Investigational New Drug Application Basics

The investigational new drug application is the doorway to selling biologics and drug products for biotech companies.

What is an IND?

An Investigational New Drug (IND) application is the method by which drug and biologics developers (sponsors) request permission from the Food and Drug Administration (FDA) to test their product in humans. The FDA’s goal is to protect human test subjects during clinical trials. Successful IND applications demonstrate a reasonably low level of risk to human subjects as well as the sponsor’s commitment to the health and safety of their study participants. 

What are CDER and CBER?

The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are the FDA centers that determine whether or not drugs and biologics, respectively, may be marketed to humans.

CDER began as the Drug Laboratory in 1902, which worked to standardize pharmaceutical agents and detect adulterated drugs. By 1908, after the passage of the Pure Food and Drugs Act, the laboratory was reorganized and renamed the Drug Division. In 1938 the Food, Drug and Cosmetics Act required that drugs be tested for safety before they could legally be marketed. Over the following decades, the Drug Division underwent numerous reorganizations.

CBER also started in 1902, as new responsibilities were added to the Hygienic Laboratory of the Public Health and Marine Hospital Service following the death of 13 children that were mistakenly treated for diphtheria with a tainted biologic. The deaths spurred Congress to pass the Biologics Control Act, to increase the safety of products made from living organisms used in a medical capacity. The Hygienic Laboratory began issuing licenses to manufacturers of vaccines, antitoxins, and serums. The Hygienic Laboratory became the National Institutes of Health in 1930, and kept the responsibility for licensing biologics until 1972, when it was transferred to the FDA.

In 1982, the responsibilities for controlling both drugs and biologics were merged into a single entity, the National Center for Drugs and Biologics (NCDB). This lasted for five years until 1987 when the NCDB was split into CDER and CBER due to the volume of applications it was receiving. CDER and CBER have continued to undergo reorganizations to handle changing volumes of submissions and advances in science, which have necessitated bringing different applications in front of different reviewers. The goal of these organizations has remained, however, to promote public health.

How to Apply for an IND

The IND is used by both CDER and CBER to evaluate whether a drug or biologic is safe for human use. IND applications can be quite long due to the vast amount of information they have to contain. The goal of an IND application is to convince the FDA that the drug or biologic you are investigating does not pose an unreasonable risk to humans.

There are requirements for the types of data that must be included, but the FDA will not and cannot tell you exactly what they want to see, as the drug is “new” and you, the developer, should be the expert on its effects. This is why many first-time IND applicants (and even experienced IND applicants) will hire a consultant or even a regulatory affairs professional as a full-time employee when it comes time to apply. Experts in regulatory affairs can help decipher the FDA’s requirements and how those should be translated into a complete IND application.

Here we will cover the requirements for an IND submission and what they generally should include, though these are approximations as a new drug or biologic may require additional information to convince the FDA of its safety.

IND Requirements

Cover Letter

Used by the FDA to decide where to route the application

Must include:

• Submission identifier: “Initial Investigational New Drug Application.”
• Type and title of the study.
• Name of the new drug product and the proposed formulation.
• The disease or condition being investigated.
• The name and contact information of the drug’s manufacturer, if applicable.
• Any applicable reference to an existing IND application.

Form 1571

• Administrative information such as name of sponsor, name of drug, etc. 

Form 1572

• Statement of investigator--investigator provides information about their qualfications, signs to agree that he/she will follow rules like using an IRB, etc.

Form 3674

• This form is for certification of compliance with the clinicaltrials.gov data bank.

Table of Contents

• For the convenience of the FDA reviewers, so it should help them locate items easily.

Introductory Statement and General Investigational Plan

• This section is usually between 2 and 3 pages long.
• The purpose is to help the FDA understand the future needs of the drug program by giving an overview of the clinical development plan. If the developmental plan depends on too many future factors to be detailed in the IND, the sponsor should state this.

Chemistry, Manufacturing, and Control Information

Drug Substance

• This section should describe the characteristics, including biological, physical, or chemical properties of the active pharmaceutical ingredients.
• Manufacturer’s name and address.
• General description of the method of preparing the drug substance including the reagents used. The easiest way to provide this description is to create a flow chart detailing the process.
• How the substance will be tested to ensure quality control, and what constitutes the acceptable limits. The test methods should also be briefly described here.
• Information showing that the drug substance is stable during storage.

Drug Product

• This section must list all of the components used in the manufacturing process. It should also include alternative options for any inactive compounds. Both components which will be included in the drug product as well as components that are used in the manufacturing process but which are not designed to be in the final product should be listed.
• The sponsor must summarize the quantitative composition of the drug product as well as the variations expected to be seen in the early investigations.
• Include a flow diagram of the manufacturing process and packaging process, plus any tests that may be conducted. This should also list the final specifications of the drug product.
• How the drug product will be analyzed and what the limits are to make sure the identity, strength, quality, and purity are correct.
• The acceptable limits and analytical methods used to ensure the drug product’s identity, strength, quality, and purity.
• Information about the stability of the drug product during storage for the clinical trials.

Placebo Formulation

• If a placebo will be used in the study, this section should include a brief description of its composition, manufacturing process, and controls.

Labeling

• This section should include copies of the labeling of the drug product.

Environmental Assessment

• The effects of the product on the environment should be assessed here and can be obtained from the manufacturer. (Most products will qualify to be excluded from the environmental assessment.)

Pharmacology Toxicology Information

Pharmacology and Drug Disposition

• The pharmacological effects and the mechanism of the drug as seen in animals should go in this section, as well as information on its absorption, distribution, metabolism, and excretion.

Toxicology

• This section should include fully tabulated data on the toxicological effects of the drug product on animals and in vitro. The test results may include acute and chronic toxicity, reproductive effects, specific toxicity related to the drug’s administration or conditions (lung tests for inhaled products), and in vitro toxicity studies.

Investigator’s Brochure

This can be obtained from the drug manufacturer.

Must include:

• Description of the drug substance and formulation.
• Summary of known pharmacological and toxicological effects in animals and humans (to the extent known).
• Summary of pharmacokinetics and biological disposition in animals and humans (to the extent known).
• Summary of safety and efficacy information in humans if there were prior clinical studies.
• Any possible risks and side effects based on prior experience with this drug or with related drugs; precautions to be taken as part of the investigation.

Clinical Protocols for Phase 1 Trials

• Include specific details of all the elements of the study that are important for safety, such as clinical safety assessments, toxicity monitoring, stopping rules for toxicity, dose adjustment rules, and adverse event recording/reporting.
• Consider the following when writing study enrollment criteria: 1)risks associated with the disease or condition, 2) existing information about the toxicity of the drug in animal or human studies, and 3) for approved products being investigated for off-label uses, any warnings and precautions on the label.
• Toxicity assessment and adverse event collection should both be reported in consistent manners.

Summary of Previous Human Experience with the Drug

• If the drug has previously been used in humans, it must be reported in the IND application. However, the format is not standardized. The following should be considered when writing the summary.
• If the drug has never been used in humans, this should be stated in this section of the IND application.
• If the drug under investigation has been studied or marketed previously, information about its safety should be detailed in this section, such as clinical trial data and publications reporting on safety. This includes drugs that were marketed or investigated in other countries.
• The countries where the drug was marketed should be listed, and the reasons given if the drug was withdrawn from any markets.
• If the drug product in question is also the subject of another IND application, a Letter of Authorization from the existing IND’s sponsor may allow the existing IND’s human experience data to be referenced. 
• In the case of a combination of previously used drugs in humans, data from all of the active components should be included. For components that have been approved for marketing, a copy of the leaflet containing prescribing information is usually enough, unless there is other published information pertaining to the proposed investigational use in the current IND application.

Additional Information

• Some drugs may require extra information, such as in the case of potentially addictive substances, radioactive drugs, or pediatric studies.

Pre-IND meeting

In 1988, the Office of Antimicrobial Products (OAP), now called the Office of Infectious Diseases (OID), started the practice of holding meetings between potential sponsors and regulators before the IND application submission. 

Pre-IND meetings have become a recommended practice for other divisions, as well. However, they are not required and thus not a formalized practice with an easily discoverable list of requirements. Instead, IND sponsors are encouraged to ask the division they are applying to for a “Type B” meeting via written request, about 2 months before the desired date of the meeting. Most pre-IND meetings will be allotted 60 minutes. The following should be included in the meeting request:

• Name of the product.
• Application number, if applicable.
• Name and structure of the chemical.
• Proposed indication for the product.
• Type of meeting being requested.
• Proposed agenda for the meeting including how much time you expect to need to discuss each agenda item.
• Brief statement of the objectives of the meeting including any background needed to understand the issues being proposed for the meeting. This may include studies or clinical trials (planned or completed).
• List of the proposed questions for the meeting, separated by discipline, including the context and reason you are asking each question.
• List of all people attending the meeting on behalf of your company including their titles and affiliations.
• List of the specific FDA staff or disciplines you’d like to have participate in the meeting.
• Suggested meeting dates and times, from 60 days in the future and beyond. Include dates and times that do not work, also.
• Propose a format for the meeting, whether via tele-conference, video-conference, or written feedback. If the FDA determines that written feedback is the most appropriate, they may choose that format even if you request another.
• The (approximate) date when you will send them the briefing document.

The FDA will respond within 21 days whether they will grant your meeting or not. If they grant your meeting, you must prepare a briefing document that provides enough information to the FDA about your product for them to answer your proposed questions and send it to them well in advance of the meeting. They will give preliminary responses to your questions 2-3 days before the scheduled meeting.

Each IND application only gets one pre-IND meeting, so if you decide to take advantage of it, make sure to prepare sufficiently beforehand. Especially with a 60-minute time limit, you must be sure that your team knows what they are going to say.