Common Pitfalls in Preparing an IND Application

As a drug successfully makes it through the development process, sponsors will inevitably need to submit a new drug application (NDA) to the Food and Drug Administration (FDA). While it may seem like a straightforward process to some, there’s room for many elements to be missed as sponsors prepare for the application submission.

Failure to Have a Pre-Investigational New Drug (IND) Meeting

There are a myriad of regulations coming into play during the drug development process. Because of this, the FDA understands sponsors may need help making sense of regulations. The FDA issued guidance on when formal interactions should occur between them and a sponsor. One such meeting is the pre-IND meeting.

The pre-IND meeting is a sponsor’s opportunity to interact with the agency before initiating the clinical study. In this meeting, they’re able to receive insight and feedback regarding critical issues. There are benefits to holding a pre-IND meeting, such as:

• Verifying the appropriate animal model is used to determine product safety
• Determining if the toxicology data is sufficient to justify a first-in-man study
• Discussing data concerns or potential roadblocks
• Developing a relationship with the agency team reviewing the submission

Even though it’s only recommended for an organization to take a pre-IND meeting with the FDA, there could be consequences if sponsors fail to take the meeting. If a sponsor chooses not to take advantage of the FDA’s pre-IND meeting, it can potentially lead to FDA rejection of the IND or result in a clinical hold.

Too Much Data or Unnecessary Information

Including unnecessary information, disorganized data, or dense text are common missteps when sponsors submit IND applications. Committing these errors increases the amount of time it will take the FDA to review your IND. Additionally, it makes it easier for errors to slip through the cracks, risking outright application rejection.

Providing too much information in your application may reveal a lack of cohesive strategy within your company, and including large amounts of data without explaining it will slow down the review process. Conversely, failing to present the information concisely is a major flaw. Providing brief points to serve as a guiding point throughout the documents helps reviewers know what is relevant in the application.

Poorly Written or Unorganized IND Application

Oftentimes, IND writers will make the mistake of focusing solely on the science and will disregard everything else. If a submission is difficult to read, reviewers are more likely to place it on hold or reject it outright. As you write your application, think of the FDA reviewers evaluating the document. Not only should you include the appropriate amount of data, but what does your grammar and formatting look like? Having a poorly written IND application will frustrate and confuse the reviewers.

In order to avoid a study placed on hold or rejected, there are best practices to abide by:

• Operate under the guise of your reviewers may know the basics of your therapeutic area but may not be as familiar with specific details.
• Similar to adding the right amount of data to your application, don’t overload the IND with unnecessary information. As you write your IND, stay focused.
• Use common words whenever possible, and if you need to use abbreviations or technical terms, accurately define them.
• Break up large paragraphs of text with figures and tables to make it more visually appealing.

Before submitting the IND, have one person review the full document to ensure consistencies. This is especially important if there are multiple writers contributing to the IND; one reviewer helps ensure consistency among writing styles.

Leaving Out Pertinent Chemistry, Manufacturing, and Controls (CMC) Details

Using nonclinical data or manufacturing information that doesn’t adequately support the clinical protocol hurts the IND application. It’s critical to ensure all nonclinical data supports the clinical design and provides adequate justification of the desired labeling claims – including basic exposure data. In order to achieve this, teams must undergo detailed planning and have a strong knowledge base of IND regulations.

In your IND application, you must specify how your organization will assure patient safety. Including information such as a drug or biologic’s quality, purity, and strength will help with specification, as well as help reviewers assess production’s adequacy and consistency.

Leaving out data pertinent for evaluating testing procedures will make it difficult for reviewers to determine the proposed study’s quality. Ensure your study has evidence to support the robustness of the assay used in evaluating the clinical trial. Include representative output data such as chromatograms and procedural details in the form of standard operating procedures (SOPs).

Inadequate Support

One of the biggest reasons sponsors receive a clinical hold is the IND lacks organization and clarity. An IND application should provide reviewers with clear data and explanation for results. Make sure these results match your protocol and avoid irrelevant information, because that can reduce your impact.

Additionally, not clearly stating the drug’s or biologic’s potential risk in the submission may raise a red flag. Potential issues of concern need to be presented in a forthcoming and transparent manner during and following the regulatory review. Failure to do so will impact the sponsor’s credibility. It’s the sponsor’s responsibility to provide the FDA with the information in a manner to help them understand the safety issues raised, as well as how they will be mitigated.

The sponsor must also provide all the information related to the application. Common errors in IND preparation include:

• Forgetting to provide relevant explanations or supporting data for the results
• Failing to properly match results to the protocol

Sponsors must note: study data standards are required for commercial INDs as of December 17, 2017, for both nonclinical and clinical studies. This is a specific requirement to comply with the Clinical Data Interchange Standards Consortium (CDISC).

Lack of Experience

Many organizations lack experience in compiling an IND submission. It takes a highly skilled team and resource sharing to produce high-quality work, as well as hands-on experience successfully submitting IND applications. With experience comes a deep understanding of the IND submission process and up to date FDA guidance to the table. Previous experience meeting with FDA personnel can help with every step of the IND process.

It’s also important to pay attention to the details. Making inadvertent mistakes in the IND submission is the most common reason for technical rejection of the electronic common technical document (eCTD) filing. Double-check the application to make sure the correct eCTD format is followed, and all pre-clinical data and documents are included. It’s also worth it to look over the submission twice to ensure it is sent to the correct center.

It’s easy for someone to underestimate the time required to develop an IND application and complete the submission – especially if they don’t have much experience preparing an application. It may take 12-14 months to complete the IND package, not including the time commitment for the pre-IND. Keeping this in mind, it’s in your best interest not to wait until the last minute to begin preparations.

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