Drugs, Biologics and Devices Used in Clinical Investigations
- FDA Requirements for New Drugs and Biologics
- FDA Requirements for New Devices
- Non-significant Risk (NSR) and Significant Risk (SR) Device Classification
- Abbreviated Requirements for NSR Devices
- FDA Definitions for Device Studies
- SR and NSR Examples
- Investigational Use of Marketed Drugs, Biologics and Medical Devices
- Control of Investigational Drugs, Biologics and Devices
- Humanitarian Use Devices
- Emergency Use of an Unapproved Drug, Biologic or Device
FDA Requirements for New Drugs and Biologics
"Investigational new drug" (IND) means a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms ''investigational drug'' and ''investigational new drug'' are deemed to be synonymous for purposes of determining whether a Notice of Claimed Investigational Exemption for a New Drug must be submitted to the US Food and Drug Administration (FDA).
- Before a new drug or biologic may be tested on humans, the sponsor (usually a pharmaceutical company, but sometimes an individual) must submit a Notice of Claimed Investigational Exemption for a New Drug to the FDA.
- FDA regulations [21 CFR 312.22 and 312.23] contain the general principles underlying the IND submission and the general requirements for an IND's content and format.
- After the sponsor submits an IND, there is a 30-day waiting period during which the FDA reviews the application to make certain subjects are not exposed to any unwarranted risks.
- Clinical studies can be initiated after the 30-day waiting period expires, unless a clinical hold is placed by the FDA. A clinical hold is an order issued by the FDA to the applicant to delay a proposed clinical investigation or to suspend an ongoing investigation.
- The FDA notifies the sponsor during the 30-day waiting period if a clinical hold is placed.
UCI IRB approval is also required prior to initiation of any drug study. Investigators interested in studying an investigational drug or biological product are required to complete Appendix J when completing the electronic IRB Application or when requesting a modification to an IRB-approved study. Investigators are asked to include the drug name, IND number and the date of IND submission. Frequently, investigators submit protocols to the IRB for review during the 30-day waiting period. If the IRB finds the protocol acceptable, approval is issued after documentation of a valid IND number from the FDA is provided to the UCI IRB. If the study is not externally funded or the UCI investigator holds the IND, a copy of FDA IND application is required prior to IRB review.
FDA Requirements for New Medical Devices
A medical device is defined, in part, as any health care product that does not achieve its primary intended purposes by chemical action or by being metabolized. Medical devices include, among other things, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis (IVD) of disease and other medical conditions such as pregnancy. Investigators interested in studying a new medical device are required to complete Appendix K when completing the electronic IRB Application or when requesting a modification to an IRB-approved study.
- Except for certain low risk devices, each manufacturer who wishes to introduce a new medical device to the market must submit a pre-market notification to FDA.
- FDA reviews these notifications to determine if the new device is "substantially equivalent" to a device that was marketed prior to passage of the Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990 (i.e., a "pre-amendments device").
- If the new device is deemed substantially equivalent to a pre-amendments device, it may be marketed immediately and is regulated in the same regulatory class as the pre-amendments device to which it is equivalent.
- The pre-market notification requirement for new devices and devices that are significant modifications of already marketed devices is set forth in section 510(k) of the Act.
- Devices determined by FDA to be substantially equivalent are often referred to as "510(k) devices." See http://www.fda.gov/cdrh/devadvice/314.html.
- If the new device is deemed not to be substantially equivalent to a pre-amendments device, it must undergo clinical testing and pre-market approval before it can be marketed unless it is reclassified into a lower regulatory class.
An investigational device is a medical device which is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device.
- Clinical investigations undertaken to develop safety and effectiveness data for medical devices must be conducted according to the requirements of the FDA IDE regulations.
- An approved IDE permits a device that otherwise would be required to comply with a performance standard or to have pre-market approval to be shipped lawfully for the purpose of conducting investigations of that device.
- An IDE study may not necessarily commence 30 days after an IDE submission to FDA.
- Certain clinical investigations of devices (e.g., certain studies of lawfully marketed devices) may be exempt from FDA IDE regulations.
- The exemption applies only to investigations in which "510(k)'d" products are being used in accordance with the labeling cleared by FDA.
- Investigation of an off-label use of a 510(k) product takes it outside this exemption.
Non-significant Risk and Significant Device Classification
Unless exempt from IDE regulations, an investigational device must be categorized as either "significant risk" (SR) or "non-significant risk" (NSR).
Non-significant Risk Device Studies
If the sponsor considers that a study is NSR, the UCI investigator must ask the sponsor to provide the IRB with an explanation of its determination and any other information that may assist the IRB in evaluating the risk of the study. The sponsor should provide the IRB with:
- a description of the device,
- reports of prior investigations with the device,
- the proposed investigational plan,
- a description of patient selection criteria and monitoring procedures, as well as
- any other information that the IRB deems necessary to make its decision.
The sponsor also should inform the UCI IRB whether other IRBs have reviewed the proposed study and what determination was made. The sponsor must inform the IRB of the FDA's assessment of the device's risk if such an assessment has been made. The IRB may also consult with the FDA for its opinion.
NSR studies do not require submission of an IDE application to the FDA. Instead, the sponsor is required to conduct the study in accordance with the "abbreviated requirements" of the FDA IDE regulations. Unless otherwise notified by the FDA, an NSR study is considered to have an approved IDE if the sponsor fulfills the abbreviated requirements.
Significant Risk Studies
SR device studies must be conducted in accordance with the full IDE requirements of the FDA and may not commence until 30 days following the sponsor's submission of an IDE application to the FDA.
- All SR risk studies require IRB full committee review.
- The IRB's risk determination is based on the proposed use of a device in an investigation, and not on the device alone. In deciding if a study poses an SR, the IRB must consider the nature of the harm that may result from use of the device.
- If the UCI IRB believes that a device study is SR, the investigation may not begin until both the IRB and FDA approve the investigation.
- Documentation of the FDA IDE number must be submitted to the IRB before UCI IRB approval will be granted.
Abbreviated FDA requirements for NSR Devices
Below is a summary of the FDA abbreviated requirements [21 CFR 812.2(b)] for NSR device studies:
- Sponsor and local investigator agree to provide the UCI IRB with a brief explanation of why the device is not a significant risk device, and to obtain and maintain UCI IRB approval;
- Sponsor labels the device in accordance with FDA requirements;
- Sponsor and local investigator ensure informed consent is obtained from each subject, unless documentation is waived by the IRB;
- Sponsor and local investigator comply with the FDA requirements for monitoring investigations, maintaining records and filing reports; and
- Sponsor complies with FDA regulations pertaining to the prohibition of promotion and other practices of the device.
- The investigation does not involve a device that was approved under an IND (on or before July 16, 1980).
FDA Definitions for Device Studies
The following definitions will assist investigators with the significant risk and non-significant risk classification.
Noninvasive when applied to a diagnostic device or procedure, means one that does not by design or intention:
- Penetrate or pierce the skin or mucous membranes of the body, the ocular cavity, or the urethra, or
- enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os.
- Blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tissues that are left over from samples taken for non-investigational purposes is also considered noninvasive.
Significant risk device means an investigational device that:
- Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
- Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;
- Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or
- Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
Implant means a device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more. FDA may, in order to protect public health, determine that devices placed in subjects for shorter periods are also "implants."
SR and NSR Examples
Below are several examples of SR and NSR devices. For a more detailed list of SR and NSR devices, see the FDA device information sheet.
Note: Inclusion of a device in the NSR category should not be viewed as a conclusive determination, because the proposed use of a device in a study is the ultimate determinant of the potential risk to subjects. It is unlikely that a device included in the SR category could be deemed NSR due to the inherent risks associated with most such devices.
| Significant Risk | Non-significant Risk |
|---|---|
| Surgical Lasers | Daily Wear Contact Lenses |
| Respiratory Ventilators | Dental Filling Materials |
| Cardiac Pacemakers | Conventional Urology Endoscopes |
| Laryngeal Implants | General Urological Catheters |
| Biliary Stents | Jaundice Monitors for Infants |
| Infusion Pumps | Menstrual Pads & Tampons (Cotton or Rayon, only) |
| Intrauterine Devices | Wound Dressings |
| Corneal Implants | Electroencephalography |
Investigational Use of Marketed Drugs, Biologics and Medical Devices
The investigational use of approved, marketed drug or biologic requires consideration of whether an IND is required. When the principal intent of the investigational use of a test article (drug, biologic or medical device) is to develop information about the product's safety or efficacy, submission of an IND or IDE may be required. In addition, investigators interested in studying FDA-approved drugs or biological products or FDA-approved or cleared medical devices are required to complete Appendix J or Appendix K, respectively, when completing the electronic IRB Application or when requesting a modification to an IRB-approved study.
- Most studies performed by researchers at academic institutions are exempt from IND requirements for certain investigations conducted with drugs already approved for marketing.
- The exemption applies where safety is not an issue (because of a similarity in dose, route of administration, and patient population with the approved labeling) and where the investigation is not being conducted for the purpose of changing the drug labeling (for example, where the study is not for purposes of adding a new indication or comparative safety claim).
- The FDA expects that the exemption criteria will apply primarily to researchers in academic or other institutions.
- The exemption is intended to reduce burdens on researchers while permitting FDA resources to be devoted to monitoring clinical investigations requiring FDA oversight and to reviewing marketing applications.
- Although exempt from most IND requirements, the investigations would nonetheless be subject to the general prohibition against promotion of investigational drugs, and to the other regulations designed to protect the rights and safety of patients, such as the IRB review and informed consent regulations.
- The IRB makes the final determination as to whether an IND or IDE application is required before the study may proceed.
According to FDA regulations the clinical investigation of a marketed drug or biologic does not require submission of an IND if all six of the following conditions are met:
- it is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug;
- it is not intended to support a significant change in the advertising for the product;
- it does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
- it is conducted in compliance with the requirements for IRB review and informed consent;
- it is conducted in compliance with the requirements concerning the promotion and sale of drugs; and
- it does not intend to invoke a waiver of informed consent for emergency research.
Control of Investigational Drugs, Biologics and Devices
Research involving the use of investigational test articles (i.e., investigational drugs, biologics or devices) requires that the Investigator or other appropriate individual or entity (e.g., hospital pharmacy), provide appropriate control of test articles.
Note: An Investigational Drug/Biologic Accountability Log or Device Accountability Log must be maintained, if the study includes an investigational drug, biologic or device.
UCIMC Dispensing Policies and Regulations for Investigational Drugs and Biologics
UCIMC and its satellite clinics have their own policies regarding the administration of investigational drugs and biologics in order to assure patient safety and comply with JCAHO standards, California law, and California Department of Health Services regulations. Investigators conducting research in clinical settings should consult with the hospital pharmacy for guidance on UCIMC hospital policies. Consultation should take place before preparing the budget for the clinical study. UCI Health Systems Drug Administration and Control Policy can be found on the UCIMC website.
UCIMC Investigational Drug Services:
| Investigational Drug Services |
(714) 456-5905 (714) 456-7833 |
Inpatient Pharmacy Services
|
(714) 456-5905 (714) 456-5981 (714) 456-6117 |
| Chao Family Cancer Center Pharmacy | (714) 456-5324 |
| Drug Information Service | (714) 456-6988 |
| General Pharmacy Administration | (714) 456-5514 |
Control of Investigational Drugs/Biologics – Lead Researcher (Investigator) Responsibilities
Investigators conducting studies in which an investigational drug/biologic will be used must ensure adequate control of the drug or biologic. Adequate control and handling of investigational drug/biologic include all of the following:
- The investigator should ensure that the investigational drug/biologic is used only in accordance with the UCI IRB approved protocol.
- An investigator must administer the investigational drug/biologic only to participants under the investigator’s direct personal supervision or under the supervision of a sub-investigator directly responsible to the investigator.
- The investigator must not supply the investigational drug/biologic to any person not authorized to receive it.
- An investigator is required to maintain adequate records of the disposition of the investigational drug/biologic, including dates of dispensing, quantity currently maintained for dispensing, and amount of the investigational product dispensed to participants (a sample Drug/Biologic Accountability Log is available).
- If the investigation is terminated, suspended, discontinued, or completed, the investigator must return any unused supplies of the investigational drug/biologic to the study sponsor, or otherwise provide for disposition of the unused supplies as directed by the sponsor.
- If the investigational drug is subject to the Controlled Substances Act, the investigator must take adequate precautions, to prevent theft or diversion of the substance into illegal channels of distribution. These precautions include: storage of the investigational drug in a securely locked, substantially constructed cabinet or other securely locked, substantially constructed enclosure to which access is limited.
UCIMC Policy for Control of Investigational Devices
Investigational devices are carefully regulated and must be appropriately managed by a qualified Investigator or other appropriate individual to ensure they are not co-mingled with similar approved devices. UCI Health Systems Control of Investigational Devices Policy can be found on the UCIMC website.
Control of Investigational Devices – Lead Researcher (Investigator) Responsibilities
Lead Researchers (Investigators) conducting studies in which an investigational device will be used must ensure adequate control of the device. Adequate control and handling of investigational devices include all of the following:
- The investigator must ensure that the investigational device is used only in accordance with the UCI IRB approved protocol, the signed agreement, the investigational plan and applicable FDA regulations.
- The investigator must administer the investigational device only to participants under the investigator’s direct personal supervision or under the supervision of a sub-investigator directly responsible to the investigator.
- The investigator must not supply the investigational device to any person not authorized to receive it.
- The investigator must maintain the following accurate, complete, and current records relating to their participation in the clinical investigation (a sample Device Accountability Log is available). Specifically, records of receipt, use or disposition of a device that relate to:
- The type and quantity of the device, the dates of its receipt, and the batch number or code mark.
- The names of all persons who received, used, or disposed of each device.
- Why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of.
- If the investigation is terminated, suspended, discontinued, or completed, the investigator must return any unused stock of the investigational device to the study sponsor, or otherwise provide for disposition of the unused stock as directed by the sponsor.
