Preparing an IND Application: 5 Best Practices from the Field

Written by The FDA Group | September 24, 2024

The Basics of an Investigational New Drug Application

What is an IND?

An investigational new drug (IND) application requests FDA authorization to administer a drug candidate to humans in clinical trials. A complete application includes data documenting the results of comprehensive preclinical safety assessments.

Before approval, the FDA carefully reviews the data submitted through the IND application to ensure that clinical research subjects will not be exposed to unreasonable risk.

Your FDA authorization must be in place before you can ship a new drug candidate or ship a drug for a clinical trial in a new clinical indication and begin any human clinical trial dosing. This program, often called an IND-enabling package, requires a combination of scientific capabilities and regulatory knowledge to move a candidate — the result of a well-designed and executed discovery campaign — to the clinic.

What are the key sections of an IND application?

The Investigator's Brochure

This document provides a detailed summary of the data and information gathered during a drug candidate's discovery, nonclinical development, and clinical development phases. As the Sponsor, you are responsible for maintaining and regularly updating this living document to support your clinical trials.

Chemistry, Manufacturing, and Control (CMC)

This section of the application outlines how you will ensure the proper identification, quality, purity, stability, and strength of your drug candidate and explains the intended manufacturing method/process. Here, you will detail the methods used to produce the active ingredients of your drug substance and describe its physical, chemical, or biological characteristics and acceptable limits.

You will define the analytical methods to ensure its identity, strength, quality, and purity. Additionally, you will include information regarding the composition of your drug product (active ingredient in formulation).

To support GLP-compliant toxicology studies, you must also include a characterization of the drug substance/product. The studies must be conducted using a drug with an impurity profile reflecting the clinical batch. Developing formulations for preclinical safety studies should consider that toxicology studies often employ doses much higher than those used in efficacy studies.

Pharmacology and Toxicology

This section provides nonclinical data and summaries. You must complete numerous activities within the nonclinical development program (i.e., all that leads to clinical phases) to select and develop a successful drug candidate (IND).

These activities include:

Discovery – Lead selection
Pharmacology
Safety pharmacology
Method development and validation
ADME
Toxicology
Genetic toxicology

Failing to account for these critical steps and the required resources can result in costly delays later in development. It’s best to take a proactive approach and collect this data early on.

Clinical Trial Protocol

This section outlines investigations in human subjects intended to discover/verify the effects of an investigational drug for its safety and/or efficacy profile. It includes details on a number of subjects, inclusion criteria, safety exclusions, and a description of the treatment plan.

A comprehensive understanding of the clinical trial design is essential for planning a nonclinical program supporting clinical trials. The route of administration for nonclinical studies should be the same, or similar as the intended for clinical studies.

Early clinical trials should be supported by toxicity studies of at least equivalent duration. Depending on the duration of the clinical studies, nonclinical studies may be referred to as subacute, subchronic, or chronic.

Preparing an IND application is a critical step in the drug development process. Here are five best practices directly from our IND support projects.

1. Strategically Design Your Pre-IND Meeting

While the pre-IND meeting is optional, it's a crucial opportunity to gain invaluable feedback from the FDA.

Here's a look inside our pre-IND meeting playbook:

Prepare a briefing package.

To maximize its effectiveness, prepare a comprehensive briefing package that includes your proposed clinical trial design, CMC strategy, and key nonclinical data. The briefing package is your opportunity to present your drug development program to the FDA before the actual meeting. It should be thorough yet concise, typically around 30-50 pages.

Key components include:

Executive summary outlining your drug's mechanism of action, target indication, and development plan
Preliminary efficacy data from animal models or in vitro studies
Summary of key toxicology findings and proposed safety monitoring plan
Overview of your CMC strategy, including any novel formulation approaches
Proposed clinical trial design, including patient population, dosing rationale, and endpoints

The goal is to give FDA reviewers a clear understanding of your program so they can provide meaningful feedback during the meeting.

Develop specific, targeted questions for the FDA.

Develop specific, targeted questions for the FDA that address potential areas of concern or ambiguity in your development plan. Developing specific questions is crucial for getting the most out of the meeting.

When crafting your questions, focus on areas where FDA guidance is unclear or your approach deviates from standard practice. Also, ask about the adequacy of your nonclinical package to support your proposed clinical trials. Get input on novel endpoints or biomarkers you're proposing and inquire about the need for special protocols (e.g., thorough QT study for small molecules).

We suggest most firms limit themselves to 5-7 key questions to ensure sufficient discussion time for each.

Include alternative approaches or proposals for discussion.

Many times, we suggest including alternative approaches or proposals for discussion, demonstrating your thoughtfulness and flexibility. Presenting alternative approaches shows the FDA that you've thoroughly considered your development strategy.

You may want to propose multiple clinical trial designs and ask for feedback on the pros and cons of each. We've also seen teams present different options for your CMC strategy (e.g., various formulation approaches) and seek guidance on the most appropriate path. Another effective strategy is outlining different nonclinical study designs and asking which would best support your clinical plan.

Assemble a cross-functional team for the meeting.

Your team composition is critical. Assemble a cross-functional team for the meeting, including experts in regulatory affairs, clinical development, and CMC. Consider including:

A regulatory affairs expert to lead the meeting and ensure compliance with FDA procedures
A clinical development lead to discuss trial design and endpoint selection
A toxicologist to address safety concerns and nonclinical study designs
A CMC expert to discuss manufacturing and formulation strategies
A biostatistician to explain your data analysis plans

Contact us to access experts via contracted full-time clinical staff augmentation or FTE recruitment in any of these areas.

Super-critically, make sure each team member is well-prepared to answer questions in their area of expertise.

Follow up in writing.

After the meeting, promptly send a follow-up letter to the FDA (within 30 days is ideal).

This letter should summarize key discussion points and any agreements reached, clarify any ambiguities or misunderstandings that may have occurred during the meeting, outline your next steps based on the FDA's feedback, and request written confirmation of any agreements or decisions.

This correspondence serves as a record of the meeting and can be referenced in future interactions with the FDA.

2. Use a Tiered Data Review Strategy

To ensure data quality and consistency across your IND application, we suggest establishing a multi-tiered review process, starting with individual contributors and progressing through team leads, functional heads, and, ultimately, cross-functional reviewers.

This approach involves multiple layers of review, each with a specific focus:

Individual contributors: Scientists, clinicians, and other specialists who generate the primary data and reports. They perform the initial quality check and ensure the accuracy of their specific contributions.
Team leads: Oversee sections related to their functional area (e.g., toxicology, clinical, CMC). They review for scientific integrity, consistency within their section, and alignment with the overall development strategy.
Functional heads: Provide a higher-level review, ensuring that each functional area's contribution aligns with regulatory requirements and supports the overall narrative of the application.
Cross-functional reviewers: Examine the application holistically, checking for consistency across sections and identifying any gaps or contradictions between different functional areas.

To implement this, consider the following high-level process:

Create a review timeline with clear deadlines for each tier.
Develop review checklists specific to each level.
Use collaborative document management tools to track changes and comments across review tiers.

Use data visualzations.

We also suggest using data visualization tools to identify trends, outliers, or inconsistencies that may not be apparent in raw data tables. Tableau and PowerBI are both great for this. Remember to incorporate visual summaries alongside traditional data tables in your application. For example:

Heat maps for toxicology data to quickly identify dose-dependent effects.
Scatter plots with regression lines to visualize pharmacokinetic/pharmacodynamic relationships.
Forest plots to compare efficacy across different studies or subgroupsInteractive dashboards that allow reviewers to explore data dynamically.

Conduct a mock regulatory review.

These simulated reviews provide an external perspective and can identify potential issues before submission. Sponsors often engage us to access former FDA reviewers or regulatory consultants not involved in the program to provide them with the same information and format the FDA will receive. These mock reviewers prepare formal questions and comments as the FDA would.

We suggest conducting mock reviews early enough to allow time for addressing identified issues — and include a diverse panel of reviewers with expertise in different aspects of drug development. Treat the mock review as seriously as you would an actual FDA review.

Stand up a formal reconciliation process.

Implement a formal reconciliation process for addressing and tracking reviewer comments and edits. This process ensures that all reviewer comments are appropriately addressed.

We suggest using a comment tracking system (e.g., a shared spreadsheet or specialized software) and assigning each comment a unique identifier. Record the original comment, the responder, the response, and the resolution status and then implement a sign-off process where reviewers confirm that their comments have been adequately addressed.

Make sure to provide clear guidelines on how to categorize comments (e.g., critical, major, minor) — and define a process for escalating disagreements or unresolved comments. Hold meetings to discuss and close out open items.

Perform a "red team" review.

Perform a final "red team" review, where a fresh set of eyes critically evaluates the entire application for potential weaknesses or gaps.

Assemble a small team of senior experts not directly involved in the day-to-day development of the application.
Provide the entire application and ask them to approach it with a critical, adversarial mindset.
Focus on identifying potential showstoppers or areas that could trigger a refuse-to-file decision from the FDA.

Select team members known for their attention to detail and critical thinking and give them at least a week for review. Encourage the team to think creatively about potential issues or alternative interpretations of the data and hold a formal debrief where the "red team" presents their findings and recommendations.

3. Develop a Comprehensive Translational Strategy

One of the most critical challenges is effectively bridging the gap between nonclinical studies and clinical trials. This transition, often referred to as the "valley of death" in drug development, is where many promising candidates falter.

A robust translational strategy is not just beneficial — it's essential for increasing the likelihood of clinical success and optimizing resource allocation.

In the context of IND preparation, a translational strategy serves as a roadmap, guiding your drug candidate from the laboratory bench to the patient's bedside. It helps predict how your drug will behave in humans based on nonclinical data, informs the design of early-phase clinical trials, and provides a scientific framework for interpreting clinical results.

It demonstrates to regulators that you deeply understand your drug's mechanism of action, potential efficacy, and safety profile across species. This scientific rigor can instill confidence in reviewers and potentially streamline the regulatory process.

Here are key elements to consider when determining the robustness of your translational strategy. Think of it as a high-level checklist of sorts.

1. You've identified and validated biomarkers that can be used across species, from in vitro studies to animal models and eventually human trials. (And you've evaluated the technical feasibility of measuring these biomarkers in a clinical setting.)

2. You've conducted in vitro to in vivo correlation (IVIVC) studies to strengthen the relevance of your nonclinical data to the clinical setting. We suggest starting IVIVC studies early in development to guide later nonclinical and clinical study designs.

3. You've used physiologically-based pharmacokinetic (PBPK) modeling to predict human pharmacokinetics and inform first-in-human dosing.

4. You've developed and validated fit-for-purpose assays that can be used in both nonclinical and clinical studies to assess pharmacodynamic effects.

5. Creating an integrated pharmacology/toxicology plan that links target engagement, mechanism of action, and potential adverse effects.

4. Optimize Your CMC Strategy for Phase I Flexibility

In the early stages of drug development, particularly for Phase I clinical trials, it's crucial to balance ensuring product quality and maintaining flexibility. Over-engineering your CMC package can lead to unnecessary delays and increased costs.

Develop a "phase-appropriate" control strategy.

A phase-appropriate control strategy focuses on critical quality attributes (CQAs) directly related to safety and basic characterization.

For example, for a monoclonal antibody, a Sponsor would likely want to focus on identity, purity, and potency assays, while deferring extensive characterization of post-translational modifications to later phases.

Identify CQAs through risk assessment tools like Failure Mode and Effects Analysis (FMEA) or Quality by Design (QbD) approaches.
Prioritize attributes that directly impact patient safety, such as sterility for parenteral products or dose uniformity for solid oral dosage forms.
Establish acceptance criteria based on limited manufacturing experience and nonclinical data, allowing for wider ranges where appropriate.
Implement in-process controls for critical steps, but avoid over-controlling non-critical parameters.

Build flexibility into your manufacturing process.

Design your manufacturing process with built-in flexibility to accommodate potential changes. A small molecule drug sponsor might consider using a flexible synthesis route that allows for changes in reagents or reaction conditions without major process overhauls.

Flexibility could mean using modular or single-use equipment where possible to allow for easy process modifications. It could also mean establishing wider specification ranges for non-critical process parameters, allowing for optimization without triggering significant changes.

Conduct multivariate studies to understand the impact of process parameters on product quality, informing your control strategy — and be sure to document your approach to change management in your IND, outlining how you'll assess and implement process improvements.

Leverage platform approaches for biologics.

For biological products, particularly monoclonal antibodies, consider employing established platform processes. These processes involve adapting proven methods for cell line development and upstream and downstream processes from similar molecules.

Use platform analytical techniques to monitor common critical quality attributes (CQAs) such as aggregation or charge variants. These techniques are well-validated and can provide reliable data to support your quality control efforts.

Additionally, utilize historical data from platform processes to justify broader specifications or reduced testing during early phases. This historical data can demonstrate the robustness of your methods and provide a rationale for regulatory flexibility. Document how your platform approach supports your control strategy and accelerates development without compromising product quality. This documentation should include detailed descriptions of the platform processes, the rationale for their use, and evidence of their effectiveness in maintaining product quality.

Develop stability-indicating methods early.

Stability-indicating methods are crucial for assessing the quality and integrity of a drug product over time. These methods are designed to detect changes in a drug substance or product's chemical, physical, and microbiological properties. While it's essential to develop these methods early in the drug development process, the approach for Phase I studies should balance thoroughness with practicality.

Stability data is a critical component of any IND application. It assures regulators that your drug product will maintain its quality, safety, and efficacy throughout its intended shelf life. However, at the Phase I stage, your understanding of the product's degradation pathways and long-term stability profile will likely evolve.

The FDA's guidance for Phase I INDs acknowledges this reality, stating that "complete stability data are not expected to support Phase 1 studies." This regulatory flexibility allows sponsors to take a more focused approach to stability testing in early development stages.

We suggest conducting forced degradation studies early in development. This approach allows you to understand the inherent stability of your molecule and develop methods that are truly "stability-indicating." It also helps in setting appropriate acceptance criteria for impurities. Use the results to identify potential degradation products and develop analytical methods capable of detecting these impurities. Focus on developing methods for the most likely and relevant degradation pathways, rather than trying to account for every possible scenario.
Establish a preliminary stability protocol. This ensures that your stability data will be relevant to real-world conditions while managing the resource-intensive nature of stability testing. Design stability protocols that cover the likely storage conditions for your product, including the intended storage temperature and humidity. Consider bracketing or matrixing approaches to reduce the testing burden while still generating meaningful data.
Defer full ICH validation of analytical methods. Full ICH validation is time-consuming and resource-intensive. At the Phase I stage, your methods may still be evolving as you learn more about your product. Deferring full validation allows for method refinement without repeatedly conducting full validation exercises. Instead of conducting full ICH Q2(R1) validation, focus on demonstrating that your methods are suitable for their intended use in Phase I. Evaluate key method parameters such as specificity, precision, and linearity, but defer more extensive validation (e.g., robustness studies) to later phases. Document your validation approach clearly in your IND, explaining how it's appropriate for the phase of development.

5. Craft a Narrative-Driven Nonclinical Summary

The nonclinical summary is critical to your IND application, serving as the scientific foundation for your proposed clinical trials. However, simply presenting data is not enough. To truly engage FDA reviewers and make a compelling case for your drug candidate, you need to craft a narrative-driven summary that tells a cohesive scientific story.

Remember that regulatory reviewers are inundated with data-heavy submissions. A well-crafted narrative helps them understand the relevance and implications of your data quickly.

Begin with a clear articulation of your molecule's MoA.

Start your summary with a concise yet comprehensive explanation of how your drug works at the molecular, cellular, and physiological levels. Link the mechanism of action to the intended therapeutic effect and discuss how this mechanism informs your expectations for both efficacy and potential safety concerns.

Keep your audience in mind here. Use clear, jargon-free language accessible to reviewers who may not be experts in your specific therapeutic area. If possible, include a visual representation of the mechanism, such as a pathway diagram or illustrated molecular interaction. Reference key publications or data that support your proposed mechanism.

Use a weight-of-evidence approach to integrate your data.

Instead of presenting studies in isolation, weave together findings from multiple studies to build a comprehensive picture of your drug's safety and efficacy profile. Highlight how different studies complement and reinforce each other.

Address any apparent contradictions in your data, explaining how you've interpreted these findings in the context of your overall program.

A great way to execute this is with a table or matrix that summarizes key findings across studies, highlighting consistencies and explaining discrepancies. Use cross-referencing liberally to guide reviewers to detailed data while maintaining narrative flow. If length is a factor, consider using a tiered approach to data presentation, with key findings in the main narrative and supporting details in appendices.

Proactively address potential safety concerns.

Identify and discuss potential safety issues based on your drug's mechanism, structural class, or nonclinical findings. For each concern, present a balanced discussion of the evidence for and against it being a significant risk. Outline your strategies for mitigating these risks and your plans for monitoring them in clinical trials.

We often suggest creating a "risk assessment" section that systematically addresses each potential concern. This includes tables thatsummarize the evidence, proposed mitigation strategies, and planned monitoring for each risk. Reference similar approved drugs (if applicable) and discuss how their post-marketing experience informs your risk assessment.

Consider visualizing your data.

We urge all Sponsors to go beyond basic tables and graphs to present your data in ways that highlight key trends and relationships. Use visualizations to make complex datasets more accessible and to support your narrative arguments.

A few ideas here:

Employ forest plots to show effect sizes across multiple studies or endpoints.
Use heat maps to display large datasets, such as gene expression changes or broad pharmacology screening results.
Always accompany visualizations with clear explanations of what they show and why it's important.

Include a forward-looking section.

Demonstrate that you have a clear plan for your ongoing nonclinical program. How do you intend to address any remaining questions or potential issues during clinical development?

Show how your nonclinical and clinical programs will complement each other to build a comprehensive understanding of your drug.

Create a timeline or roadmap of planned nonclinical studies aligned with your clinical development phases.
Discuss how ongoing or planned nonclinical work will inform dose selection, safety monitoring, or patient selection in future clinical trials.
If applicable, outline your plans for developing companion diagnostics or biomarkers in parallel with clinical development.

When implementing this narrative-driven approach, keep in mind:

Consistency is key. Ensure that your narrative aligns with and is supported by the detailed data in other sections of your IND.
While storytelling is important, never sacrifice scientific accuracy or overstate your conclusions.
Consider having your summary reviewed by someone not intimately familiar with your program to ensure it's accessible to a broader scientific audience.
Be prepared to defend your narrative approach in discussions with regulators, backing up your story with solid data.

Strategically design and execute your pre-IND meeting, maximizing your chances of productive FDA interactions.
Implement our proven multi-tiered data review process, ensuring the quality and consistency of your submission.
Develop comprehensive translational strategies that bridge the gap between nonclinical and clinical development.
Optimize your CMC strategy for Phase I, balancing quality assurance with the flexibility needed in early-stage development.
Craft compelling, narrative-driven nonclinical summaries that effectively communicate your drug's story to regulators.

Our regulatory experts manage the entire registration process for new drugs, biologics, generic products, and medical devices.

Review of client technical dossiers and developmental plans
Research and interpretation of regulations
Determination of regulatory status
Pre-submission review of technical documents
Critical writing and review of documentation
Clinical trial applications and notifications (IND, IDE, CTX, etc.)
Marketing Application Support (NDA, BLA, ANDA, 510(k), PMA, etc.)
Orphan Drug, Treatment Use, and ANDA Suitability petitions

Our experts prepare all major regulatory submissions and provide extensive quality control review for all trial-related documentation, such as:

Regulatory Agency and IRB/EC submissions
Procurement of Import/Export license
Initial submissions, amendments, notifications, and closeout submissions

Working collaboratively, our regulatory specialists coordinate all aspects of your trial’s document collection and submissions, including:

Managing all regulatory documentation as part of the start-up, conduct, and close-out phases
Coordinating clinical trial application filings to regulatory agencies
Ensuring submissions comply with regulations
Managing submissions and document storage processes
Staying abreast of all regulations to ensure documentation compliance

Our team of experienced regulatory scientists can write the nonclinical, clinical, and CMC sections in CTD and traditional format for your new drug and biologic applications.

We don't just advise — we become an extension of your team, working alongside you to prepare a submission that stands up to regulatory scrutiny and accelerates your path to clinical trials.

Don't let the complexities of IND submission slow down your drug development journey. Partner with The FDA Group to leverage our expertise, streamline your process, and increase your chances of regulatory success.

Additional resources

SDTM in Focus with Sunil Gupta

The FDA Group's CEO Nick Capman, sits down with Sunil Gupta, a seasoned expert in pharmaceutical data, to shed light on the nuances of SDTM (Study Data Tabulation Model) compliance and its pivotal role in clinical trial processes.

Clinical Outsourcing vs. Insourcing: Selecting the Right Model or Mix with Mark Shapiro

The FDA Group’s CEO, Nick Capman, sits down with Mark Shapiro, a Partner with biopharmaceutical consulting firm Pharma Initiatives, to discuss outsourcing and insourcing models in the current clinical R&D environment and what to consider when selecting the right model or mix of models for a project.

Contact us today for a consultation on how we can support your IND submission and broader regulatory strategy. Let's work together to bring your innovative therapies to patients faster and more efficiently.

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