Prepare Your Clinical Trial Application in the US: A Guide to the Investigational New Drug (IND) Application

In this article, we'll walk you through what an IND is, what the application should include, and how to work alongside the FDA for maximum success.  

Table of Contents

1. What is an IND?
2. What are the categories of INDs? 
3. What are the types of INDs?
   
4. Do I need to submit an IND? 
5. What does the IND include?
6. Pre-IND Meeting
7. Organizing the IND for the FDA
8. My IND is with the FDA - now what? 

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What is an IND? 

A new Investigational New Drug (IND) Application allows sponsors to legally ship drug or biological product to be used in human clinical trials.  Per FDA code 21 CFR 312.20, a sponsor shall submit an IND to conduct a clinical investigation with an investigational new drug and cannot not begin a clinical investigation until the IND is in effect. 

 FDA's primary objectives in reviewing an IND application for Phase 1 trials are to assure the safety and rights of subjects, and in later clinical programs to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety. FDA's review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations. 

What are the categories of INDs? 

 

Commercial and Research INDs:

Commercial and Research INDs make up most IND applications. Sponsors  (usually a corporate entity) typically submit commercial INDs as the intent is to market the drug/biologic for profit. The research IND or investigator- initiated IND is sponsored by a non-profit institution. Studies run under the Research heading are shorter and may result in publications. 

IND Submission Volume in 2022  In 2022 FDA received a total of 1865 submissions, including 1124 Commercial and 741 Research IND applications.

 

 

What are the types of INDs? 

The FDA outlines three (3) types of INDs.  

• Investigator IND: submitted by a physician who both initiates and conducts the trial, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population. 

• Emergency Use IND: allows the FDA to authorize use of an experimental drug in an emergency that does not allow time for submission of an IND in accordance with 21CFR , Sec. 312.23 or Sec. 312.20.  It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist. 

• Treatment IND: submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted, and the FDA review takes place. 

Other Special Designations: 

Breakthrough Therapy: This designation is for drugs that treat a serious or life-threatening condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies. A sponsor should submit a request for breakthrough therapy designation with the submission of a new IND¹⁶. The Food Drug and Cosmetic Act (21 USC 356) states that a request for a breakthrough therapy designation may be made concurrently with, or at any time after, the submission of an application for [the IND]. 

2023 Breakthrough Designation Success Rates For fiscal year 2023, FDA’s two divisions received and granted the following number of requests for Breakthrough designations.  CDER Breakthrough Therapy Requests: 60, Granted: 19.  CBER: Breakthrough Therapy Requests: 20, Granted: 6.

 

Expanded Access (Sometimes referred to as “Compassionate Use”): New drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options. 

 

Do I need to submit an IND? 

Sponsors under both Commercial and Research INDs need to submit an IND. An IND submission or application to the FDA is required by law (21 CRF 312)¹ to start human clinical trials in the US. In addition to the IND being submitted to the FDA, an IRB (Institutional Review Board) or EC (Ethics Committee) must review and approve the study before initiating a trial per 21CFR56 and 21CFR312. The IRB review of the clinical investigation may be conducted in parallel with the FDA review of the IND.  

The IND application itself is a collection of approximately 180 documents and datasets. The purpose of the IND is to communicate the sponsor’s intent to start human trials. The sponsor must demonstrate through the pre-clinical and manufacturing documentation: 

1. The drug is reasonably safe for humans.
2. The drug shows some efficacy towards disease or syndrome that warrants commercial development. 

Ensuring your IND is complete, compliant, and efficiently reviewed reduces the risk of a clinical hold and possible financial setbacks. 

What does the IND include? 

The IND includes pre-clinical (non-clinical) studies, manufacturing (quality), regulatory (administrative), and clinical documentation and data. Documentation in the form of reports is authored by scientists, chief medical officers, medical writers, data statisticians, chief scientific officers, clinical operations, quality engineers and various other subject matter experts either internal to your organization or sources externally. Raw data are provided in analysis formats (SAS, .xpt), and summaries of that data are represented in tables, listings and/or graphs within the reports. 

Broadly the IND application must include information in following modules:  

Module 1: Administrative, Regulatory and Regional

Module 1 includes: a cover letter, Investigator Brochure, Form 1571 (type of cover sheet), Correspondence, Meeting requests, investigational labeling, General investigational plan, and contact information of sponsor.  

Module 2: Summary Information:

Summarizes Quality and Pre-Clinical data and reports. 

Module 3: Manufacturing and Chemistry

Module 3 includes the Chemistry, Manufacturing, and Control information for:

1. Drug substance
2. Drug product
3. Placebo formulation, if applicable
4. Labeling information for the labeled products relevant to the investigational drug; and
5. An environmental analysis for assessment of the effects of the investigational new drug or biological product on the environment.   

Module 4: Pre-clinical Datasets and Reports

Module 4 includes: 

1. Pharmacology and Drug Disposition: description of the pharmacological effects and the mechanisms of action of the drug in animals and information on the absorption, distribution, metabolism, and excretion of the investigational product, if known. 
2. Toxicology: Animal and invitro reports to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review is expected. This should consist of line listings of the individual data points, including laboratory data points for each animal along with appropriate summary tabulations.  

Module 5: Describe the intent of Human Trial 

Module 5 includes:

1. Clinical Protocol specifying clinical safety assessments, toxicity monitoring, description of toxicity, based stopping rules, dose adjustment rules for individual patients and the overall trial, and adverse event recording and reporting; Study enrollment criteria. Describe methods for toxicity assessment and adverse events are collected, recorded, and reported consistently.
2. CVs of investigators.
3. Form 1572 signed by the investigators.
4. Informed Consent and IRB Oversight. 

More information about the modules in included below in the IND submission section.

Plan a Pre-IND Meeting: You won't regret it!  

Consider the FDA a valuable resource and partner. Scheduling a pre-IND meeting with the FDA begins a discussion with the project manager. There is no cost to the sponsor to request or have a Pre-IND meeting with the FDA. Plan to request the meeting approximately 60 or more days out from your submission date. Typically, the FDA will respond within 2-3 weeks with a date. Prepare with a briefing package and presentation. The Pre-IND meeting is a type B meeting. The background package (briefing book) should be sent thirty (30) days before the meeting.  

Objectives, benefits, and topics to cover at your Pre-IND Meeting 

• Understanding proof of concept of the human trial and initiating dialogue. 
• Requesting advice for issues related to data needed to support testing in humans. 
• Design of non-clinical pharmacology, toxicology, and drug activity studies, including design and potential uses of proposed treatment studies in animal models. 
• Data requirements for IND application. 
• Initial drug development plans, and regulatory requirements for demonstrating safety and efficacy.¹⁷ 

The meeting is an opportunity to ask questions and request feedback.   Establishing the relationship early with your reviewer and project manager will pay dividends in the future. 

Figure: Opportunities for FDA: Interactions with The Office of Therapeutic Products Website.¹³ 

Organizing the IND for the FDA and Submission 

Organizing the IND 

FDA accepts INDs in eCTD format. The eCTD format is a globally accepted five (5) module format maintained by the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). ICH eCTD is inclusive of Quality, Safety and Efficacy, Administrative/Regional and Clinical documents, and data. Refer to the contents and modules in the sections above for more information.  

Module 3 includes Quality, Chemistry, Manufacturing and Controls. Module 4 contains non-clinical reports and data. Clinical documents are filed in Module 5. Summaries are included in Module 2 and Administrative documents in Module 1.  

ICH and the FDA provide granular organization down to the document level. For each component of the IND required, there is a corresponding section and document associated. For example, for Pre-clinical Single Dose Toxicology Reports, the section and document number are 4.2.3.1. Single dose toxicity report to be “filed” in the 4.2.3 folder.  

IND Submission 

As you consider preparing for the IND submission, aligning resources specific to tasks and timelines will help prioritize and mitigate risk. Resources include the people, systems, and outside vendors to support the business processes.  

High level tasks associated with the IND submission include: 

• Author, review and approve the content for the ICH 5 modules and sections of the IND. This is typically done inside a RIM system.  
• Prepare the PDF content for electronic submissions 
• Publish into the eCTD format. Note that eCTD is currently in transition to Version 4.0. Learn more about 4.0 here.  
• Dispatch to the FDA 
• Archive the submission at the sponsor   

FDA and ICH both provide guidance on how the documents and content should be organized for the reviewers. Document templates are available with pre-built sections, tables, and headings to make your life even easier -  some templates are publicly available via academic institutions, but most have to be purchased. If you are considering purchasing a template package, be sure to ask how recently it was updated, what macros (if any) they require, and understand how to use the formatting. 

Content created for each section of the IND goes through several rigorous processes to ensure completeness and compliance. The first process is authoring creation, review, and approval. Typically, data from animal studies, for example, are compiled in large datasets and analyzed. Content is written from the data and captured in tables, graphs, and listings. Each of these data points must be correlated and checked to ensure accuracy. Once the content is approved by the internal team at the sponsor site, the second process of preparing the documents for regulatory publishing commences.  Word documents are converted to PDF, internal hyperlinks and TOCs are built. Regulatory publishing software is required to create the eCTD submission package inclusive of cross document hyperlinks and the XML backbone. The submission package is uploaded to FDA via the ESG gateway.¹²   The gateway provides a couple of acknowledgements verifying receipt of the submission. Submissions are filed and kept at sponsor sites. If the FDA has any questions, the sponsor needs to quickly refer to the submission and respond.    

Below is a flow chart of an example process.

Resources include people, systems, and outside vendors to support the tasks above and the business processes to efficiently meet the submission goals. Examples of resources include:  

• CRO vendors for dataset creation and analysis, draft reporting, and writing. 
• Collaboration and EDMS solutions for authoring, reviewing and approving content. 
• Regulatory Operations publishing for eCTD submission creation, validation and ensuring PDF compliance. 

Planning a complete team of people and resources smooths the IND submission tasks and process. Having put the pieces together ahead of time, subject matter experts can focus on the science and messaging in the IND to ensure a successful start of clinical trials. 

A word about timelines...

IND timelines vary widely and depend on each sponsors’ program. Drug and biologic research products differ compositionally and as such producing manufacturing protocols do not compare. Outcomes from an FDA meeting could result in performing another non-clinical toxicology study which may add more time. Authoring reports is a cross functional exercise and if a critical subject matter expert is on vacation, the timelines may be delayed. In today's workplace, sponsors work with many vendors who are responsible for portions or all the data, testing and reports. Collaborating closely in a secure, quick, and compliant manner can eliminate delays in retrieving and checking the information. IND projects are usually kicked off within a 3–4-month window of the submission date, though we have certainly seen shorter timelines. Typically, once content is finalized and approved an IND totaling approximately 150-190 documents / around 1500 pages can be published and dispatched to the FDA in 4-6 weeks. 

My IND is with the FDA, now what? 

The FDA project manager receives the IND and assigns resources. The team has 30 days to review the application in its entirety.  FDA reviewers seek concise information supporting the sponsor’s ability to run a human trial safely and provide feedback on efficacy. From the CMC perspective, the agency expects to reduce risk to subjects by defined release testing standards and methods and adherence to Good Manufacturing Guidelines (GMP) for clinical products. 

FDA’s resources are inclusive of: 

• Clinical 
• Non-Clinical pharmacology 
• CMC (Chemistry, Manufacturing, and Controls)
• Clinical Pharmacology 
• Biostatistics 
• Clinical Microbiology 
• Microbiology-Sterility 

In addition to the subject matters above, the team will cross-reference comparable products previously submitted to FDA and data published in peer reviewed journals. 

During the thirty (30) day review period, the reviewer may respond at any time with an RFI (Request for Information). Sponsors must comply and respond in full to the request before moving forward with a trial. If reviewers have many questions or so much information is missing or under safety scrutiny, then the FDA will issue a clinical hold. Some divisions issue a “safe to proceed letter;” otherwise, if no response is received within the 30-day time period, then sponsor may begin the trial.  

Best Practices  

Applying for a new clinical trial is an exciting milestone for your company. Good planning will ensure the project runs smoothly. If this is your first IND, this is an opportunity to set the tone of your future relationship with the FDA. Taking advantage of the Pre-IND meeting engages the project manager and reviewer about the sponsors program and products.  

Best practices suggest sponsors work closely with the CRO, medical writers and internal teams using a collaboration/EDMS system to streamline the handoffs and processes to build efficiencies by delivering content on a rolling basis to the regulatory operations publishing vendor. 

Plan ahead, ask your colleagues, read the guidance documents and work with the FDA, and you'll be set up for success! 

For more guidance on IND Submissions, or any aspect of the regulatory process, reach out to our team. 

References 

1. Code of Federal Regulations. 21CFRpt 312- Regulation on when an IND is required. 
   https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312 
2. FDA Code 21 CFR 312.23 Content of an IND 
   https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312#312.23 
3. FDA Code 21 CRF 56 Institutional Review  
   Boards. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-56 
4. FDA Draft Guidance “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products” (December 2017) https://www.federalregister.gov/documents/2017/12/29/2017-28140/formal-meetings-between-the-food-and-drug-administration-and-sponsors-or-applicants-of-prescription 
5. FDA Guidance for IND Meetings for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information (May 2001) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ind-meetings-human-drugs-and-biologics-chemistry-manufacturing-and-controls-information
6. FDA IND Applications for Clinical Investigations: Chemistry, Manufacturing, and Control (CMC) Information; https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-applications-clinical-investigations-chemistry-manufacturing-and-control-cmc-information 
7. FDA: IND Applications for Clinical Investigations: Clinical Protocols; https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-applications-clinical-investigations-clinical-protocols 
8. FDA Requesting a Pre-Assigned Application number; https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/requesting-pre-assigned-application-number 
9. FDA eCTD Resources. https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ectd-resources 
10. FDA IND Receipts https://www.fda.gov/drugs/ind-activity/ind-receipts 
11. FDA Forms and Instructions https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-forms-and-instructions 
12. E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1); https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e6r2-good-clinical-practice-integrated-addendum-ich-e6r1 
13. Milstein, J. Lwin, E., “How to put together an IND application.” Lecture presented at FDA Clinical Investigator Training Course. 2018. 
14. FDA Gateway Page: https://www.fda.gov/industry/electronic-submissions-gateway; https://www.fda.gov/industry/about-esg/esg-submission-process.  
15. FDA: Interactions with The Office of Therapeutic Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/interactions-office-therapeutic-products 
16. FDA : Frequently Asked Questions: Breakthrough Therapies. https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/frequently-asked-questions-breakthrough-therapies 
17. “Demystifying the Investigational New Drug (IND) Application for Drugs and Biologics” video. US Food and Drug Admin. Bugin, Kevin. Office of New Drugs. CDER. REdI Conference-Spring 2018.