Research involving a drug or biologic that has not yet reached the marketplace or that studies a new use of the marketed product requires an IND (21CFR 312). A sponsor develops a research protocol, which is then evaluated by the Food and Drug Administration. A sponsor can be a drug company, a cooperative group, or even an individual physician. After careful review, the FDA will allow human studies to proceed if it determines that the risk of exposure to the drug is reasonable. This determination is based upon:

• Data from prior animal or human testing.
  
• Methods of manufacturing.
  
• Plans for testing and reporting significant toxicities.
  
• A well-developed clinical research plan that minimizes risks to the subjects.

Investigators may want to use an approved product in the context of clinical studies. When the principal intent of the investigational use of the product is to develop information about safety or efficacy, an IND may be required. However the clinical investigation of a marketed drug does not require an IND if the following conditions are met:

• The data will not be used to support a new indication, new labeling, or change in advertising.
  
• The research does not involve a route of administration/dosage level or subject population that significantly increases the risks of the drug product.
  
• The research is conducted in compliance with IRB review and informed consent requirements.
  
• The research is conducted in compliance with requirements for promotion and sale.

(21CFR312.2(b))

Exemption from IND submission requirements does not mean exemption from IRB review and approval or from informed consent from subjects. The FDA should be consulted if there are any changes.

• Investigators participating in drug and biologic studies subject to the IND regulations MUST sign Form 1572. (FDA Form 1572; this link will launch a new browser window)
  
• Form 1572 outlines the commitments that must be made by the investigator(s) regarding the conduct of the study.
  
• Form 1572 must list co-investigators who will be administering the drug or separate forms need to be submitted for these individuals.
  
• Form 1572 must list the IRB of record for that study site.

Good medical practice and the best interests of a patient require that physicians use legally available drugs, biologics, and devices according to their best knowledge and judgment. If physicians use products for an indication not listed in the approved labeling, they have the responsibility to be well informed and to base the proposed use on scientific rationale and medical evidence.

Use of a marketed product in this manner when the intent is practice of medicine does not require the submission of an IND or IDE. However, an individual institution may under its authority require oversight for this practice such as review by a Medical Practice or Pharmaceutics and Therapeutics Committee (21CFR312.2(d)).

A significant risk device presents a potential for serious risk to the health, safety, or welfare of the subject and it:

• Is intended to be implanted into a human;
  
• Is used in supporting or sustaining human life;
  
• Is of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise prevents impairment of human health;
  or
  
• Otherwise presents serious risk to health, safety, and welfare of a subject.

(21CFR812.3(5)(m))

The sponsor must submit an IDE application to the FDA (21CFR812.20). There is no specific form for this purpose, but the regulations list elements required in the application. The trial cannot begin until FDA grants an IDE and the IRB grants approval for the study. By definition, a study with a significant risk device poses more than minimal risk to the human subjects and requires full IRB review.

A non-significant risk device, by default, does not meet the criteria of significant risk. It is considered to have an approved IDE application (i.e., no application is filed with the FDA), and is studied without FDA oversight if the sponsor complies with certain FDA requirements such as monitoring, record-keeping, and properly labeling the investigational device. The IRB must agree that the study meets the criteria for non-significant risk. The clinical trial of a non-significant risk device requires IRB approval, informed consent, and proper study monitoring and it must meet all other regulatory compliance requirements.

Elements of informed consent are found in the FDA regulations at 21 CFR 50.25.

Elements of informed consent are found in the regulations at 21 CFR 50.25

The FDA 21 CFR 50.23 and 21 CFR 50.24 provide exceptions to the requirement for informed consent under certain circumstances:

• In situations where requirements for exception from informed consent are met for emergency research (21 CFR 50.24).
  
• In life-threatening conditions involving an individual subject where requirements for an exception from informed consent are met. More specifically, FDA regulations (21 CFR 50.23) permit exception for informed consent in life-threatening situations where:
  
  1. The investigator, with the concurrence of another physician, believes the situation for the human subject is life-threatening and necessitates the use of a test article (i.e., an investigational drug, device, or biologic).
     
  2. The subject and/or legally authorized representative is unable to communicate consent. The FDA indicates that a Legally Authorized Representative is "An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research."
     
  3. There is insufficient time to obtain consent.
     
  4. No alternative exists that will provide an equal or better chance of saving the subject's life.

The FDA allows waiver of written informed consent:

• When study participation presents minimal risk of harm to the subject
• And when the research involves no procedures requiring consent outside the context of participation in a research study.
  

The IRB may require the investigator to provide the subject with written materials about the research. (21CFR56.109)

Investigators and IRBs may be confronted with the need to use an unapproved investigational drug or device in an emergency situation. In these circumstances, review by a full IRB may not be feasible because of the emergent nature of the problem. When this happens attention must be given to the IND/IDE requirements, informed consent, and IRB procedures. Please note that regulations exist-21 CFR 50.23-for unplanned emergency use (Regulations also exist for "planned" emergency research and can be found at 21 CFR 50.24).

Emergency use is the use of an investigational drug or device with a human subject in a life-threatening situation or in which no standard acceptable treatment is available and there is not sufficient time to obtain IRB approval. Life-threatening means that the likelihood of death is high unless an intervention interrupts the process. It also applies to a condition that is immediately and severely debilitating and that causes irreversible morbidity such as blindness or paralysis. (21CFR56.102(d))

Sponsor Responsibilities

Investigator responsibilities include:

• Ensuring IRB approval for the study is obtained before any subjects are enrolled.
  
  
• Ensuring that informed consent is obtained in accordance with FDA regulations.
  
  
• Ensuring that the investigation is conducted according to the investigational plan and applicable regulations.
  
  
• Administering the drug or using the device only in subjects under the investigator's supervision or under the supervision of a recognized sub-investigator.
  
  
• Maintaining adequate records of the dispensation of the drug or device.
  
  
• Returning unused materials at the end of trial.
  
  
• Preparing and maintaining adequate case histories and signed informed consent documents.
  
  
• Maintaining correspondence with the IRB and the sponsor to make sure that both have reviewed protocol amendments, recruitment materials, investigator brochures.
  
  
• Retaining records in accordance with regulations.
  
  
• Providing progress, safety, final and financial disclosure reports.
  
  
• Notifying the sponsor if IRB approval is withdrawn.
  
  
• Comply with International Conference on Harmonization (ICH) guidelines, if applicable. See Conference on Harmonization for ICH guidance (this will launch a new browser window).

The Bioresearch Monitoring Program of the FDA conducts routine, "not for cause," and "for cause" audits of IRBs, clinical investigators, and sponsors. The purpose of this monitoring is to ensure the quality and integrity of data submitted to FDA for regulatory decisions and to protect human subjects. The FDA may conduct on-site reviews of IRBs, research sites, pharmacies, manufacturing sites, etc. The FDA may also inspect, review, and copy records associated with the research.

Revised 09-12-05