Investigational New Drug Application

Investigational New Drug Application: What, Why, and How?

An Investigational New Drug Application (INDA) is a request form to the Food and Drug Administration (FDA) from the clinical study sponsor’s end to administer a novel biological product or investigational drug to humans. The purpose of an INDA is to provide the FDA with sufficient information about the drug’s safety, efficacy, and manufacturing process to allow the regulatory agency to decide whether to permit clinical trials in humans. The requested drug is investigated in clinical trials to assess its safety and efficacy in treating a particular disease or condition. It is a crucial step in the drug development process and is required before a drug can be tested in humans.

Why is an investigational new drug application needed?

The INDA has great significance in the novel drug development process. It makes sure that the new drug being investigated is safe for the patients since it got approval from the FDA itself. The following are the key reasons why the INDA is needed and its roles:

  1. It is a prerequisite of the drug development process as it needs to be submitted to the FDA to request permission to test an investigational drug in humans. Since the FDA approves the INDA, it signifies that the drug product data has been deeply reviewed, including the study protocol, drug safety data, and manufacturing information provided by the sponsors, and has deemed it appropriate to proceed with the clinical trials.
  2. The primary purpose of an INDA is to ensure the safety and welfare of the human participants in the clinical trials. An INDA provides detailed information about the drug’s pharmacology, toxicology, and documentation of the processes involved in the development of the proposed molecule, which the FDA then evaluates to determine the potential risks and benefits associated with the drug for the betterment of the study participants.
  3. Scientific rationale and evidence supporting the investigational drug’s potential efficacy and safety are also demonstrated by the INDA. It includes the preclinical study data (animal testing and laboratory research) as well as early-phase clinical trial results in humans (if available). This comprehensive data package helps establish the scientific foundation and credibility of the new drug, guiding the decision-making process for regulatory authorities, sponsors, and investors.
  4. The IND application marks the transition from preclinical research to human trials, allowing pharmaceutical companies and researchers to advance the drug development process. Once the INDA is authorized, clinical trials can start, allowing for data collection on treatment efficacy, safety, and dose necessary for later stages of drug development, such as Phase II and Phase III trials.
  5. The planned clinical trial protocols are outlined in the INDA, including the research design, objectives, participant inclusion and exclusion criteria, dosage strategies, and safety monitoring methods. This information is critical for regulatory authorities and ethics committees to evaluate the scientific validity and ethical implications of the study, as well as to provide adequate oversight and monitoring during the trial.
  6. The INDA approval can attract investments, collaborations, opportunities, and partnerships with pharmaceutical companies, accelerating the drug development timeline and increasing its market potential.
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In short, IND applications play a crucial role in advancing new drugs through the regulatory process and ultimately bringing safe and effective therapies to patients in need.

Classification of an investigational new drug application

As per the FDA, INDA is classified into three types: investigator INDA, emergency use INDA, and treatment INDA. The following information provides the context for these three categories:1

Investigator INDA

This INDA is submitted by a physician who starts and conducts an investigation and is directly responsible for administering or dispensing the investigational drug. A research INDA might be submitted by a physician for an unapproved or approved drug or product in a new patient population or for a further indication.

Emergency use INDA2

This application is submitted to authorize the use of an experimental drug in an emergency situation when there is no time for the submission of an INDA. It is submitted per 21 CFR 312.23 or 312.20.3 It is used for patients who do not meet the criteria of an existing study protocol or if an approved study protocol does not exist.

Treatment INDA

Treatment INDAs are submitted for investigational drugs that have shown promise in clinical testing for severe or immediately life-threatening disorders.

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How should an Investigational new drug application be submitted?

As per the FDA, the INDA must contain information from three broad areas, including animal pharmacology and toxicology studies, manufacturing information, and clinical protocols and investigator information.1

 

Moreover, as per 21 Code of Federal Regulations (CFR) 312.23, ‘a sponsor who intends to conduct a clinical investigation subject to this part shall submit an “investigational new drug application” (IND) including, in the following order:3

  1. Cover sheet (Form FDA-1571)4
  2. A table of contents
  3. Introductory statement and general investigational plan
  4. [Reserved]
  5. Investigator’s brochure (in accordance with 21 CFR 312.55)
  6. Protocols (in accordance with 21 CFR 312.30(a))
  7. Chemistry, manufacturing, and control information
  8. Pharmacology and toxicology information
  9. Previous human experience with the investigational drug
  10. Additional information
  11. Relevant information

Additional documents are required as per 21 CFR 312.23, including information previously submitted, material in a foreign language, the number of copies, the numbering of IND submissions, and identifications of exceptions from informed consent.

Investigational new drug application review process

The FDA review process for INDA is rigorous and thorough to ensure the safety and efficacy of experimental drug being tested on humans. After receiving the INDA application, the FDA reviews it to ensure it contains all necessary components. Before starting any clinical trial, the sponsor is required to wait 30 calendar days. The FDA may ask for additional information or clarification to be provided to complete the review.

If the INDA is complete and meets all requirements, the FDA will:

  • Either approve the application and allow the clinical trials to proceed, or
  • It might place the INDA on clinical hold if it identifies any safety concerns or deficiencies in the application.

The sponsors must follow the FDA’s guidelines and procedures to remove the clinical hold from the INDA.5

Amendments to the application

After the submission of an INDA, any new additions or modifications to the submitted application are required to be amended by the sponsor to ensure the safe and ethical conduct of the clinical investigation. If there’s any change in the study protocol, the sponsor has to amend the changes as per 21 CFR Part 312.30. Per these guidelines, a sponsor has to make amendments to the application if a new protocol is to be submitted by the sponsor, if there are modifications to the existing study protocol, or if a new investigator is added to carry out a previously submitted protocol.6

In addition, information outside the protocol amendment’s scope, such as IND safety reports (21 CFR 312.32) or annual reports (21 CFR 312.33), are to be made as per 21 CFR Part 312.31 information amendments. As per this guideline, information amendments to the IND should be submitted as necessary but, to the extent feasible, not more than every 30 days.’7

Conclusion

An INDA is a pivotal step in the drug development process. It facilitates regulatory compliance, ensures ethical considerations, assesses safety and benefits, validates scientific rationale, facilitates drug development, and opens doors to further opportunities in the pharmaceutical industry. To submit an INDA, it is crucial to follow the relevant regulatory guidelines to facilitate the successful submission of the application. The sponsors should be aware of such procedures and wait until the INDA is approved to start any further clinical investigation process. Once the INDA is submitted, the FDA will review the application to determine whether the trial can proceed, be put on clinical hold, or request additional information. The review process may take up to 30 days for the initial review, and subsequent reviews can take up to 60 days. The sponsors should comply with the FDA’s guidelines and provide accurate documentation for a successful INDA submission.

References

  1. Food and Drug Administration. Investigational New Drug (IND) Application. fda.gov. Updated 20 July, 2022. Accessed 08 September, 2023.
  2. Food and Drug Administration. Emergency Use Of An Investigational Drug Or Biologic. fda.gov. Updated 16 February, 2021. Accessed 08 September, 2023.
  3. Code of Federal Regulation. Part 312—Investigational New Drug Application. ecfr.gov. Published 24 March, 2004. Accessed 08 September, 2023.
  4. Food And Drug Administration. Instructions For Filling Out Form Fda 1571. fda.gov. Accessed 08 September, 2023.
  5. Food and Drug administration. IND Application Procedures: Clinical Hold. fda.gov. Published 09 October, 2004. Accessed 08 September, 2023.
  6. Code of Federal Regulation. Part 312.30 Protocol Amendments. ecfr.gov. Published 24 March, 2004. Accessed 11 September, 2023.
  7. Code of Federal Regulation. PART 312.31 Information Amendments. ecfr.gov. Published 24 March, 2004. Accessed 11 September, 2023.

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