Federal law requires drugs to have an approved marketing application before transportation or distribution across state lines. However, a drug may undergo human testing long before it reaches the market for sale. So, how can an investigational drug legally be shipped for a clinical investigation before it obtains marketing approval?
Let’s look into it by understanding what an Investigational New Drug (IND) application is. Below is a detailed explanation of it. Take a look at its types, application, process, and more.
What Is IND?
IND = Investigational New Drug. Its application is submitted to the FDA when a drug or biological product is not authorized for marketing in the United States. However, it is intended for clinical investigation. Or, in certain circumstances, for clinical treatment under expanded access provisions. Such a drug is being studied in clinical trials to test its effectiveness and safety. Thus, it becomes an experimental drug.
The IND application contains information that lets FDA assess whether the proposed clinical investigation can proceed without exposing participants to unreasonable risk. The submission includes information on pharmacology and toxicology, manufacturing, clinical protocols, and investigators.
An IND is not itself an approval to market a drug. Its purpose is to support the lawful conduct of clinical investigations of the investigational product. It may be submitted by a pharmaceutical company, academic institution, physician-investigator, or another eligible sponsor.
FDA therefore uses the term “sponsor” rather than limiting IND submissions to researchers or pharmaceutical companies.
Types of IND for Pharmaceutical Products
FDA’s current IND framework identifies three specific IND types in its overview. These include investigator IND, emergency Use IND, and treatment IND.
Investigator IND
An Investigator IND is submitted by a physician who both initiates and conducts an investigation. Here, the physician assumes responsibility for both the regulatory requirements applicable to a sponsor and those applicable to an investigator. An investigation may involve an investigational drug or, where the regulatory requirements are met, an approved drug being investigated for a different use.
Emergency IND
An Emergency Use IND allows an investigational drug to be made available for an individual patient in an emergency when there is not enough time to submit a conventional written expanded-access application before treatment is needed.
The request may initially be made by telephone or another rapid means of communication. If FDA authorizes emergency use, treatment may begin according to the applicable requirements. The written submission must subsequently be provided within the required timeframe.
Emergency use also has applicable Institutional Review Board (IRB) requirements and reporting obligations.
Treatment IND
A Treatment IND is an expanded access mechanism. It makes an investigational drug available for treatment to use outside a clinical trial when the FDA’s expanded-access requirements are met.
Expanded access is intended for patients with serious or immediate life-threatening diseases. It also applies to conditions when there is no comparable or satisfactory alternative therapy, and the other regulatory criteria are met.
FDA recognizes expanded access for individual patients, intermediate-size patient populations, and larger populations under a treatment protocol or Treatment IND.
Investigational New Drug Categories
FDA also identifies two broad IND categories, which are Commercial and Research (non-commercial).
Commercial IND
This kind of IND is filed by companies that wish to market the drug after its approval. It is generally part of a broader drug development program in which clinical and nonclinical evidence is generated to support a future marketing application.
Research IND/Non-commercial IND
A Research IND is associated with non-commercial research. It covers investigations that are not conducted primarily for commercial purposes, including research sponsored by academic institutions, government agencies, and other research organizations.
How To Prepare an IND Application?
The sponsor must compile the information required by the FDA. It can be about the investigational drug, the proposed clinical investigation, the investigators, and the sponsor. The application must also include the required FDA forms and supporting information.
The key forms for an original IND are given below:
- Form FDA 1571 (Investigational New Drug Application)
- Form FDA 1572 (Statement of Investigator)
- Form FDA 3674 (Certification of Compliance)
Additional forms may apply depending on the circumstances of the clinical investigation.
The application should contain a sufficiently detailed content table and information covering the investigational plan, pharmacology and toxicology, manufacturing information, clinical protocols, and investigator information. FDA uses the electronic Common Technical Document (eCTD) format for applicable IND submissions electronically.
IND Application Submission Procedure
In the pre-IND stage, the sponsor develops the nonclinical, manufacturing, and clinical information needed to support the proposed investigation. Sponsors may also interact with FDA before submission when regulatory feedback would be useful.
The steps to take for IND application submission are as follows:
Step 1: Identify the information and regulatory requirements that apply to the study.
Step 2: Interact with the Regulatory Authority before submitting the IND (optional, but advised)
Step 3: Compile the necessary information and documents.
Step 4: Prepare the application according to FDA’s IND content and format requirements. eCTD applies to electronic submissions.
Step 5: Submit everything.
Step 6: Complete the initial FDA review period of 30 calendar days.
Step 7: Once the IND is in effect and applicable IRB requirements are satisfied, conduct the clinical investigation according to the submitted protocol and applicable FDA requirements.
FDA IND Application Components
An IND application brings together the scientific, clinical, manufacturing, and administrative information the FDA needs to evaluate a proposed clinical investigation. FDA identifies the following key components of an IND application:
Cover Letter
The cover letter is typically one page or less and helps FDA triage and route the IND. For an original IND, it should identify the submission as an “Initial Investigational New Drug Application” and briefly describe the proposed investigation, including the study type and title, investigational drug and formulation, disease or condition being studied, and manufacturer information where applicable.
Required FDA Forms
The IND submission includes the applicable FDA forms, including the forms given below. The applicability of individual forms depends on the submission and investigation.
Table of Contents
The application should include a detailed table of contents. It should enable FDA reviewers to locate information efficiently. The FDA recommends identifying the location of information by volume and page where appropriate.
Introductory Statement and General Investigational Plan
This section provides the FDA with an overview of the clinical development program for the investigational drug. It should place the proposed investigation in the context of the overall development plan and explain future development plans where they are already known.
Chemistry, Manufacturing, and Controls (CMC) Information
The IND includes information concerning the investigational drug’s chemistry, manufacturing, and controls. FDA uses this information to evaluate the identity, quality, purity, strength, and manufacturing controls that apply to the investigational product.
Pharmacology and Toxicology Information
The application includes nonclinical pharmacology and toxicology info supporting the proposed clinical investigation. These data provide the basis for evaluating the potential risks associated with administering the investigational drug to humans.
Investigator’s Brochure
The Investigator’s Brochure provides investigators with relevant information about the investigational drug. The FDA states that it should include, as applicable, the following:
- Information on the drug substance and formulation
- Pharmacology and toxicology
- Pharmacokinetics and biological disposition
- Previous human safety and effectiveness information
- Anticipated risks, adverse effects and precautions.
The Investigator’s Brochure is updated as the development program progresses and new information becomes available.
Clinical Protocols
The IND must include the protocol or protocols for the proposed clinical investigation. These describe how the clinical study will be conducted and provide the FDA with information needed to evaluate the proposed investigation.
Previous Human Experience
Where human experience with the investigational drug already exists, the IND should include a summary of that experience. This can include relevant information from previous clinical investigations and other available human experience.
Additional and Other Relevant Information
Depending on the investigational product and proposed development program, FDA may require additional information. Examples identified by the FDA include information concerning drug dependence and abuse potential, radiation absorption calculations for radioactive drugs, and plans for pediatric studies. FDA may also request other relevant information that is pertinent to its review of the IND.
FDA’s IND Review and Feedback
Once FDA receives an IND, the agency conducts an initial review to determine whether the proposed clinical investigation may proceed and whether participants may be exposed to unreasonable risk. FDA generally has 30 calendar days from receipt of the IND before the investigation may begin, unless FDA permits it to proceed earlier or places it on clinical hold.
Clinical Hold
If FDA places the proposed investigation on clinical hold, the sponsor cannot proceed with the affected investigation until the issues are addressed and FDA permits it to proceed. If the IND is not placed on clinical hold, the investigation may generally begin after the 30-day period, provided the applicable IRB and other regulatory requirements have been satisfied.
After IND Becomes Effective
Once an IND becomes effective, sponsors must comply with the applicable requirements for conducting the clinical investigation and for submitting required amendments and reports to the FDA. These may include protocol amendments, information amendments, IND safety reports, and annual reports.
IND Transition to New Drug Application (NDA)
An IND does not automatically transition into an NDA. The sponsor generates and evaluates the clinical, nonclinical, manufacturing, and other information during drug development. It’s needed to support a marketing application. When the sponsor has enough evidence to seek marketing approval, it may submit a separate New Drug Application (NDA) to the FDA.
Challenges in the IND Application Process
The following conditions may pose a challenge during the application process:
- Incomplete or poorly organized application information.
- Nonclinical data that does not support the proposed clinical investigation sufficiently.
- Insufficient CMC information that concerns the identity, quality, manufacture, stability, or controls of the investigational product.
- Clinical protocols that do not adequately address the proposed investigation or participant safety.
- Incomplete or inconsistent information across different sections of the application.
- Failure to provide required amendments, safety reports, or other information during the IND lifecycle.
Conclusion
An IND is a key regulatory mechanism. It allows eligible clinical investigations of investigational drugs to proceed under FDA oversight. Preparing an IND involves more than completing the required forms. Sponsors must provide appropriate nonclinical, manufacturing, and clinical information and continue to meet applicable reporting and safety requirements throughout the investigation.
For sponsors developing an investigational drug in the United States, understanding the IND requirements and maintaining the application throughout the clinical development program are essential steps toward a potential future marketing application.
For support with IND strategy, preparation, submission, and other pharmaceutical regulatory requirements, explore Artixio’s pharmaceutical regulatory and compliance services.
FAQs
1. What is the purpose of filing an IND with the FDA?
An IND provides the FDA with information to evaluate a proposed clinical investigation. It provides the regulatory mechanism for the investigation to proceed when requirements that apply are satisfied.
2. How long does the FDA take to review an IND submission?
There’s usually a 30-day review period. The trial can begin if there are no concerns. Otherwise, the FDA may request additional information or impose restrictions.
3. What happens if an IND application is placed on clinical hold?
The FDA will provide reasons for it, such as safety concerns, insufficient preclinical data, or inadequate clinical trial design. The sponsor will not be able to proceed with the affected investigation until the deficiencies are addressed and the FDA permits its progression.
4. Are there different regulations for IND filing in different countries?
Yes, IND filing regulations vary across countries. While the FDA governs IND submissions in the US, other countries have their own regulatory bodies. For example, the EMA in Europe or the PMDA in Japan each have different requirements.
5. Where is the IND application submitted?
The IND application is submitted to the US Food and Drug Administration (FDA). The FDA is the regulatory body responsible for reviewing the application. They decide whether the investigational new drug can proceed to clinical trials.
