Investigational New Drug (IND) Investigational Device Exemption (IDE)
The IND is a document that must be submitted to the FDA to obtain permission to ship an investigational drug or biologic via interstate commerce to start clinical trials. The IDE is a similar document that is required to start studies with an investigational device. INDs are usually filed by BioPharm company or research organization but an individual investigator can also obtain an IND.
A drug is considered to be “investigational” if it has not been approved for marketing by the FDA. An IND is required for studies of any unapproved drug and an IND may also be required for an “approved” drug which is going to be studied for a new indication, a new route of administration, a new dose level, or a new patient population. Note: We will generally use the term “drug” and “IND” in this section, but the steps for a biologic or medical device are similar.
The IND includes information about the formulation and manufacturing of the compound. It also includes summaries of the preclinical studies (chemistry, animal pharmacology, pharmacokinetics, and toxicology) that have been completed. Most US INDs require multiple dose animal toxicology studies in two mammalian species (one in rodents, one in a non-rodent species) of at least 2 weeks duration. The IND must also describe any international clinical trials and any marketing experience with the drug. The IND outlines the investigational plan for the compound including the protocol for the first study; the Investigator’s Brochure; and information about the Principal Investigator and the IRB that will oversee the initial clinical study.
The IND is a complex document that requires input from many sources. Usually a company will have a pre-IND meeting or teleconference with the FDA to discuss the information will be submitted in the IND. If the company and the FDA agree what studies must be completed and agree on the clinical study design, the chances for obtaining an IND are bolstered.
A Regulatory Director or a Regulatory Consultant usually assembles the team that will prepare the the FDA meeting and will prepared the IND. The team includes usually includes representatives from Pharmacology and Toxicology, Manufacturing and Clinical. A medical writer may be brought in to finalize the document. In a medium-size or large company, team members will usually be company employees; in smaller companies, some of these roles may be filled by outside consultants. The draft of the IND document usually undergoes extensive review by the team members and their supervisors as well as review by the company's Executive team and Legal Department or advisors.
Filing an IND or IDE is a major step for a BioPharm company. It tells the world that you think a compound in your pipeline has enough promise to start clinical studies. It also says you think you have organized the information well enough to meet FDA requirements; that you have adequate resources to fund and conduct the study; and that your investigator and an IRB have reviewed your plans and they agree that it is acceptable to expose humans to the drug or device.
When the FDA receives your IND application, they will assign you an IND number. You will use this IND number to identify drug and your development program until the drug is approved or until you withdraw the IND. You will put the IND number on all your protocols and on every report that you file to the FDA about this drug. Every time you complete a study (human or non-human), draft a new protocol, or produce and analyze a new batch of drug, you send a copy of the data to the FDA and it is filed under your IND number. Each of these reports is submitted using an FDA form 1571 as a cover page. The IND submissions will be numbered sequentially; your initial IND submission will be 0000, the next will be 0001, etc.
The FDA has 30 days to review your IND application. If they think your application is inadequate or that your clinical study is not acceptable, they can put your IND on hold. If you are put “on hold,” you cannot start any clinical studies until you correct any problems that have been identified and the FDA agrees that you can start. The FDA does not send you a formal IND approval letter. You can start your studies after 30 days if the FDA does not inform you of a clinical hold.
There are actually several types of INDs which we will discuss in more detail below.
The following outlines the contents of a standard commercial IND that would be submitted by a pharmaceutical or biotech Sponsor to start their first US clinical studies.
Contents of IND Application
1. Form FDA 1571
2. Table of Contents
3. Introductory Statement
4. General Investigational Plan
5. Investigator's Brochure
6. Study Information
a. Study Protocol
b. Investigator Data/ Facilities Data
c. IRB data
7. Chemistry, Manufacturing and Control Data
a. Environmental Assessment or Claim for Exclusion
8. Pharmacology and Toxicology Data (Toxicology data is usually obtained from two mammalian species)
9. Previous Human Experience, if any (This should include any ex-US clinical trials and/or marketing experience)
10. Additional Information
a. Special Topics e.g. potential for abuse
Other types of INDs
Exploratory IND
The concept of Exploratory INDs was introduced by the FDA in 2005. An exploratory IND is a request to conduct very short term studies in humans to obtain preliminary pharmacologic or pharmacokinetic data to assist in selecting a product for further development. These studies are usually conducted very early in Phase I; some call these “Phase 0” studies. These studies involve very limited human exposure (up to 7 days of dosing) and they have no therapeutic intent. They are often used to choose a lead compound. For example, a company may have identified several investigational drugs that share a common biologic target. It would be inefficient to develop all of these compounds so the company needs to select the most promising candidate for further development. Under an Exploratory IND, the company can conduct exploratory studies on up to 5 compounds to evaluate mechanisms of action (e.g. binding properties or enzyme inhibition), biodistribution, and/or pharmacokinetics.
A microdose is defined as less than 1/100th of the dose calculated to yield a pharmacological effect up to a total dose of <100 micrograms. Up to 7 daily doses of the drug may be administered. The combination of short term dosing and the use of microdoses is thought to limit the risks to the healthy volunteers or minimally ill patients who will be enrolled in the study. The goal of an Exploratory Study is to achieve a pharmacological response but not to reach a MTD (maximum tolerated dose).
The amount of toxicology data required for an Exploratory IND is usually less than that required for a standard IND. Toxicology requirements usually include a 14-day study in one mammalian species (usually rat) using the clinical route of administration plus a repeated dose study in second species (e.g. dog) at rat NOAEL with administration equivalent to number of dosing days in the exploratory clinical trial. Identification of the minimally toxic dose is not required. These studies must be done for each drug that will be evaluated in the Exploratory IND.
There are several FDA Guidance Documents or other links that can help you understand how to organize the contents of an IND and even to decide whether or not you need an IND for your studies.
Guidance for Industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well Characterized, Therapeutic, Biotechnology-derived Products
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm074980.pdf
Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078933.pdf
Guidance for Clinical Investigators, Sponsors, and IRBs Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND
http://www.fda.gov/downloads/drugs/guidances/ucm229175.pdf
Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm107434.htm
Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators Guidance for Industry DRAFT GUIDANCE
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM446695.pdf
Guidance for Industry Q & A Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM078928.pdfwww.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078928.pdf
Expanded Access to Investigational Drugs for Treatment Use — Questions and Answers Guidance for Industry U.S. Department of Health and Human
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm351261.pdf
The IND is a document that must be submitted to the FDA to obtain permission to ship an investigational drug or biologic via interstate commerce to start clinical trials. The IDE is a similar document that is required to start studies with an investigational device. INDs are usually filed by BioPharm company or research organization but an individual investigator can also obtain an IND.
A drug is considered to be “investigational” if it has not been approved for marketing by the FDA. An IND is required for studies of any unapproved drug and an IND may also be required for an “approved” drug which is going to be studied for a new indication, a new route of administration, a new dose level, or a new patient population. Note: We will generally use the term “drug” and “IND” in this section, but the steps for a biologic or medical device are similar.
The IND includes information about the formulation and manufacturing of the compound. It also includes summaries of the preclinical studies (chemistry, animal pharmacology, pharmacokinetics, and toxicology) that have been completed. Most US INDs require multiple dose animal toxicology studies in two mammalian species (one in rodents, one in a non-rodent species) of at least 2 weeks duration. The IND must also describe any international clinical trials and any marketing experience with the drug. The IND outlines the investigational plan for the compound including the protocol for the first study; the Investigator’s Brochure; and information about the Principal Investigator and the IRB that will oversee the initial clinical study.
The IND is a complex document that requires input from many sources. Usually a company will have a pre-IND meeting or teleconference with the FDA to discuss the information will be submitted in the IND. If the company and the FDA agree what studies must be completed and agree on the clinical study design, the chances for obtaining an IND are bolstered.
A Regulatory Director or a Regulatory Consultant usually assembles the team that will prepare the the FDA meeting and will prepared the IND. The team includes usually includes representatives from Pharmacology and Toxicology, Manufacturing and Clinical. A medical writer may be brought in to finalize the document. In a medium-size or large company, team members will usually be company employees; in smaller companies, some of these roles may be filled by outside consultants. The draft of the IND document usually undergoes extensive review by the team members and their supervisors as well as review by the company's Executive team and Legal Department or advisors.
Filing an IND or IDE is a major step for a BioPharm company. It tells the world that you think a compound in your pipeline has enough promise to start clinical studies. It also says you think you have organized the information well enough to meet FDA requirements; that you have adequate resources to fund and conduct the study; and that your investigator and an IRB have reviewed your plans and they agree that it is acceptable to expose humans to the drug or device.
When the FDA receives your IND application, they will assign you an IND number. You will use this IND number to identify drug and your development program until the drug is approved or until you withdraw the IND. You will put the IND number on all your protocols and on every report that you file to the FDA about this drug. Every time you complete a study (human or non-human), draft a new protocol, or produce and analyze a new batch of drug, you send a copy of the data to the FDA and it is filed under your IND number. Each of these reports is submitted using an FDA form 1571 as a cover page. The IND submissions will be numbered sequentially; your initial IND submission will be 0000, the next will be 0001, etc.
The FDA has 30 days to review your IND application. If they think your application is inadequate or that your clinical study is not acceptable, they can put your IND on hold. If you are put “on hold,” you cannot start any clinical studies until you correct any problems that have been identified and the FDA agrees that you can start. The FDA does not send you a formal IND approval letter. You can start your studies after 30 days if the FDA does not inform you of a clinical hold.
There are actually several types of INDs which we will discuss in more detail below.
- Standard or commercial IND
- Exploratory IND
- Investigator IND
- Emergency IND
- Treatment IND
The following outlines the contents of a standard commercial IND that would be submitted by a pharmaceutical or biotech Sponsor to start their first US clinical studies.
Contents of IND Application
1. Form FDA 1571
2. Table of Contents
3. Introductory Statement
4. General Investigational Plan
5. Investigator's Brochure
6. Study Information
a. Study Protocol
b. Investigator Data/ Facilities Data
c. IRB data
7. Chemistry, Manufacturing and Control Data
a. Environmental Assessment or Claim for Exclusion
8. Pharmacology and Toxicology Data (Toxicology data is usually obtained from two mammalian species)
9. Previous Human Experience, if any (This should include any ex-US clinical trials and/or marketing experience)
10. Additional Information
a. Special Topics e.g. potential for abuse
Other types of INDs
Exploratory IND
The concept of Exploratory INDs was introduced by the FDA in 2005. An exploratory IND is a request to conduct very short term studies in humans to obtain preliminary pharmacologic or pharmacokinetic data to assist in selecting a product for further development. These studies are usually conducted very early in Phase I; some call these “Phase 0” studies. These studies involve very limited human exposure (up to 7 days of dosing) and they have no therapeutic intent. They are often used to choose a lead compound. For example, a company may have identified several investigational drugs that share a common biologic target. It would be inefficient to develop all of these compounds so the company needs to select the most promising candidate for further development. Under an Exploratory IND, the company can conduct exploratory studies on up to 5 compounds to evaluate mechanisms of action (e.g. binding properties or enzyme inhibition), biodistribution, and/or pharmacokinetics.
A microdose is defined as less than 1/100th of the dose calculated to yield a pharmacological effect up to a total dose of <100 micrograms. Up to 7 daily doses of the drug may be administered. The combination of short term dosing and the use of microdoses is thought to limit the risks to the healthy volunteers or minimally ill patients who will be enrolled in the study. The goal of an Exploratory Study is to achieve a pharmacological response but not to reach a MTD (maximum tolerated dose).
The amount of toxicology data required for an Exploratory IND is usually less than that required for a standard IND. Toxicology requirements usually include a 14-day study in one mammalian species (usually rat) using the clinical route of administration plus a repeated dose study in second species (e.g. dog) at rat NOAEL with administration equivalent to number of dosing days in the exploratory clinical trial. Identification of the minimally toxic dose is not required. These studies must be done for each drug that will be evaluated in the Exploratory IND.
There are several FDA Guidance Documents or other links that can help you understand how to organize the contents of an IND and even to decide whether or not you need an IND for your studies.
Guidance for Industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well Characterized, Therapeutic, Biotechnology-derived Products
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm074980.pdf
Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078933.pdf
Guidance for Clinical Investigators, Sponsors, and IRBs Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND
http://www.fda.gov/downloads/drugs/guidances/ucm229175.pdf
Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm107434.htm
Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators Guidance for Industry DRAFT GUIDANCE
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM446695.pdf
Guidance for Industry Q & A Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM078928.pdfwww.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078928.pdf
Expanded Access to Investigational Drugs for Treatment Use — Questions and Answers Guidance for Industry U.S. Department of Health and Human
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm351261.pdf