A Short Guide to the FDA’s Investigational New Drug Application
Last updated on March 1, 2023 by
The US Food and Drug Administration is responsible for ensuring the safety and effectiveness of new drugs and medicines before they are marketed to the public. To achieve this, the FDA reviews various types of data and information submitted by sponsors, including pharmaceutical companies, drug manufacturers, independent investigators, and more.
The data that must be submitted includes preclinical data, results from animal studies, and results from clinical trials. The FDA also inspects the facilities where drugs are manufactured and conducts ongoing monitoring of medicines once they are on the market.
The drug development journey is a complex and multi-step process that includes several phases and can take many years and millions of dollars to complete.
The journey typically includes discovery and preclinical research, Investigational New Drug (IND) submissions, clinical trials, New Drug Application (NDA) submissions (also known as a marketing application), FDA reviews, and post-market monitoring. In this article, we’ll review INDs and the application process.
What Is an IND?
An Investigational New Drug (IND) is an experimental drug that has not yet been approved for marketing by a regulatory agency, such as the FDA, but is being tested in clinical trials to determine its safety and efficacy.
An IND is considered “investigational” because it is still in the process of being investigated, and its safety and effectiveness have not yet been fully established.
The drug’s sponsor must submit an Investigational New Drug application to the FDA to conduct clinical trials on the new drug.
The application must contain data from preclinical studies (pharmacokinetics, dose-response, formulation, toxicology studies), manufacturing information (labeling, production methods, batch records), information regarding the study site (facilities, equipment), and the proposed clinical trial protocol (study design, endpoints, informed consent, adverse event reporting). The FDA reviews the application to ensure that the proposed trials are scientifically sound and ethically conducted and that the drug is safe for use.
In drug development, INDs serve as the starting point for a drug’s journey toward eventual approval and marketing. The submission and subsequent clinical trials are necessary steps in demonstrating the safety and efficacy of the new drug. The process is designed to ensure that new medicines for patients are developed and marketed safely.
If the IND is approved, the sponsor will conduct clinical trials on patients to determine if the drug is effective and safe for use. If the clinical trials are successful, the sponsor may then submit a New Drug Application (NDA), also known as a marketing application, to the FDA for approval to market the drug to the public. NDAs are generally the final step in the drug development process.
The NDA application must include all the data generated from preclinical and clinical studies, information regarding the manufacturing process, quality control data, statistical analysis, labeling for the drug, and more.
The FDA reviews the marketing application to determine whether the drug is safe and effective for its intended use and whether the benefits of the drug outweigh the risks, similar to an IND review. If the agency determines that the drug is safe and effective, it may approve the marketing application and allow it to be marketed in the United States.
In addition to INDs and NDAs, the FDA uses other tools and processes to assess the safety and efficacy of new drugs, including things like adverse event reporting, risk management plans, and Abbreviated New Drug Applications (ANDAs), another type of drug approval application.
Adverse reporting reports any adverse events or side effects associated with drug use, while risk management plans aim to minimize potential risks associated with the new drug.
ANDAs provide information about a generic drug, including quality, safety, and efficacy data of the generic drug and more. The FDA uses this application to determine whether a generic drug is equivalent to a previously approved brand-name drug, or reference listed drug (RLD).
Types of INDs
There are two types of INDs: commercial and research. A commercial IND is submitted by a sponsor, such as a drug manufacturer, that intends to market the investigational drug for commercial use once the regulatory agency has approved it.
In contrast, a research IND is submitted by a single investigator or a group of investigators who want to study an investigational drug in a clinical trial. Research INDs are often used for early-phase clinical trials, such as phase 1 trials, when the primary goal is to determine the safety and pharmacokinetics of the drug.
The regulatory agency will review the IND to ensure that the proposed clinical trials being conducted are scientifically sound and ethically run, that the clinical investigator or sponsor-investigator is qualified and experienced and that the drug is reasonably safe for human subjects.
In addition to the commercial and investigator IND categorizations, there are three types of applications:
- Research IND or Investigator IND: An application submitted by a physician who starts and carries out the study. The physician is responsible for administering or dispensing the investigational drug under their direct supervision. The IND may be submitted for approval to study a new, unapproved drug or for studying an approved drug’s use in a new indication or patient population.
- Emergency Investigational New Drug (EIND): An application that, when approved, allows the use of an experimental drug in an emergency situation where there isn’t enough time for a complete IND application submission. It is also utilized for patients who do not fit the criteria of an existing study plan or if there is no approved study plan available.
- Treatment IND: An application submitted for experimental drugs that demonstrate promise in clinical trials for severe or life-threatening conditions during the ongoing clinical studies and FDA review process.
How Does the IND Application Process Work?
The IND application process is a critical step in the drug development journey, as it allows drug manufacturers to request permission to conduct clinical trials in humans with an IND. Sponsors can take the following steps to apply for an IND in the US:
- Conduct preclinical testing: Run laboratory and animal studies to determine the safety and efficacy of the drug.
- Prepare for the IND application: Assemble all relevant information, including preclinical data, manufacturing information, proposed clinical trial protocols, and other required information.
- Submit the IND application: Apply to the FDA electronically through the agency’s Electronic Submissions Gateway (ESG) or by mail.
- Go through FDA review: The FDA will review the IND application to determine if the proposed clinical trials are scientifically sound and ethically conducted and if the drug is safe for human subjects.
- Conduct clinical trials: If the IND is approved, the sponsor, whether it’s a drug manufacturer or clinical investigator, can then conduct clinical trials in humans to evaluate the safety and efficacy of the drug.
- Provide annual reporting: Once clinical trials begin, an IND safety report must be sent to update the FDA on the study’s progress. The annual report must be submitted by the sponsor of the IND within 60 days of the anniversary date of the IND submission and include updates on the safety of the IND, changes to the clinical protocols, and more.
Information and reporting requirements for IND applications may vary, making it important to consult with regulatory agencies like the FDA to understand the criteria for IND submissions. A clinical hold may be put in place after an application has been approved, stopping the trial’s initiation or continuation.
This action is taken when the FDA determines a significant safety concern for the study’s participants or the reliability of the data being generated is inaccurate or flawed. Preparation and proper study design are critical.
Working with experienced professionals, such as regulatory affairs specialists, can help ensure a smooth and successful IND application process.
IND Submission Process
To successfully submit an IND application, you must collect and prepare the following information and materials:
- Preclinical data: Laboratory and animal studies demonstrating the drug’s safety and efficacy. The preclinical data must be detailed and provide a basis for the proposed clinical trials.
- Manufacturing information: The drug’s formulation, manufacturing processes, and quality control measures. This information must demonstrate that the drug can be manufactured consistently and reproducibly, meeting appropriate quality standards.
- Clinical trial protocols: Detailed information about the proposed clinical trials, including the trial design, inclusion/exclusion criteria, endpoints, and sample size.
- Investigational Brochure: A document that provides an overview of the preclinical and clinical information available on the drug.
- Other relevant information: The drug’s pharmacology and toxicology data, as well as any additional information required by the FDA.
The IND application must be in the format specified by the FDA and include all required information and documentation. The FDA may request additional information or clarification during the review process.
Can You Make Amendments to the Application?
Amendments are changes or additions to an Investigational New Drug application already on file with the FDA. They are a common part of the IND process.
During the IND process, a sponsor may need to make changes to the application for various reasons, including changes in the study design, the addition or removal of clinical investigators, or updates to the manufacturing process.
When a sponsor wants to make changes to their application, they must submit an amendment to the FDA. The amendment must include detailed information about the changes being made and why they are necessary. The amendment must also include any updated, relevant information to the application, including revised protocols, manufacturing information, or new safety data.
The FDA reviews amendments to determine if the changes are acceptable and if they impact the safety and efficacy of the investigational drug. If the changes are significant, the FDA may require additional information or request that the sponsor conducts further preclinical or clinical studies before proceeding with the study.
Resources for IND Applications
A variety of resources are available for individuals and organizations who want to learn more about INDs, applications, and submissions, including government websites, organizations, conferences, workshops, consultants, and service providers:
- Government websites like FDA.gov provide information on INDs, including FDA regulations, guidance documents, and FDA forms and instructions.
- Government programs like the Pre-IND Consultation Program, established by the Office of Infectious Diseases (OID), formerly the Office of Antimicrobial Products (OAP), offer early guidance and advice to potential new sponsors of new therapeutics.
- Organizations like the Regulatory Affairs Professionals Society (RAPS) and the Drug Information Association (DIA) offer training, resources, and networking opportunities for professionals involved in IND submissions and drug development.
- Various conferences and workshops focus on INDs and drug development. These events provide opportunities to learn from experts, network with peers, and stay up-to-date on the latest developments in the field.
- Consultants and service providers specializing in regulatory affairs, clinical research, and drug development offer services to help with IND submissions and other aspects of the drug development journey. (Simply search for “investigational new drug consultants.”)
It can be helpful to use a combination of these resources to understand INDs and the IND submission process comprehensively. It’s also essential to stay up-to-date on the latest developments and regulatory changes, as these can impact the IND submission process and drug development.
IND Guidance Documents
The FDA provides several guidance documents to help individuals and organizations prepare applications, including regulations, clinical trials, preclinical, manufacturing, and application papers, all of which provide information on the requirements and expectations for submissions and help ensure that applications are complete, accurate, and scientifically sound.
These guidance documents are updated periodically to reflect new developments and regulatory changes, and it’s crucial to stay up-to-date on the latest guidance documents to ensure that IND applications are compliant and accurate.
CDER Learn Courses
The Center for Drug Evaluation and Research (CDER) is a division of the FDA responsible for reviewing and approving new drugs in the United States.
Because of their role in the drug approval process, the CDER provides various learning courses on topics related to drug development, such as Good Clinical Practice (GCP) training, regulatory submissions, and IND applications.
The guidance and support helps companies and individuals seeking to develop and bring new drugs to market better understand the requirements and regulations involved in the IND process, ensuring that applications are complete, well-documented, and meet regulatory requirements.
IND Laws & Regulations
The IND process and FDA’s approval review are governed by several laws and regulations, including the Federal Food, Drug, and Cosmetic Act (FD&C Act) and its implementing statutes. These regulations provide the framework for developing, testing, and approving new drugs in the United States. The key rules that guide the IND process include the following:
- 21 CFR 312: Investigational New Drug Application
- 21 CFR 314: Applications for Approval to Market a New Drug
- 21 CFR 600: Biological Products
- 21 CFR 812: Investigational Device Exemptions
IND Policies & Procedures
In addition to the laws and regulations mentioned, the application and review process is guided by various policies and procedures, known as the Manual of Policies and Procedures (MaPPs), which is overseen by the CDER. These include instructions like the Guidance for Industry, Draft Guidance, Draft and Final Policy Documents, Standard Operating Procedures (SOPs), and more.
Firstly, the Guidance for Industry provides recommendations on various aspects of drug development and IND submissions, including study design, data quality, patient safety, and more.
The Draft Guidance comprises information on current thinking and evolving regulatory policies and procedures related to drug development and IND submissions. The Draft and Final Policy Documents provide additional guidance on specific topics related to IND applications, such as the format and content of IND submissions, review procedures, and post-approval obligations. You can search for these documents using the FDA’s search page.
Lastly, the FDA’s Standard Operating Procedures (SOPs) offer detailed instructions for reviewing and managing IND applications, including the timeline for review, information requirements, and other key considerations. You can find an updated summary of SOPs required by the FDA in the Federal Register index.
Policies and procedures like these can help ensure the consistent and systematic review of drug approval applications and support the efficient development and approval of new drugs.
The safety and efficacy of marketed drugs are of utmost importance in the United States as they directly impact public health. To ensure that new drugs are safe and effective, the FDA established a comprehensive regulatory framework to oversee the development and approval of new drug products.
An IND application is a critical component of this framework, as it allows the sponsor of a new drug to request permission from the FDA to begin clinical trials. The application must provide extensive information about the proposed drug, including preclinical data, study design, and clinical trial protocols.
Submitting an IND application to the FDA involves:
- Following a detailed and complex process includes preparing and submitting the application.
- Responding to any questions or requests for additional information from the FDA.
- Tracking the review process.
Once an IND application is received, the FDA reviews it to determine if the proposed clinical trials can proceed safely and effectively. During the review process, the agency may request additional information or clarification from the sponsor or raise concerns about the safety and efficacy of the proposed drug.
If the IND application is approved, clinical trials can proceed. If not, the sponsor may need to revise the application or provide additional information to address the FDA’s concerns.
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