The Path to IND Part 1: Milestones & Common Roadblocks

The Investigational New Drug (IND) application is the primary pathway through which new drugs and biologics are approved to be tested in humans. But, what exactly is an IND and does your program really need one? What are the requirements for a successful IND and what paths can you take to get there? In this post, we will discuss how to successfully navigate the FDA’s IND program and highlight some common mistakes and how to avoid them.

What is an IND and Do You Need One?

An Investigational New Drug (IND) application is the launching point for clinical investigations. The purpose of an IND is two-fold. First, it is a mechanism by which FDA reviews the quality attributes, nonclinical safety package, and proposed clinical protocol prior to the initiation of human clinical trials. From the FDA’s perspective, the primary concern for an initial IND submission is to ensure, as much as possible, the safety and rights of clinical trial participants. The second function of an IND is to exempt the investigational drug from a federal law (21 CFR 312.1) requiring an approved marketing application (e.g., NDA or BLA) prior to shipping the drug across state lines. This law applies for drugs and for biologics. This is important because in most cases, a Sponsor will want to be able to provide the investigational product to clinical investigators outside the Sponsor’s home state. Before you decide to file an IND, the most important question you need to ask is, “Do I need to conduct a clinical study?” If the answer is yes, then the second question you need to ask is, “Do I need an IND to conduct this clinical study?” Below are two questions that can help you decide whether an IND is required. 1. Is your product an unapproved drug or biologic?

Yes – You do need an IND.

2. Is your product an approved drug and does your proposed clinical study involve a labeled indication(s)?

Yes – You do not need an IND. No – You may need an IND; however, many factors can affect this scenario.

The FDA offers some insight into this via the Guidance for Industry, “Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND.” More information on this topic can also be found in our post on IND Requirements and Exemptions.

Begin with the End in Mind

Choosing the right path to an IND depends on many factors, including your product’s indication, platform/modality, regulatory pathway, development partners, and funding sources. All of those aside, the most important thing to remember is to begin with the end in mind. In the words of the late, great Yogi Berra, “if you don’t know where you’re going, you’ll wind up somewhere else.” The same is true with pursuing an IND. If you do not have a good understanding of the clinical study you plan to conduct, then it is difficult to design an IND package to support it. Without knowledge of where you are going (clinical indications, study populations, type and duration of treatment, etc.), it will be difficult to build a successful IND.

A Typical Path to IND

What is Your Molecule?

There are many types of drugs and biologics that require an IND prior to the initiation of clinical studies. These include small molecule drugs, large molecules, and cellular therapies. A small molecule drug typically refers to a synthetically derived organic compound, but inorganic compounds are also included. Large molecule drugs include biologics like peptides, antibodies, fusion proteins, antibody-drug conjugates, and gene therapies. Cellular therapies, as their name implies, are not molecules at all, but are comprised of cells or tissues that usually come from a donor (e.g., islet cells for the treatment of type 1 diabetes) or the patient themselves and/or have been engineered in some way to fulfill a particular therapeutic purpose (e.g., CAR-T cells for the treatment of various cancers).

Typical Path to a Small Molecule IND

For the purposes of this blog post, we will walk through a typical path to an IND using a small molecule drug as an example. A typical path to a small molecule IND is reflected in the following diagram: For most drug programs, the path to IND begins with basic research where a target is discovered that is believed to have a disease modifying effect. Once a target is identified, the next steps are to:

• Synthesize and screen compounds to identify those that interact with your target (often via high-throughput screening of compound libraries and/or structure activity relationship [SAR] screening)
• Optimize promising compounds using in vitro assays
• Select one or often several compound(s) to move forward based on desirable physiochemical (e.g., target binding) and pharmacokinetic properties

After the initial discovery stage, attention turns to manufacturing (i.e., chemistry, manufacturing, and controls; CMC) and to pre-clinical evaluations of the molecule. At the early stages, manufacturing efforts are focused on initial formulation development activities and on generating sufficient quantities of drug to support pre-clinical evaluations. Ultimately, these activities become more and more focused on defining and refining the quality attributes of the drug, optimizing the manufacturing process, and scaling up production to support clinical evaluations. Pre-clinical evaluations include in vitro and in vivo pharmacology (including initial evidence of efficacy, ideally in an appropriate animal model of the disease), pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion; ADME), and toxicology studies (non-GLP). Together, the process of discovery through initial pre-clinical evaluation often takes several years. If the molecule looks promising following initial pre-clinical evaluations, then the next step is to perform what are known as IND-enabling studies. These include GLP toxicology studies and safety pharmacology studies. These studies provide critical information about the safety of the molecule and will help the FDA to make a determination of whether or not to allow clinical studies to proceed. Successfully completing the IND-enabling studies signals the beginning of the final leg on the path to an IND. During this stage, Sponsors typically meet with the FDA in a Pre-IND meeting to discuss the IND submission and clinical development plans. Finally, the IND is prepared and electronically submitted to the FDA.

Roadblocks: Common Mistakes to Avoid

Having worked with many clients over the years on their pre-clinical programs, clinical development plans, study designs, and IND submissions, Allucent understands what it takes to support a successful IND. Below is a list of some of the most common mistakes to avoid.

General Pitfalls

• Disorganization of the pre-clinical program, the submission, and/or the overall development plan
• Underestimating the time and resources required to get to an IND
• Putting timelines before the science
• Trying to “do-it-yourself” without consulting with experts
• Failing to account for eCTD (electronic submission) requirements
• Not preparing for the predictable – i.e., those issues that tend to pop up in similar development programs or simply not following the available FDA guidance
• Not preparing for the unpredictable – i.e., not considering all potential outcomes and planning for setbacks
• Not starting with the end in mind – i.e., not thinking about the most direct route for supporting initiation of human studies and what those studies will look like

CMC

• Underestimating the challenges with scale up (especially important with large molecule drugs)
• Failing to identify and fully characterize the formulation
• Failing to understand the stability attributes and impurity profile of the molecule (may require additional toxicology studies)

Pharmacology

• Not establishing an exposure-response relationship (requires examining a sufficiently broad dose range in pre-clinical studies)
• Failure to understand the clinical translation (often due to poor animal models of disease)

PK/ADME

• Failing to develop robust assays for detection/quantification of the molecule
• Inadequate characterization of the PK in animal models and how it relates to efficacy and toxicology

Toxicology

• Poor dose selection in pivotal studies
• Poor species selection (often by failing to account for ADME differences)
• Inadequate formulation development
• Poor study design and data collection

Conclusions

The path to IND can be long and resource-intensive. The first key to success is understanding the IND process and how best to support your clinical program. This includes paying attention to manufacturing and pre-clinical development, and avoiding mistakes that could delay or derail your development program. If you need help with your pre-clinical program, clinical study design, or IND submission, Allucent has a team of experts with many years of experience helping our clients achieve successful INDs.