Making Sense of INDs – Your Key to Clinical Trials

Developing a new drug and bringing it to market is a long and complex process requiring dedicated research and regulatory oversight. One milestone is obtaining clearance from the FDA to begin clinical trials in human subjects through an Investigational New Drug (IND) application. The IND evaluates safety and efficacy for initial human use. However, navigating IND requirements can seem daunting. Yet understanding each step and using the available resources enables optimizing IND packages, potentially advancing compounds into tomorrow's ground-breaking treatments.

An Investigational New Drug (IND) application is a request for approval from the FDA to administer an experimental drug or biologic to humans in clinical trials. Before initiating any clinical studies in people, sponsors must obtain IND clearance from the FDA. The IND review process allows the FDA to evaluate whether the initial-stage clinical testing is reasonably safe for participants, helps identify any risks, and ensures proper informed consent.

The IND exempts the investigational drug from certain regulatory requirements, allowing it to be shipped across state lines for use in clinical studies. Most INDs are sponsor-initiated with an eye towards commercialization. Researchers may also evaluate an investigational product in humans through investigator-initiated INDs. Emergency use INDs can also be initiated during public health emergencies, such as the recent COVID-19 pandemic.

The first step is ensuring that all required preclinical work is complete for the investigational product. During early drug development, the sponsor's goal is to determine reasonable safety for initial human use and confirm adequate pharmacological activity for efficacy. Once a drug candidate demonstrates a positive profile, extensive data and information must be compiled into the three main sections of the IND application:

• Nonclinical information
• Chemistry, manufacturing, and controls (CMC) information
• Clinical information

A key component of nonclinical information is in vivo animal studies, which allow the sponsor to understand how the investigational product is absorbed, distributed, metabolized, and excreted (pharmacology), and how the animal responds to the investigational product (pharmacodynamics).   Toxicology studies are also performed to understand side effects (e.g., effects on development and reproduction, potential carcinogenicity, etc.), maximum tolerated doses in model animals, and any organs in which the drug may accumulate.  Key safety studies must follow GLP requirements.

In vitro studies are also performed to demonstrate pharmacologic effect.  For example, an oncology drug can be administered to cell lines of the target cancer.  In addition to demonstrating efficacy, these studies help understand how the drug is absorbed into the cell.

CMC information documents that a rigorous manufacturing and testing process has been established to ensure the highest quality and consistency of investigational product.  The sponsor should demonstrate an understanding of expected impurities, the stability of the molecule, and have controls in place to ensure all raw materials and components support product quality.

The clinical information includes the clinical study protocol, justification for the first-in-human (FIH) dose, and qualifications of the principal investigator.  It is also important to include the informed consent form, which documents that the sponsor has communicated benefits and risk to the patient and obtained the patient’s consent to participate in the study.

The FDA allows sponsors an optional Pre-IND meeting, where targeted questions can be asked.  This meeting grants early agency feedback on the proposed development plan, which significantly reduces the risk of a clinical hold during the IND review.  It also allows the sponsor to start building their relationship with their FDA reviewers and project manager.  In addition to requesting this meeting, the sponsor will be required to submit a Meeting Package containing background information.  More details can be found in the Small Business and Industry Assistance: Frequently Asked Questions on the Pre-Investigational New Drug (IND) Meeting from FDA.

IND applications must be submitted to the FDA for review prior to beginning clinical trials. This can be made either electronically or via mail depending on the type of sponsor. Electronic submissions are preferred when possible as they facilitate a streamlined review process. Significant time and resources are required to compile the extensive application package given the large amount of preclinical and manufacturing information that must be provided. Developers should initiate application preparation well in advance to avoid delays in receiving FDA clearance to start human testing.

The goal of the submission is to provide the agency sufficient detail on safety, quality and study design for initial evaluation and clearance to proceed with clinical trials, if appropriate. Close coordination between sponsors and the FDA reviewers helps facilitate an efficient review of the application.

After the IND is submitted, sponsors must wait 30 calendar days before initiating any clinical trials. This period allows the FDA to review the application and ensure research participants will not be subjected to unreasonable risks.

Per requirements, if the FDA does not notify the sponsor that they have concerns within 30 days, then the sponsor may start clinical trials.  In recent practice, however, FDA has been forwarding Study May Proceed letters and emails.  Should a sponsor be placed on Clinical Hold because of agency concerns, then the sponsor must take corrective action.  In response, the agency will issue a Study May Proceed letter that lifts the clinical hold, place the study on partial hold (specific restrictions), or communicate that the study continues to be on hold pending resolution of continuing questions. Until the FDA indicates that a hold has been removed, a study must not proceed.

By following a logical framework and using the available FDA resources, such as guidance documents, applicants can optimize their IND package.

Common pitfalls to avoid are:

• include insufficient preclinical data,
• disorganized formatting, and
• missing required forms or information sections.

Starting the application process early allows time for FDA feedback or clarification questions. Ensuring that GLP, GMP and human subject protection standards are met strengthens the application and clinical program integrity. With attentive planning and assembly, researchers can submit high quality INDs and move forward with their innovative treatments into human trials.

Navigating the IND process is a major undertaking for any sponsor. Effective planning is important to ensure that the FDA receives well-conducted non-clinical studies, CMC data, and trial plans that prioritize participant safety. This comprehensive submission package provides reviewers with confidence that potential risks have been adequately addressed before exposing humans to untested compounds. By carefully preparing at each stage to meet FDA standards, sponsors can increase the chances of advancing potentially transformative treatments into clinical trials.

Preparing an IND submission requires significant effort to meet all regulatory requirements. Our scientific and regulatory team can provide guidance at every stage of the IND process. We'll work closely with you to ensure your nonclinical data, CMC information and clinical plans meet FDA standards. Contact us today to discuss strategies for IND preparation and submission.