Section 10: Research with Investigational Drugs
If a proposed research activity involves evaluation of an investigational drug or biological material in humans or before a Food and Drug Administration (FDA)-approved drug can be used for unapproved indications, the sponsor or researcher may need to obtain an FDA Investigational New Drug Exemption (IND). Whenever possible, the IND should be obtained prior to review by the IRB.
It is critical that the Principal Investigators (PI) understand that by obtaining and holding an IND they assume sponsor and investigator responsibilities for the conduct of the research as described in 21 CFR 312.
If research involves the use of a food, nutritional or food supplement that might fit the FDA definition of a “drug,” the IRB Program Coordinators will review the protocol to determine whether the research involves the use of a drug as defined by FDA. Generally, bioavailability and bioequivalence studies are exempt from the IND requirements.
The FDA defines a drug as:
- An article recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and
- An article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and
- An article (other than food) intended to affect the structure or any function of the body of man or other animals; and
- An article intended for use as a component of any article specified in the numbered statements 1, 2 and 3 above.
If required, IND numbers are usually obtained by the study sponsor and can usually be found on the sponsor protocol. PIs should confirm that the number is either on the protocol, in some form of communication from the sponsor or in a letter from the FDA to the sponsor. The IRB primary reviewer for the study will expect to find and will verify existence of an IND from one of these sources. If the PI of the study holds the IND then a copy of the communication from the FDA noting the IND number should accompany the protocol submission.
When completing the application, the PI will be asked to provide a copy of the research and informational materials generated by the drug company, if applicable. The storage, preparation and dispensing of investigational drugs should be described in the protocol.
Biological products subject to licensure may also be considered drugs within the definition. A dietary supplement may also fit the definition of a drug, in which case research activities with dietary supplements should be considered under the numbered statements 1 and 2 above. If the intended research with a dietary supplement is to evaluate its use under statement 3 above, it is not considered a drug, and the study is not FDA-regulated and will not require an IND.
An FDA-regulated study is a study in which a PI uses a drug in one or more persons and the drug is not an approved drug in the course of medical practice and/or the data collected in the study is intended to be submitted to or held for inspection by the FDA.
Some examples are:
- A psychology professor gives people ginkgo biloba to look at its effects on learning or memory.
- As part of student lab, a biology professor gives a student an aspirin and other students collect blood and urine to demonstrate the first order kinetics of aspirin.
- A kinesiologist gives people caffeine to look at the effect of arm blood flow.
- The agriculture department has developed a genetically modified watermelon with high levels of vitamin A and wants to test if it can be used to treat vitamin A deficiency.
During initial review of a drug study, the IRB primary reviewer will determine whether the study has a valid IND by reviewing the sponsor protocol, communication from the sponsor or a letter from the FDA to the sponsor. If there is no IND, the primary reviewer will determine if the study meets one of the exemptions from the requirement to have an IND.
While IND numbers are generally required for drug studies there are several possible FDA exemptions from this requirement listed in 21 CFR 312.2(b). PIs should submit documentation to support an exemption and may contact an FDA consumer safety officer for confirmation that the investigation fits one of the exemptions.
10.2.1 For Exemption under 21 CFR 312.2(b)(1)
To qualify for this exemption, the study must meet all of the following:
- The drug is lawfully marketed in the United States. (Sponsors or sponsor-investigators are allowed to make low-risk modifications to the lawfully marketed dosage form, i.e., changing the color, scoring or capsule, or the size of the dosage.)
- The investigation is not intended to be reported to the FDA as a well-controlled study in support of a new indication for use nor is it intended to be used in support of any other significant change in the labeling for the drug.
- If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in advertising for the product
- The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks or decreases the acceptability of the risks associated with use of the drug product.
- The investigation will be conducted in compliance with the requirements for institutional review as set forth in 21 CFR Part 56 and with the requirements for informed consent as set forth in 21 CFR Part 50.
- The investigation will be conducted in compliance with 21 CFR 312.7 which restricts promotion, commercial distribution or charging for the drug or undue prolongation of the study.
10.2.2 For Exemption under 21 CFR 312.2(b)(2)
To qualify for this exemption, the study must meet all of the following:
- The clinical investigation will involve an in vitro diagnostic biologic product that involves blood grouping serum, reagent red blood cells and/or anti-human globulin.
- The diagnostic test is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure.
- The diagnostic test will be shipped in compliance with 21 CFR 312.160 that delineates investigational labeling, assurance of shipment to an authorized user, record keeping and disposition of unused drugs.
10.2.3 For Exemption under 21 CFR 312.2(b)(3)
To qualify for this exemption, the study must meet the following:
The drug is intended solely for tests in vitro or in laboratory research animals if shipped in accordance with 21 CFR 312.160.
10.2.4 For Exemption under 21 CFR 312.2(b)(5)
To qualify for this exemption, the study must meet the following:
The clinical investigation involves use of a placebo and the investigation does not otherwise require submission of an IND.
10.2.5 Exemption for Bioavailability (BA) or Bioequivalence (BE) Studies
FDA regulations describe criteria under which BA/BE studies using unapproved versions of approved drug products can be conducted without submission of an IND. A BA/BE study in humans does not require an IND if all of the following are met:
- The drug product does not contain a new chemical entity (21 CFR 314.108), is not radioactively labeled, and is not cytotoxic.
- The dose (single dose or total daily dose) does not exceed the dose specified in the labeling of the approved version of the drug product.
- The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and the requirements for informed consent (21 CFR part 50).
- The sponsor meets the requirements for retention of test article samples (21 CFR 320.3(d)(1)).
10.2.6 Exemption for Studies using Stable Isotopes
When used for basic research purposes, cold (or stable) isotopes ordinarily present fewer safety concerns than radioactive isotopes. FDA does not intend to object to clinical investigations using cold isotopes of unapproved drugs being conducted without an IND, provided the following conditions were met:
- The research is intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a drug labeled with a cold isotope or regarding physicology, pathophysiology, or biochemistry.
- The research is not intended for immediate therapeutic, diagnostic, or preventive benefit to the study subject.
- The dose to be administered is known not to cause any clinically detectable pharmacologic effect in humans based on clinical data from published literature or other valid human studies.
- The quality of the cold isotope meets relevant quality standards.
10.2.7 Dietary Supplements
For studies with dietary supplements, if the clinical investigation is intended only to evaluate the dietary supplement’s effect on the structure or function of the body, an IND is not required.
However, if the clinical investigation is intended to evaluate the dietary supplement’s ability to diagnose, cure, mitigate, or prevent a disease, an IND is required under part 312.
10.3 Applying for and/or Filing an IND
An IND application should include the facts that satisfy the FDA that the agent may be justifiably administered to a human as proposed. If the PI wishes to apply for and hold an IND, they must give the FDA the information specified in "Notice of Claimed Investigational Exemption for a New Drug (IND),” Form FD-1571. Visit the FDA website for instructions for completing and submitting an IND:
After the submission of the IND, the sponsor (person or persons initiating the clinical trial) must wait 30 days before beginning clinical tests. The 30-day period can be extended if the FDA requires additional time for the sponsor to correct deficiencies.
10.4 Investigator Responsibilities
- Ensure that the clinical research is conducted according to the signed investigator statement for clinical investigations, the investigational plan and applicable regulations.
- Inform the subjects, or any persons used as controls, that the drugs/biologics are being used for investigational purposes. Include a statement in the consent form.
- Administer the study drug or biologic only to subjects under the investigator’s personal supervision or the supervision of a sub-investigator.
- Follow reporting requirements in Section 9 for problems that require prompt reporting.
- Do not supply the study drug or biologic to any person not authorized to receive it (patient or another investigator).
- Comply with all requirements regarding the obligations of clinical investigators and all other pertinent requirements of 21 CFR 312.
- Provide for control of drugs or biologics in accordance with 21 CFR 312.60.
- Maintain adequate records of the disposition of the study drug or biologic to include dates, quantity and use by subjects.
- Return any unused supply of study drug to the sponsor upon completion, suspension, termination or discontinuation of the clinical investigation. (21 CFR 312.59 and 312.62)
- Permit the FDA to have access to and copy and verify records or reports (generally not required to divulge subject names) made during the study. (21 CFR 312.68)
- If the investigational drug is subject to the Controlled Substances Act, take adequate precautions, including storage of the drug in a securely locked, substantially constructed cabinet or enclosure to which access is limited to prevent inappropriate distribution. (21 CFR 312.69)
- Read and understand information in the Investigator’s Brochure, including potential risks and side effects of the drug.
- As noted in Section 10.1 above, researchers who apply for and hold an IND are also subject to sponsor responsibilities.
- Comply with Section 21: Data and Safety Monitoring in Clinical Research.
10.4.2 Lead Investigator of a Multi-Center Study
When the PI is the lead investigator of a multi-site study, the PI must submit information to the IRB regarding the communication process between sites and the management of information obtained during the course of the study such as:
- Unanticipated problems involving risks to subjects or others.
- Interim results.
- Protocol modifications.
The IRB will evaluate the management plan as it relates to adequacy of the protection of subjects.
10.4.3 Additional Reporting Requirements
If the PI does not hold the IND and an external sponsor funds or supports the study, then the PI is responsible for notifying the sponsor of any serious adverse events or unanticipated problems. For any studies under FDA jurisdiction, it is the PI and/or sponsor’s responsibility to notify the FDA within 24 hours of any serious adverse events or unanticipated problems.
Similarly, if the study is a multi-site project and the unanticipated problem occurs at a site other than the University, then the sponsor (PI if they hold the IND) is required to inform researchers of unanticipated problems or reactions that occur at other sites. When PIs are informed of unanticipated problem(s) in sponsor safety memos or other correspondence, then the PI must notify the IRB as promptly as possible after receipt of the report from the sponsor
Note that notifying the IRB does not relieve the PI from their responsibility to notify the sponsor and/or FDA, as applicable.
10.5 Emergency Use of an Investigational Drug or Biologic –FDA-Regulated Studies
Since the University is not a medical campus nor does it perform industry sponsored clinical trials, there should never be an occasion to use this provision of the FDA regulations. If this changes in the future, specific policies and procedures will be established.
10.6 Registering Applicable Clinical Trials
All Applicable Clinical Trials with drugs or biological products subject to FDA regulation must, by law, be registered on http://www.ClinicalTrials.gov.