Drugs, Biologics, and Devices: Regulations
The Food and Drug Administration (FDA) regulations apply to all clinical investigations that support applications for research or marketing permits for drugs, devices and biologics. 21 CFR §50.1.
IRB Member's Role
No clinical investigation as defined in Parts 312 and 812 of the Food, Drug and Cosmetic Act (Act), relating to INDs and IDEs, may begin without prior IRB approval and must be subject to continuing review. The only exception (relevant here) is the emergency use of a test article (discussed below).
Before approving a protocol, the FDA regulations require the IRB to determine that all of the following criteria are satisfied:
- Risks to subjects are minimized (sound research design, or use of approved treatment procedures when appropriate)
- Risks are reasonable in relation to benefits
- Selection of subjects is equitable
- Informed consent will be sought from subject or legally authorized representative (LAR) in accordance with Nevada State Law
- Informed consent is appropriately documented
- Appropriate data monitoring plan
- Adequate provisions to protect privacy of subjects and maintain confidentiality of data
- Additional safeguards in place for vulnerable populations
The IRB must also determine that the legally effective informed consent of the subject or the subject's legally authorized representative is obtained consistent with those elements outlined in the Common Rule for the informed consent document. The FDA regulations do not provide for a waiver of informed consent like the Common Rule. Two exceptions are emergency use and emergency research. Like the Common Rule, the FDA regulations allow for the waiver of documentation of informed consent.
The FDA may disqualify an IRB or a parent institution if it determines that an IRB has refused or repeatedly failed to comply with FDA requirements, and such noncompliance adversely affects the rights and welfare of subjects. 21 CFR §§56.120-56.121.
Like the Common Rule, the FDA regulations require the IRB to report to appropriate institutional officials and to the FDA: (1) serious noncompliance; (2) unanticipated problems involving risks to subjects or others; and (3) suspension or termination of IRB approval. 21 CFR §56.108.
Investigational New Drug Application
Before a new drug or biologic may be approved for marketing by the FDA, clinical investigations must be conducted to establish the safety and efficacy of the drug. Before such clinical investigations may begin, the drug manufacturer must obtain an IND. The IND permits the manufacturer to ship the drug for the purpose of the clinical investigation.
The IND may be submitted for one or more phases, which may overlap:
- Phase I: Initial introduction of drug into humans, designed to determine metabolism and pharmacologic actions.
- Phase II: Controlled clinical studies conducted to evaluate the effectiveness of drug for particular indication(s).
- Phase III: Expanded controlled and uncontrolled trials intended to gather additional information about effectiveness and safety. 21 CFR §312.21.
The clinical investigation of a new drug that is lawfully marketed in the US is exempt from the IND requirement if all of the following apply:
- The investigation is not intended to be reported to the FDA in support of a new indication for use or other significant change in labeling;
- The investigation is not intended to support a significant change in advertising;
- 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 acceptability of risks).
The manufacturer of an investigational drug may not charge subjects for the drug except with permission of the FDA.
No IND is required when a radioactive drug is used for "basic research". "Basic research" means research intended to obtain basic information regarding the metabolism of a radioactively labeled drug or regarding human physiology, pathophysiology, or biochemistry. The radioactive drug cannot be intended for immediate therapeutic, diagnostic, or similar purpose or to determine safety and efficacy of drug. Certain studies to determine whether the drug localizes in particular organ or fluid space and to describe the kinetics of that localization may have eventual therapeutic or diagnostic implications, but initial studies can still be basic research.
Investigational Device Exemption
The class of device determines what type of premarketing submission or application to the FDA is required before clearance to market:
- Class I: Very low risk devices that are generally exempt from FDA regulations (e.g. stethoscope).
- Class II: Moderate risk devices that are generally subject to "510K clearance" (e.g. implantable port). "510K clearance" means the device is "substantially similar" to a predicate device (one in commerce prior to May 28, 1976). 510(k) clearance is not FDA approval, but clears a device for marketing. 510(k) clearance is obtained by submitting a Premarket Notification to FDA. In some cases, clinical investigations will be used to support a 510(k) application, in which case an IDE is needed. An IDE is also needed if a clinical investigation uses a 510K cleared device inconsistent with its labeling.
- Class III: Higher risk devices that require Premarket Approval (PMA) (e.g. cardiac assist devices). Before the FDA will approve a PMA for a Class III device, clinical investigations are necessary to establish the safety and efficacy of the device. Before such clinical investigations may begin, the device manufacturer must obtain an IDE. The IDE permits the manufacturer to ship the device for the purpose of the clinical investigation. An IDE is also needed if an investigation uses an approved Class III device inconsistent with its labeling.
Some devices, even Class III, may qualify as "non-significant risk" (NSR) devices. A NSR device is considered to have an approved IDE and the investigator may begin the study without obtaining an IDE number from the FDA. The sponsor should make a NSR determination, but the IRB must agree before the investigator may begin the study. A NSR device is a device that does not meet the definition of "significant risk". "Significant risk" means a device that presents a potential for serious risk to health, safety or welfare of subject and:
- Is intended as an implant;
- Is purported or represented to be for a use in supporting or sustaining human life;
- Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health; or
- Otherwise presents a potential for serious risk to health, safety, or welfare of subject.
The following are exempt from the IDE requirement:
- A device that was in commercial distribution prior to May 28, 1976 when used consistent with labeling ("predicate device");
- A device in commercial distribution on or after May 28, 1976 that FDA has determined to be substantially equivalent to predicate device when used consistent with labeling ("510(k) clearance");
- A diagnostic device if the testing: (1) is noninvasive; (2) does not require an invasive sampling procedure that presents significant risk; (3) Does not by design or intention introduce energy into a subject; and (4) Is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure. 21 CFR §812.2(c).
The device manufacturer and investigator may not charge subjects for the device a price larger than necessary to recover costs of manufacture, research, development and handling.
In Vitro Diagnostic Devices
Studies that are exempt from the IDE requirements still need IRB review and informed consent of the subject. The FDA has decided to exercise enforcement discretion with respect to informed consent requirements for in vitro diagnostic devices. No informed consent is required if:
- Study uses leftover specimens not collected for this research;
- Specimens are not identifiable to investigator or sponsor;
- Individuals caring for patients are not part of research;
- IRB reviewed.
Expanded Access to Unapproved Drugs/Devices
Treatment IND/IDE: Use of unapproved drug/device in the treatment of patients not in a clinical trial. The purpose is to facilitate availability of promising new drugs/devices to desperately ill as early in device development process as possible. Investigator may collect safety and efficacy data. Need IRB approval, informed consent, and a treatment IND/IDE number from the FDA. Criteria for a treatment IND/IDE:
- Serious or immediately life-threatening situation (life-threatening means stage of disease where reasonable likelihood that death will occur in matter of months or premature death is likely without treatment);
- No comparable or satisfactory alternative
- Drug/device is under investigation in a controlled clinical trial under an IDE
- Sponsor is actively pursuing marketing approval or clearance
An unapproved drug/device may be used in an emergency prior to initiation of a clinical trial or on a patient who does not fit the eligibility criteria of a clinical trial if the patient has a life threatening disease or condition and there is no acceptable alternative. The investigator must notify the sponsor of the use and the sponsor reports the use to the FDA within 5 working days. In the case of an unapproved device, if possible, the investigator should obtain an independent assessment by an uninvolved physician that the above criteria are met.
In an emergency, if the above conditions are met, the investigator may proceed with the unapproved drug/device without IRB approval if there is no time to obtain it. The investigator should notify the IRB chair or director ahead of time, if possible, and should submit a report to the full IRB within 5 working days.
The investigator may also proceed with the unapproved drug/device in an emergency without the informed consent of the subject if the subject cannot provide informed consent and there is no time to obtain consent from the legally authorized representative. The investigator should obtain an independent assessment by an uninvolved physician that the above criteria are met.
Humanitarian Use Device (HUD)
A HUD is a medical device that is intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 patients per year. A HUD designation will be granted if there is no marketed comparable device. The HUD is exempt from demonstrating to the FDA the effectiveness requirements of the PMA. The HUD is approved and may be marketed once it has HUD designation. 21 CFR §814.100.
If the HUD sponsor wants a PMA, it must obtain an IDE and undergo clinical investigation. Use of a HUD does not constitute research. Thus, the FDA does not require research consent. Under the FDA regulations, however, IRBs must approve the use of a HUD. The FDA strongly encourages IRBs to require and review HUD consent forms. The IRB may approve the use of a HUD without further restrictions, under a protocol, or on a case-by-case basis.
- Biological product:
- A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative thereof, applicable to the prevention, treatment or cure of a disease or condition of human beings. 42 USC §262(i)
- Clinical investigation:
- Any experiment that involves a test article and one or more human subjects and that is subject to the requirements for prior submission to the FDA, or where results will be submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit. 21 CFR §50.3
- An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is: (1) recognized in the official National Formulary, or the United States Pharmacopoeia; (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease; or (3) intended to affect the structure of any function of the body and which does not achieve its primary purposes through chemical action and which is not dependent upon being metabolized. This definition includes in vitro diagnostic devices. 21 USC §321(h)
- Articles recognized in the official Unites States Pharmacopoeia, official Homeopathic Pharmacopoeia, or official National Formulary; articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; or articles intended to affect the structure or any function of the body. 21 USC §(g)(1)321
- Any use of a drug except for the use of a marketed drug in the course of medical practice. 21 CFR § 312.3
- Human subject:
- An individual who is or becomes a participant in research, either as a recipient of the test article or as a control. 21 CFR § 312.3
- An investigational device exemption.
- An investigational new drug application. 21 CFR § 312.3
- A clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device. 21 CFR §812.3
- Investigational device:
- A device that is the object of an investigation. 21 CFR §812.3
- Investigational new drug:
- A new drug or biological drug that is used in a clinical investigation. Includes a biological product that is used in vitro for diagnostic purposes. 21 CFR § 312.3
- A human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used, or as a control. 21 CFR §812.3
- Test article:
- Any drug (including a biological product for human use) or device subject to regulation under the Act. 21 CFR §50.3