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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:
- Drug substance
- Drug product
- Placebo formulation, if applicable
- Labeling information for the labeled products relevant to the investigational drug; and
- 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:
- 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.
- 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:
- 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.
- CVs of investigators.
- Form 1572 signed by the investigators.
- Informed Consent and IRB Oversight.
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.
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 22.214.171.124. Single dose toxicity report to be “filed” in the 4.2.3 folder.
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 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:
- Non-Clinical pharmacology
- CMC (Chemistry, Manufacturing, and Controls)
- Clinical Pharmacology
- Clinical Microbiology
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.
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.
- Code of Federal Regulations. 21CFRpt 312- Regulation on when an IND is required.
- FDA Code 21 CFR 312.23 Content of an IND
- FDA Code 21 CRF 56 Institutional Review
- 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
- 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
- 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
- FDA: IND Applications for Clinical Investigations: Clinical Protocols; https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-applications-clinical-investigations-clinical-protocols
- FDA Requesting a Pre-Assigned Application number; https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/requesting-pre-assigned-application-number
- FDA eCTD Resources. https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ectd-resources
- FDA IND Receipts https://www.fda.gov/drugs/ind-activity/ind-receipts
- FDA Forms and Instructions https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-forms-and-instructions
- 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
- Milstein, J. Lwin, E., “How to put together an IND application.” Lecture presented at FDA Clinical Investigator Training Course. 2018.
- FDA Gateway Page: https://www.fda.gov/industry/electronic-submissions-gateway; https://www.fda.gov/industry/about-esg/esg-submission-process.
- FDA: Interactions with The Office of Therapeutic Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/interactions-office-therapeutic-products
- 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
- “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.
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.