Keys to submitting a successful IND application to the FDA

Aug. 3, 2020
Steps to help your company understand, prepare and master the FDA's IND application

The Investigational New Drug (IND) application is the first sizeable regulatory assessment that drug sponsors face in the development process, and it can be quite daunting. With the goal of beginning clinical trials and scaling-up drug manufacturing, it's critical to understand the requirements for this necessary regulatory milestone.

A thorough understanding of the IND application will make it easier to navigate this process. Drug sponsors with a strong, detailed background can prepare for unanticipated barriers, save valuable time and minimize spending.

What is the IND?

Before drug sponsors can dive into First in Human (FIH) studies, they first have to demonstrate the safety and efficacy of the proposed drug in their IND application. The application should give a full synopsis of the drug, including all salient data collected from the development and testing phases, along with manufacturing information.

All new drugs must have the U.S. Food and Drug Administration's (FDA) permission before starting a clinical investigation in the United States. It also applies to existing drugs that have experienced a change in composition. In the FDA's view, the primary concern for an initial IND application is to ensure the safety of clinical trial participants. This regulatory stage is no small feat, and for many smaller biotech and biopharma companies, it may be their first exposure to a regulatory agency.

The road to the IND

A helpful starting point to better grasp the IND application is to review the typical path to a successful application filing. The development and screening process varies for large molecules, small molecules and cell therapies, as they each have distinct characteristics and challenges. Although large molecule submissions have grown in popularity over the years, small molecules still account for the highest volume of products in this space. A typical path for the development of a small molecule is illustrated below:

The standard process for a small molecule starts with the research component, what the industry calls "early discovery and development," where a therapeutic target (e.g. gene or protein) is first identified (i.e. target identification). A target is selected by the sponsor because it is believed to play a significant role in the disease of interest. The sponsor would then conduct a series of screening assays consisting of target validation, hit discovery, assay development and screening, hit to lead and lead optimization. As such, sponsors would advance to conduct the first synthesizing and relationship screening to decipher which compounds could have a future as a potential treatment as they interact with the target. Based on the desirable pharmacokinetic and physiochemical properties, the sponsor can then select one, or sometimes several, compounds to move forward into the next stage.

Following the initial discovery and screening stages mentioned above, work can finally begin on the manufacturing process and preclinical testing plans. All the information gathered from this point and moving forward is necessary for the IND application and contributes to the success of approval. 

The contents of an effective IND

Regulators expect IND applications to be a highly detailed and all-encompassing data package relating to the safety and efficacy of the compound. When compiling all of the necessary information, it's imperative to thoroughly vet the three main components to the application: the chemistry, manufacturing and control, the preclinical animal data and the clinical trial information.

Chemistry, manufacturing and control (CMC)
The CMC information is the first component of the IND application, providing regulators with a detailed analysis of the inner workings of the drug itself. The CMC can break down into two parts: substance and methods.

The substance of the drug refers to its identity, purity, potency and stability. A successful IND application has thorough information on the biological, physical and chemical characteristics of the drug, including all of the ingredients and their purpose.[1] It's critical to support the stability of the drug in this section and provide information that proves the compound's intended effect materializes. To avoid the risk of information gaps, manufacturers should have all of the supporting molecule data before they begin to compile the application.

The second part of the CMC, or the methods, relates specifically to the manufacturer. The sponsor is required to disclose all the substances that may be present in the manufacturing process. The most successful applications contain descriptions of the manufacturing processes and methods used to help understand how the drug is made and the sponsor's plan to proceed with production.

Preclinical studies
Preclinical study data is the second component of an IND application. During this step, the sponsor's primary goal is to determine if the drug is safe for initial use in humans and the compound exhibits pharmacological activity to support commercial development. Sponsors can only begin the application when they have experienced success with their preclinical studies, including pharmacology, pharmacokinetics (PK), absorption, distribution, metabolism, excretion (ADME) and toxicology studies.

This preclinical data can break down into two pillars: initial preclinical, what the industry calls "Proof of Principle," and IND-enabling studies. The initial preclinical studies include in vitro and in vivo pharmacology, PK and pilot non-Good Laboratory Practice (GLP) toxicology studies.

If the compound reports encouraging results during initial preclinical evaluations, then the compound can advance to IND-enabling studies which can include GLP toxicology and safety pharmacology studies. Whether testing is completed in-house or with a lab testing partner, it's crucial to conduct IND-enabling studies in compliance with GLP regulations. This regulation assures regulatory bodies of the application's quality when reviewing the study data. These IND-enabling studies provide essential information about the safety profile of that compound and will help the FDA determine whether first in human clinical trials can proceed.

Technical competency and expertise in these testing areas are vital to critically assess and collect results. It's a common practice for sponsors to outsource these studies to a lab testing partner, which can streamline the process, ensure accuracy and save valuable internal resources. Experts in regulatory affairs, available for consultation, can assist with the compilation of the IND materials, such as organizing and drafting the actual application package. If a sponsor's team doesn't have the necessary background or experience to support this step, vet a contract research organization for IND support capabilities to provide customized help for your program.

Preclinical study data needs to be reliable and demonstrate intended clinical usage, which is easier said than done. While it's easy to summarize these procedures, in reality, the process is extensive and can take years to complete conducive studies and detailed data collection — leaving room for reporting errors and roadblocks.

Keep in mind that the purpose of compiling this data is to establish reasonable safety of the drug for its initial use in humans and describing the compound's pharmacological activity. By leading with this goal at the forefront, sponsors can focus on developing a comprehensive application.

Clinical trials
Clinical trial information is the final stage of the IND application and often regarded as the centerpiece to the application. Sponsors need to demonstrate that the proper clinical trial protocols are in place to safely and successfully execute the studies while mitigating potential risks to the study subjects. These protocols should be detailed, step-by-step plans with comprehensive supporting data. Laying this out in an organized manner is critical to creating an exemplary application.

It's also essential to include data on the clinical investigators, the professionals that will manage the clinical trials and record the compound's potential effects. These investigators are responsible for the administration of the drug, so it is important to prove to the regulatory agency that these individuals have been thoughtfully selected and are well qualified to fulfill their clinical trial duties.

Sponsors must have their study reviewed by an institutional review board (IRB) under FDA regulations, who can then require changes for the purpose of protecting human research subjects. There are many components they will look for, such as an Investigator's Brochure, to educate the investigators of the significant facts of the drug. The investigators need to have all the information and data in order to conduct their clinical trial on a course that is least hazardous to the subjects or patients. Information as to the subjects taking part in the study, the safety plan and dosage amounts are also essential factors to include. Preclinical summaries should support this evidence and explain the reasoning behind these choices.

Before sending the IND package off to the FDA, thoroughly vet and scrutinize the chemistry, manufacturing and control (CMC), preclinical animal data and clinical trial information to achieve the best results.

Considerations for a successful submission

The path to a successful IND application depends on a variety of factors, and the best practices for IND submission success can often get lost in the chaos of preparation. Before jumping into the next project, consider these key points to ease the strain of the process and increase the chances for approval.

Start with the end goal and work backward: Think about the most direct route for supporting the initiation of human studies and map out what studies are needed to achieve the goal. Working backward can help identify potential pressure points in your plan and timeline miscalculations.

Work with competent development partners or consult with appropriate experts: Expertise is required to have the studies and activities conducted successfully that meet the regulatory agency's requirements. Don't underestimate the challenges and wear the team too thin.For example, if a sponsor doesn't have the expertise to summarize the preclinical study data correctly, it is critical to consider partnering with a credible consultant or contract research organization. 

Know the molecule: This background will determine the study design, necessary tests and ultimately, make it easier to assemble data for the IND application. Then apply this to the understanding of the common pathways for small molecules, large molecules and cellular therapies.

Build a robust and practical plan: If it feels like the planning is complete, there is usually room to finesse and improve its clarity. Disorganization of the preclinical program or the overall development plan is one of the most frequent causes of delays in timelines and submission.

Build a relationship with the regulatory agency: They are willing to answer questions and provide guidance. Establishing trust with the agency early on can help sponsors better understand the process and build credibility.

A successful IND submission is a significant milestone for sponsors. Ensuring that drug sponsors and manufacturers have a viable understanding of the process, the contents of an effective application and predictable challenges can make the IND application more approachable. Reach out to a lab testing partner for additional background on this process within their organization.

1. The United State Food and Drug Administration. (2020). IND Applications for Clinical Investigations: Chemistry, Manufacturing, and Control (CMC) Information | FDA. Retrieved July 10, 2020. 

About the Author

Xiaoxia Li | Executive Technical Director at WuXi AppTec Laboratory Testing Division