achieved by a successful clinical development program, which must be weighed against the risks of individual subjects participating in the clinical trial.

• Toxicology: A robust evaluation of the toxicological effects of the drug through in vitro and animal testing is critical to ensure subject safety. Animal testing will include single-dose and multiple-dose toxicity studies across relevant species, typically rodent and non-rodent models, to evaluate acute, subacute, and chronic toxicity. You should address any target organ toxicities, evaluate fetal toxicity, identify a no-observed-adverse-effect-level (NOAEL), and characterize the relationship between dose and toxicity. Additionally, if you are developing biologics or gene therapies, you should consider species-appropriate models or specialized study designs that address immunogenicity or off-target effects.

• Safety Pharmacology: While sometimes included under toxicology, safety pharmacology often warrants special mention. These studies focus on the potential impact of your product on vital physiological systems, such as cardiovascular, respiratory, and central nervous systems. Thorough assessments of this type can help identify potentially serious acute adverse effects in humans, and therefore further protect human trial subjects from experiencing serious adverse events. Studies of this type may evaluate parameters like QT interval assessments for small molecules or potential cytokine release for certain biologics.  

Chemistry, Manufacturing, and Controls (CMC)

An IND is required to include information and data describing the composition, manufacture, and control of the active ingredient (drug substance) and finished dosage form (drug product) to assure the proper identification, quality, purity, and strength of the product. The type and amount of information you will need to provide can vary widely depending on many factors including the phase and duration of the clinical trial, the type (modality) of the drug substance, and the dosage form, but needs to be sufficient for the Agency to evaluate safety and stability of the drug for the planned duration of the proposed clinical study.  At a minimum, this will include:

• Drug Substance: include a description of the characteristics and general method of preparation of the drug substance, including identification and control of raw and starting materials; the manufacturer(s); and the specification for release and stability studies, including acceptable limits and appropriately qualified analytical methods for strength, impurities, and other relevant attributes.  For products manufactured using or derived from cell lines, a description of cell line development and cell banking procedures will be required.  

• Drug Product: include a description of the composition, manufacturer, manufacturing and packaging procedure, and all inactive ingredients used in the manufacture or final formulation of the drug product.  As with the drug substance, you will also need to provide the release and stability specification used to assure the identity, strength, quality, and purity of the drug product.  The drug product stability program must be sufficient to ensure the product’s stability throughout the planned clinical trial, and stability data will need to be updated at least annually.  For products that require additional preparation at the clinical site prior to patient administration, in-use stability data will also need to be provided to support the duration of the preparation and administration procedures in the clinical trial protocol.  

• Additional Safety Considerations: biologics, cell therapies, and gene therapies will need to have a well-supported strategy for control of contamination by viral agents, beginning with any animal or human-derived materials through any manufacturing steps intended to remove or inactivate viruses. Cell and gene therapies may have unique requirements for safety evaluation outlined in the relevant Agency guidance documents, e.g. screening of donor-derived starting materials for an allogeneic cell therapy product to detect oncogenic or other relevant mutations.  

Clinical Development

Your proposed initial clinical development program will need to be clearly presented so that the Agency can assess whether the potential benefits of the product and the design of the proposed clinical study are sufficient to protect the rights and ensure the safety of human trial subjects. For Phase I studies, this evaluation will focus on safety of the proposed study, while in later phases, the Agency will also assess whether the scientific quality of the study design is sufficient to support an evaluation of the safety and effectiveness of the drug.  For certain therapeutic areas (e.g. oncology, rare diseases) these evaluations may be combined into a Phase I/II study.  

• General Investigational Plan: include a brief description of the overall plan for clinical investigation of the drug in the year after submission, including the rationale, indication(s) to be studied, general approach, other planned trials, estimated number of patients, and anticipated serious or severe risks.  

• Investigator’s Brochure (IB): This document is your single source of truth for investigators, summarizing all available nonclinical and any existing clinical data. It should be well-structured to guide clinical investigators on how to safely conduct the trial, including dosing guidelines, potential adverse events, and mitigation measures. It will also include a brief description of the drug and summaries of the pharmacological, pharmacokinetic, and toxicological information known based on animal and prior human studies.  

• Protocol: Develop a clear and concise Phase I (or Phase I/II) clinical protocol that outlines your study design, objectives, endpoints, and target population. Specific requirements for the content of a protocol are outlined in the regulation, including but not limited to the criteria for patient selection or exclusion, a description of the study design (including any control group and methods used to minimize bias), the dose regimen, and the clinical procedures, laboratory tests, or other measurements done to fulfill the objectives of the study and minimize risk. If you plan to incorporate innovative trial designs—such as adaptive designs—ensure you can justify them with strong scientific rationale.

Regulatory Strategy

• Overall Development Plan: Consider your longer-term goals from the outset. Are you aiming for standard approval, or do you intend to pursue expedited pathways such as Fast Track, Breakthrough Therapy, or Regenerative Medicine Advanced Therapy designations? If so, understand the additional requirements and benefits associated with these programs. A high-level roadmap showing how you plan to progress through clinical development —indicating when pivotal studies might begin—helps the FDA see that you have a well-thought-out strategy.  

• Gap Analysis: Conduct a thorough gap analysis to identify any remaining uncertainties in your data. This may include incomplete toxicity findings, insufficient manufacturing validation runs, or unclear clinical endpoints. Address these gaps proactively—or at least have a plan to address them—before filing your IND.

By taking the time to compile and scrutinize each component of your IND package, you position your program for a smoother review process. Comprehensive data, presented in a coherent manner, demonstrates that you have done the necessary groundwork to ensure that your investigational product is reasonably safe to proceed into human clinical trials.

2. The Value of a Pre-IND Meeting

A pre-IND meeting with the FDA is one of the most strategic tools you can leverage to set your clinical program on the right path. Although it requires time and preparation, the benefits often far outweigh the investment.

Reduced Risk of Clinical Hold:
During a pre-IND meeting, you can present your preliminary data and development plans to FDA reviewers. This early feedback helps you pinpoint possible deficiencies—such as gaps in toxicology data or unclear manufacturing processes—that might otherwise trigger a clinical hold. By addressing these issues proactively, you reduce the risk of your IND being delayed or placed on hold once formally submitted.

Clarity on Data Requirements and Regulatory Expectations:
Each investigational product has unique attributes. Meeting with the FDA early on allows you to gain clarity on specific technical questions, from how to handle unusual manufacturing steps to what additional toxicology studies may be required for novel platforms or combination products. This guidance helps you avoid conducting unnecessary studies while ensuring the data you generate meets the Agency’s criteria for safety and efficacy.

By investing in a pre-IND meeting, you can ultimately save time, resources, and maintain momentum in your development program. These interactions also set the tone for open communication with the FDA, which can be invaluable as you progress through later phases of clinical research.

Do you need a pre-IND meeting? See our next post for more information, including effective preparation strategies.

Not sure if your IND meets requirements? Click here to contact GLOBAL and see how our IND experts can review your strategy and make sure you are submission ready.