INVESTIGATIONAL MEDICAL DEVICES
Medical Device Definition
Medical Device Classes
Exemption for Devices
Significant (SR) and Non-Significant Risk Devices
Who Must Apply for an IDE?
Unanticipated Adverse Device Effect Reports
Emergency Use of a Device
Other Types of IDE's
Device Study Record Requirements
Investigators as Sponsors
Required Approval Process to Use a New Device at UVa Health System
Device Summary Table
All clinical investigations of devices must have an approved IDE (Investigational Device Exemption) from the FDA or be exempt from the IDE regulations. An investigational device exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification 510(k) submission to FDA.
First one must determine if something is a device according to the federal definitions. Per the statute: Federal Food, Drug, and Cosmetic Act Sec 201.h [21USC321]
DEVICE: The term "device" (except when used in paragraph (n) of this section and in sections 301(i), 403(f), 502(c), and 602(c)) means 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 Pharmacopeia, or any supplement to them,
(2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
(3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.
Per FDA Information Sheet Guidance for IRB’s, Clinical Investigators, and Sponsors: Frequently Asked Questions About
Medical Device Definition
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. A medical device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is—
- recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,
- intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
- intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes (21 U.S.C. 321(h)).
Who Must Apply for an IDE?
The sponsor of the clinical trial is responsible for submitting the IDE application to FDA (§812.40) and obtaining Institutional Review Board (IRB) approval before the study can begin. Foreign companies wanting to conduct a clinical study in the U.S. MUST have a U.S. sponsor (§812.18). Under certain circumstances, the clinical investigator may wish to submit an IDE and would, therefore, also act as the sponsor of the study.
Federal law prohibits the distribution of medical devices until the FDA has reviewed clinical data and determined that a particular product is safe and effective for a specific use in human subjects. In order to test a new medical device in clinical trials, it is necessary to obtain an exemption from the FDA. Thus a device sponsor is required to apply for an Investigational Device Exemption (IDE) before tests with human subjects may begin. The investigator is responsible for obtaining the IDE number and providing it to the IRB. Studies that involve FDA-regulated products that are submitted without an IDE number will be reviewed by the IRB with respect to determining the need for an IDE, based on federal requirements and the investigator’s response to questions contained in the protocol.
If the IRB determines that the study does not require an IDE and approves the study, the study may begin. If the IRB determines that an IDE is needed, the investigator/sponsor must submit an IDE application to the FDA and provide documentation of the outcome of the FDA determination (IDE number) to the IRB before the IRB gives approval to enroll subjects in the study.
Medical Device Classes
In 1976, Medical Device Amendments to the Food, Drug and Cosmetic Act gave the FDA the responsibility for assuring the safety and effectiveness of devices intended for human use. In implementing these Amendments, the FDA has classified devices according to their level of risk.
Class 1 Medical Devices
Class 1 Medical Devices include those devices for which safety and effectiveness can be assured as long as there is compliance with provisions for notification of defects, repair, replacement or refund, records and reports. Device manufacturers are required to also avoid distribution of adulterated, misbranded, or banned devices.
Class 2 Medical Devices
Class 2 Medical Devices are those that require something more than proper labeling and quality assurance to ensure their safety and effectiveness.
Class 3 Medical Devices
Class 3 Medical Devices are those that are life-sustaining, life-supporting, implanted in the body, or of substantial importance in preventing impairment.
When a new device is substantially equivalent to one marketed prior to enactment of the Medical Devices Amendments (1976), it may be sold without additional proof of safety and effectiveness under Section 510(K) of the Federal Food, Drug and Cosmetic Act. These devices are commonly referred to as "510(K) devices." A sponsor planning to market the device must notify the FDA 90 days in advance of placing the device on the market. If the FDA agrees that the device is substantially equivalent to one already on the market, the device may then be sold without further research. Research activities involving a 510(K) device do not require an FDA Investigational Device Exemption (IDE) prior to approval by the IRB.
If the FDA determines that a new device is not substantially equivalent to a pre-amendment device, the new device is automatically designated a Class 3 medical device and the sponsor is required to obtain pre-marketing approval from the FDA. Studies conducted to develop safety and effectiveness data for such devices must be conducted according to the FDA requirements or Investigational Devices.
Exemption for Devices
If something is determined to be a device, one must then determine if the device is exempt from FDA regulations. Devices that are exempted from 21 CFR 812 are described in §812.2(c) of the IDE regulation. A summary of the FDA regulations for studies exempt from the IDE regulation include:
- a legally marketed device when used in accordance with its labeling
- a diagnostic device if it complies with the labeling requirements in §809.10(c) and if the testing:
- is noninvasive; *
- does not require an invasive sampling procedure that presents significant risk;
- does not by design or intention introduce energy into a subject; and
- is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure;
- For a diagnostic device, IRB approval is required and no Investigational Device Exemption application must be made to the FDA. In addition, the IRB is not required to make any further determinations related to risk at the time of approval.
* Noninvasive when applied to a diagnostic device or procedure, means one that DOES NOT by design or intention:
Additional guidance for an in vitro diagnostic device studies can be found in "Regulating In Vitro Diagnostic Device (IVD) Studies."Regulating In Vitro Diagnostic Device (IVD) Studies." http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm072277.htm
- 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.
- consumer preference testing, testing of a modification, or testing of a combination of devices if the device(s) are legally marketed device(s) [that is, the devices have an approved PMA, cleared Premarket Notification 510(k), or are exempt from 510(k)] AND if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk;
- a device intended solely for veterinary use;
- a device shipped solely for research with laboratory animals and contains the labeling "CAUTION – Device for investigational use in laboratory animals or other tests that do not involve human subjects."
- a custom device
According to 21CFR812.2(c) (7) a custom device as defined in 812.3(b) is exempt unless the device is being used to determine safety or effectiveness for commercial distribution. A custom device means a device that:
(1) Necessarily deviates from devices generally available or from an applicable performance standard or premarket approval requirement in order to comply with the order of an individual physician or dentist;
(2) Is not generally available to, or generally used by, other physicians or dentists;
(3) Is not generally available in finished form for purchase or for dispensing upon prescription;
(4) Is not offered for commercial distribution through labeling or advertising; and
(5) Is intended for use by an individual patient named in the order of a physician or dentist, and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice.
Depending upon the nature of the investigation, those studies which are exempt from the requirements of the IDE regulation may or may not be exempt from the requirements for IRB review and approval under Part 56 and the requirements for obtaining informed consent under Part 50. For guidance regarding the applicability of these regulations with respect to investigations being conducted under the provisions of §812.2(c), contact the IDE Staff at (301) 594-1190.
For a custom device, IRB approval is required as this would also not meet the definition of human subject research under 45CFR46.
Computer programs may be medical devices – it depends on the specific program and exactly what it does. A determination for whether or not a product is a medical device can be obtained by submitting a 513(g) request for classification. More information can be found at http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/ucm127147.htm
Medical Mobile Apps: Mobile medical applications (apps) may be considered a device. See
examples below. For additional information see the FDA Guidance on Mobile Medical Apps- 9-23
For more information see: Guidance on Electronic Storage of Highly Sensitive Data Policy
Examples of medical apps which are considered a device and thus regulated by the FDA:
Mobile apps that perform patient-specific analysis and provide patient-specific diagnosis, or treatment recommendations.
o apps that use patient-specific parameters and calculate dosage or create a dosage plan for radiation therapy;
o Computer Aided Detection software (CAD);
o image processing software24; and
o radiation therapy treatment planning software 25.
Examples of medical apps which are NOT considered a device and thus are NOT regulated by the FDA:
Mobile apps that perform simple calculations routinely used in clinical practice – These are apps that are intended to provide a convenient way for clinicians to perform various simple medical calculations taught in medical schools and are routinely used in clinical practice. These apps are generally tailored for clinical use, but retain functionality that is similar to simple general purpose tools such as paper charts, spread sheets, timers or generic mathematical calculators.
o Body Mass Index (BMI)
o Total Body Water / Urea Volume of Distribution
o Mean arterial pressure
o Glascow Coma Scale score
o APGAR score
o NIH Stroke Scale
o Delivery date estimator
Significant Risk (SR) and Non-Significant Risk (NSR)Devices
If a device is determined to NOT be exempt from IDE regulations, then the IRB must determine if the device is SR/NSR. If SR then the investigator will be required to submit an IDE application to the FDA and obtain an IDE number.
The initial determination regarding whether the device is exempt from device regulations or not, is made by the PI/sponsor. If the study is initiated by the UVa PI, the PI must submit document from the FDA or the School of Medicine Clinical Trials Office with their guidance on the need for an IDE.
If the FDA has already made the SR or NSR determination for the study, the agency’s determination is final. Otherwise the exempt determination is made by the full IRB-HSR.
A non-significant risk device is one that does not present significant risk to the research subject. Investigators should clearly explain in their protocol to the IRB why the sponsor believes the device to present no significant risk to study participants and provide supporting information, such as reports of prior investigations. The investigator should inform the IRB whether the FDA or any other IRB (IRB) has made a risk assessment and what the results of those assessments were.
The IRB then will make an independent assessment of the risk of the investigational device to be used in the study. If the IRB agrees that the devices poses no significant risk to research subjects, the investigator will not be required to obtain an IDE from the FDA to conduct the study. If the IRB instead believes that the device poses significant risk to research subjects, the investigator will be notified by the IRB. The investigator in turn is required to notify the sponsor of the IRB's decision, and the sponsor must notify the FDA of the IRB determination regardless of whether the study is ultimately conducted at UVA. Investigational devices determined by the IRB to poses significant risk to research subjects, will be reviewed according to the requirements described below.
Significant Risk Device Criteria
A significant risk device by definition is an investigational medical device that presents a serious risk to the health and safety of the research subjects. A significant risk investigational device must have FDA approval for use (e.g. must have an IDE#) According to 21CFR812.3(m) a Significant Risk (SR) device study is one that presents a potential for serious risk to the health, safety, or welfare of a subject and
- is intended as an implant*; or
- is used in supporting or sustaining human life; or
- is for use of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents impairment of human health; or
- otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
If the participant must undergo a procedure as part of the investigational study, e.g., a surgical procedure to implant the device, the IRB-HSR must consider the potential harm that could be caused by the procedure in addition to the potential harm caused by the device.
*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."
Unanticipated Adverse Device Effect Reports
The reporting requirements for adverse device effects are different from those for drugs and biologics. The sponsor-investigator must immediately conduct an evaluation of any unanticipated adverse device effect. If this effect presents an unreasonable risk to subjects, the sponsor-investigator is required to terminate all investigations as soon as possible, but no later than five working days after the sponsor makes this determination. This also must occur within 15 working days of when the sponsor was notified of the adverse effect.
Exception from Informed Consent (EFIC) Requirement
Even for an emergency use, the investigator is required to obtain informed consent of the subject or the subject's legally authorized representative unless both the investigator and a physician who is not otherwise participating in the clinical investigation certify in writing in the subject/subject's medical record all of the following [21 CFR 50.23(a)]:
- The subject is confronted by a life-threatening situation necessitating the use of the test article.
- Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject.
- Time is not sufficient to obtain consent from the subject's legal representative.
- No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject's life.
If, in the investigator's opinion, immediate use of the test article is required to preserve the subject's life, and if time is not sufficient to obtain an independent physician's determination that the four conditions above apply, the clinical investigator should make the determination and, within 5 working days after the use of the article, have the determination reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. The investigator must notify the IRB within 5 working days after the use of the test article [21 CFR 50.23(c)].
Planned Emergency Research and Exception from Informed Consent Requirements
Planned emergency research involves the systematic investigation of a condition experienced by individuals "in a setting where the emergency circumstances require prompt action and generally provide insufficient time and opportunity to locate and obtain consent from each subject's legally authorized representative" (FDA 2013).
In addition, “the research must have the prospect of direct benefit to the patient and must involve an investigational product that, to be effective, must be administered before informed consent from the subject or the subject’s legally authorized representative can be obtained and in which there is no reasonable way to identify prospectively individuals likely to become eligible for participation.” FDA Guidance
Planned emergency research is different than the emergency use of an investigational drug or device in a single patient. Emergency use of an investigational drug or device involves the treatment of a patient using an investigational drug or device outside of the research setting.
Per notice in the Federal Register (October 2, 1996) DHHS has waived the general requirements for informed consent for the class of research consisting of Emergency Research which falls under FDA regulations 21CFR50.24. Because informed consent cannot be obtained prior to initiating research procedures, there are many additional participant protections that must be in place before the IRB can approve planned emergency research.
Legally Authorized Representative (LAR): 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. [45CFR.46.102(c) and 21CFR50.3(l)].
Family Member: Both FDA and DHHS define a “family member” as any one of the following legally competent persons: spouse; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship
Community Consultation: Providing the opportunity for discussion with, and soliciting opinions from, the community(ies) in which the study will take place and from which the study subjects will be drawn. These communities may not always be the same; when they are not the same, both communities should be consulted.
Public Disclosure (a) Before a planned emergency research protocol begins, the dissemination of information in the community(ies) in which the study will take place and from which the subjects will be drawn sufficient to allow a reasonable assumption that the communities are aware that the study will be conducted, and its risks and benefits; and (b) after the study has been conducted, the dissemination of information to the community(ies) in which the study was conducted and to scientific researchers sufficient to describe the study’s demographic characteristics and the study’s results
Therapeutic Window: The protocol defines the time period, based on available scientific evidence, during which the intervention under investigation in the planned emergency research might reasonably produce a demonstrable clinical effect.
Conditions Required to Conduct Planned Research in Emergency Settings with Wavier of Consent and WAIVER OF HIPAA AUTHORIZATION
The IRB reviews the protocol and subsequent informed consent procedures to ascertain ‘approvability.’ If the protocol is not approvable by the IRB-HSR, because it does not meet the requirements or there are ethical concerns, explanatory documentation must be promptly supplied to the investigator and sponsor.
The convened IRB determines whether the research activity is subject to 21 CFR § 50. If the research is FDA regulated, the IRB follows the FDA regulatory criteria to allow an exception to the requirement to obtain consent (Sec. 50.24).
21 CRF 50.24 (a) The IRB responsible for the review, approval, and continuing review of the clinical investigation described in this section may approve that investigation without requiring that informed consent of all subjects be obtained if the IRB (with the concurrence of a licensed physician* who is a member of the IRB and who is not otherwise participating in the clinical investigation) finds and documents each of the following points:
*Concurrence by an Independent Physician: The IRB must obtain the documented concurrence of a physician, licensed in the state where the research will occur, who is a member of or consultant to the IRB but who is not otherwise connected to the study or involved in the research, before approving an exception to informed consent for planned emergency research.
- Life Threatening Situation: The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular interventions. (all three must be true)
- Informed Consent is Not Feasible: The IRB must find that informed consent is not feasible because: (all three must be true):
(a) The subjects will not be able to give their informed consent as a result of their medical condition;
(b) The interv ention under investigation must be administered before consent from the subjects' legally authorized representatives is feasible; and
(c) There is no reasonable way to prospectively identify the individuals likely to become eligible for participation in the clinical investigation.
- Prospect of direct benefit: The IRB must find that participation in the research holds out the proposal of direct benefit to the subject because: (all three must be true):
(a) Subjects are facing a life-threatening situation that necessitates intervention;
(b) Appropriate animal and other preclinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the intervention to provide a direct benefit to the individual subjects; and
(c) Risks associated with the investigation are reasonable in relation to what is known about the medical condition of the potential class of subjects, the risks and benefits of standard therapy, if any, and what is known about the risks and benefits of the proposed intervention or activity.
- Research Impracticable in Absence of Waiver of Informed Consent: The IRB must find that the clinical investigation could not practicably be carried out without the waiver.
- Therapeutic Window: The IRB must find that the proposed investigational plan defines the length of the potential therapeutic window based on available scientific evidence.
- Informed Consent Process and Documents: The IRB must review and approve informed consent procedures and an informed consent document consistent with FDA and HHS regulations. The procedures for obtaining informed consent and the informed consent document are to be used with subjects or their legally authorized representatives in situations where use of such procedures and documents is feasible. The IRB must also review and approve procedures and information to be used when providing an opportunity for a family member to object to a subject's participation in the clinical investigation consistent with information below.
The consent process includes the following:
• The investigator has summarized efforts that will be made to contact and obtain consent from a legally authorized representative within the window of time rather than proceeding with consent (if feasible). The investigator will summarize efforts made to contact a legally authorized representative and make this information available to the IRB at the time of continuing review
• If obtaining consent is not feasible and a legally authorized representative is not reasonably available, the investigator has committed, if feasible, to attempting to contact within the therapeutic window the participant’s family member who is not a legally authorized representative, and asking whether he or she objects to the participant’s participation in the clinical investigation. The investigator will summarize efforts made to contact family members and make this information available to the IRB at the time of continuing review.
• If a legally authorized representative or family member is told about the clinical investigation and the participant’s condition improves, the participant is also to be informed as soon as feasible.
• If a participant is entered into a clinical investigation with waived consent and the participant dies before a legally authorized representative or family member can be contacted, information about the clinical investigation is to be provided to the participant’s legally authorized representative or family member, if feasible.
- Community Consultation and Public Disclosure: Researchers are required to complete community consultation and public disclosure activities. Full information about community consultation and public disclosure can be found in FDA Guidance, April 2013, including a list of the minimum requirements for each activity.
Researchers are required to describe the following in the IRB application/protocol:
• An appropriate plan for consultation with representatives of the communities in which the clinical investigation will be conducted and from which the participants will be drawn.
• An appropriate plan for public disclosure to the communities in which the clinical investigation will be conducted and from which the participants will be drawn, prior to initiation of the clinical investigation, of plans for the investigation and its risks and expected benefits.
• An appropriate plan for public disclosure of sufficient information following completion of the clinical investigation to apprise the community and researchers of the study, including the demographic characteristics of the research population, and its results.
According to FDA 2013, community consultation means providing the opportunity for discussions with, and soliciting opinions from, the community in which the study will take place and the community from which the study subjects will be drawn. These communities may not always be the same; when they are not the same, both communities should be consulted.
The goals of community consultation are to:
• show respect for persons by informing the community about the study in advance;
• inform community members about the trial in advance and provide a means for affected communities to provide meaningful input to the IRB before its decision to approve, require modifications to, or disapprove the study;
• show respect for the community by allowing representatives of the community to identify potential community-level concerns and effects of the research; and
• show respect for subjects’ autonomy. Respect may be shown by including in community consultation activities individuals who may have, or be at risk for, the condition under study (and thereby obtain input from a group that is expected to be similar to the eventual study subjects).
According to FDA 2013, public disclosure means dissemination of information (i.e., one-way communication) to the community(ies), the public, and researchers about the emergency research.
The goal of public disclosure prior to initiation of the study is to provide sufficient information to allow a reasonable assumption that the broader community is aware of the plans for the investigation, its risks and expected benefits, and the fact that the study will be conducted without obtaining informed consent from most study subjects.
The goal of public disclosure after the study is completed is to ensure that the communities, the public, and scientific researchers are aware of the study’s results. Disclosure to researchers of the results, both positive and negative, of studies conducted under 21 CFR 50.24 is particularly important because such disclosure may help FDA and researchers learn from these studies involving vulnerable subjects who are unable to consent.
The IRB will determine whether it is appropriate for the IRB to carry out community consultation in addition to that performed by the investigator. Community consultation and public disclosure should engage the affected communities in discussion about the proposed research, with the possibility of appropriate modification to the design and/or conduct of the study as a possible outcome. The plan for consultation and disclosure should consider the following:
(i) Radio/TV advertisements
(ii) Press releases - newspaper, press interviews
(iii) Community meetings/gatherings
(iv) Civic groups, churches, minorities organizations, public officials
(v) Target groups more likely to be involved
(vi) Information related to procedures for opting out
- Independent Data Monitoring Committee: The PI’s plan to establish an independent data monitoring committee to exercise oversight of the clinical investigation;
- Separate IND/IDE: Evidence that the study will be performed under a separate investigational new drug application (IND) or investigational device exemption (IDE) that clearly identifies the research may include subjects who are unable to consent. (The requirement for a separate IND/IDE is required even if an IND for the same drug product or an IDE for the same device already exists). The initial IRB application for this research may not be submitted as an amendment under 21 CFR section 312.30 or 812.35.
- Verification that the protocol does not allow for the enrollment of prisoners or women known to be pregnant
- The IRB must find that the protocol has an appropriate plan for emergency testing prior to enrollment (if feasible and appropriate) or follow – up to ensure the safety of the pregnant woman or fetus after incidental enrollment. Any study procedures performed after pregnancy is identified must meet the criteria found in the
The IRB determinations are documented in the Scientific Reviewer Checklist: Planned Emergency Research and Exception from Informed Consent (EFIC)-as well as the IRB meeting minutes and retained by the IRB for at least 3 years after completion of the clinical investigation, and the records shall be accessible for inspection and copying by FDA in accordance with 21 CFR 56.115(b).
If an IRB determines that it cannot approve a clinical investigation because the investigation does not meet the criteria in the exception provided above or because of other relevant ethical concerns, the IRB must document its findings and provide these findings promptly in writing to the clinical investigator and to the sponsor of the clinical investigation. The sponsor of the clinical investigation must promptly disclose this information to FDA and to the sponsor's clinical investigators who are participating or are asked to participate in this or a substantially equivalent clinical investigation of the sponsor, and to other IRB's that have been, or are, asked to review this or a substantially equivalent investigation by that sponsor.
Vulnerable Populations: Children, Prisoners and Pregnant Women
Children: Children may be included in federally-funded emergency research under EFIC provided that the additional criteria for involving children in research are met. Most emergency research that meets the criteria for EFIC will also meet the criteria for inclusion of children because the research is greater than minimal risk, but holds out the prospect of direct benefit to the subjects. If the study involves children, the community consultation and public disclosure plans should carefully consider how to reach parents of children who would potentially be included and, if appropriate, the children themselves. (See Vulnerable Populations Checklist-Children)
Prisoners: Per DHHS regulations, prisoners may not be included in federally-funded emergency research under EFIC. However, given the emergent circumstances under which subjects are enrolled in these studies, it may not be apparent that a subject is a prisoner at the time of enrollment. Likewise, a subject could become a prisoner following enrollment and during the study period (including long-term follow-up periods).
Therefore, the protocol should be clear that known prisoners will be enrolled and should address either: 1) the plan for safely removing subjects from the study who become prisoners after enrollment; or20 how the protocol meets the criteria for approval of research with prisoners with respect to the study procedures that take place after the emergency intervention .
Pregnant Women and Fetuses: Per DHHS regulations, pregnant women and fetuses may not be included in federally-funded emergency research under EFIC. However, given the emergent circumstances under which subjects are enrolled in these studies, it may not be apparent that a subject is pregnant.
Investigators must carefully consider the impact that the study intervention could have on a pregnant women or fetus where the pregnancy is not identified at the time of enrollment. A plan for emergency testing prior to enrollment (if feasible and appropriate) or follow-up to ensure the safety of the pregnant woman or fetus after incidental enrollment should be described in the protocol. Any study procedures performed after pregnancy is identified must meet the criteria in Vulnerable Populations Checklist-Pregnant Women, Fetuses, Neonates)
Other Types of IDE's
There may be circumstances under which a health care provider may wish to use an unapproved device to save the life of a patient or to help a patient suffering from a serious disease or condition for which there no other alternative therapy exists. Patients/physicians faced with these circumstances may have access to investigational devices under one of four main mechanisms by which FDA may make an unapproved device available:
The compassionate use provision allows access for patients who do not meet the requirements for inclusion in the clinical investigation of a device, but for whom the treating physician believes the device may provide a benefit in treating and/or diagnosing their disease or condition. This provision is typically approved for individual patients but may be approved to treat a small group.
Study Team Responsibilities:
The researcher at UVa should not submit an application to the IRB prior to a patient being identified and the sponsor having submitted a new IDE submission to the FDA for that particular patient.
1. The Principal Investigator either through the sponsor or directly with the FDA must submit an IDE supplement requesting approval for a protocol deviation under section §812.35(a) in order to treat the patient under Compassionate Use. The FDA review time for IDE submissions is 30 days from the date of their receipt of the submission so please plan accordingly.
2. The IDE supplement should include:
- A description of the patient's condition and the circumstances necessitating treatment;
- A discussion of why alternatives therapies are unsatisfactory and why the probable risk of using the investigational device is no greater than the probable risk from the disease or condition;
- An identification of any deviations in the approved clinical protocol that may be needed in order to treat the patient; and
- The patient protection measures that will be followed. (Informed consent, concurrence of IRB chairperson, clearance from the institution, independent assessment from uninvolved physician, authorization from IDE sponsor)
3. Submit the New Medical Device Form to Clinical Engineering
4. Submit the following items to the IRB:
o Cover letter stating request for compassionate use of a device.
o Copy of IDE supplement to FDA for compassionate use
o Copy of consent form from sponsor to be used to consent subject
o Copy of protocol currently being used in ongoing clinical trial
o IDE# (This must be a different IDE # from the IDE# for the ongoing clinical trial )
o Copy of New Medical Device Form you submitted to Clinical Engineering. This form is NOT required if the device is already being used at UVa under an ongoing clinical trial.
Emergency Use of Unapproved Medical Devices
An unapproved medical device is a device that is used for a purpose or condition for which the device requires, but does not have, an approved application for premarket approval under section 515 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 360(e)].
An unapproved device may be used in human subjects only if it is approved for clinical testing under an approved application for an Investigational Device Exemption (IDE) under section 520(g) of the Act [21 U.S.C. 360(j)(g)] and 21 CFR part 812. Medical devices that have not received marketing clearance under section 510(k) of the FD&C Act are also considered unapproved devices which require an IDE.
The Food and Drug Administration (FDA) recognizes that emergencies arise where an unapproved device may offer the only possible life-saving alternative, but an IDE for the device does not exist, or the proposed use is not approved under an existing IDE, or the physician or institution is not approved under the IDE. Using its enforcement discretion, FDA has not objected if a physician chooses to use an unapproved device in such an emergency, provided that the physician later justifies in writing to the FDA and the IRB that an emergency actually existed.
Requirements for Emergency Use: FDA website- Additional Information
Each of the following conditions must exist to justify emergency use:
- the subject is in a life-threatening condition that needs immediate treatment;
- no generally acceptable alternative for treating the subject is available; and
- because of the immediate need to use the device, there is no time to use existing procedures to get FDA approval for the use.
Emergency Use of an unapproved device may occur before an IDE is approved.
If consent is obtained, it may be done with a consent form from the sponsor, or clinicians may use a standard surgical consent form via the health system.
FDA expects the physician to determine whether these criteria have been met, to assess the potential for benefits from the unapproved use of the device, and to have substantial reason to believe that benefits will exist. The physician may not conclude that an "emergency" exists in advance of the time when treatment may be needed based solely on the expectation that IDE approval procedures may require more time than is available. Physicians should be aware that FDA expects them to exercise reasonable foresight with respect to potential emergencies and to make appropriate arrangements under the IDE procedures far enough in advance to avoid creating a situation in which such arrangements are impracticable.
In the event that a device is to be used in circumstances meeting the criteria listed above, the device developer should notify the Center for Devices and Radiological Health (CDRH), Program Operation Staff by telephone (301-594-1190) immediately after shipment is made. [Note: an unapproved device may not be shipped in anticipation of an emergency.] Nights and weekends, contact the FDA Office of Emergency Operations (HFA-615) 301-443-1240.
FDA would expect the physician to follow as many subject protection procedures as possible. These include:
- obtaining an independent assessment in writing, documented in the subject/subject's medical record by an uninvolved physician;
- obtaining informed consent from the subject or a legal representative;
- notifying institutional officials as specified by institutional policies;
- notifying the Institutional Review Board (IRB); and
- obtaining authorization from the IDE holder, if an approved IDE for the device exists.
After an unapproved device is used in an emergency, the physician should:
- report to the IRB within five days [21 CFR 56.104(c)] and otherwise comply with provisions of the IRB regulations [21 CFR part 56];
- evaluate the likelihood of a similar need for the device occurring again, and if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IDE for the device's subsequent use; and
- if an IDE for the use does exist, notify the sponsor of the emergency use, or if an IDE does not exist, notify FDA of the emergency use (CDRH Program Operation Staff 301-594-1190) and provide FDA with a written summary of the conditions constituting the emergency, subject protection measures, and results.
Subsequent emergency use of the device may not occur unless the physician or another person obtains approval of an IDE for the device and its use. If an IDE application for subsequent use has been filed with FDA and FDA disapproves the IDE application, the device may not be used even if the circumstances constituting an emergency exist. Developers of devices that could be used in emergencies should anticipate the likelihood of emergency use and should obtain an approved IDE for such uses.
Study Team Responsibilities
- The Principal Investigator should communicate with the sponsor (device manufacturer) and the FDA to confirm that all FDA requirements are being met for emergency use.
- If Emergency Use is approved by the Sponsor/ FDA consent should be obtained from the patient using a consent form provided by the sponsor.
- If the patient is unable to give consent, the physician must provide written documentation from him/her and another physician not involved in the clinical trial, verifying the following criteria:
o The subject is confronted by a life-threatening situation necessitating the use of the test article.
o Informed consent cannot be obtained because of an inability to communicate with , or obtain legally effective consent from the subject
o Time is not sufficient to obtain consent from the subject's legal representative
o No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject's life.
- The device may then be given to the patient.
- The Principal Investigator must notify the IRB-HSR in writing within 5 working days stating that he/she has used the Emergency Use provision. A copy of the consent form or the documentation verifying consent could not be obtained should be attached. IRB-HSR Notification Template
- Following the next IRB-HSR meeting the Principal Investigator will receive notification from the IRB verifying that the board concurred with the emergency use.
The FDA allows for only one emergency use of a test article without prospective IRB approval. See FDA Requirements above for additional information. If you expect to have an additional patient who will need the same test article- please begin work on submitting a protocol to the IRB.
Emergency Use of a Humanitarian Use Device (HUD)
Guidance for HDE Holders, Institutional Review Boards (IRBs), Clinical Investigators, and FDA Staff - Humanitarian Device Exemption (HDE) Regulation: Questions and Answers
A Humanitarian Use Device (HUD) is a device that is intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect or are manifested in fewer than 4000 individuals in the United States per year. The sponsor must get a HDE designation from the FDA’s Office of Orphan Products Development. The Federal Food, Drug, and Cosmetic Act and the HDE regulation do not require informed consent because a HDE provides for marketing approval, and so use of the device does not constitute research or an investigation which would normally require informed consent. The sponsor may provide the patient with patient labeling to assist the patient in making an informed decision about the use of the device. Even though the device is not considered investigational, IRB review is required. The FDA in their FAQ’s (see link below) specifies a difference between use of an HUD and investigational use of an HUD. If used according to labeling, this is not considered an “investigational use” of an HUD and therefore 45CFR46, 21CFR50 do not apply. The initial review must by done by full board, although continuations may be done by expedited review.
FDA Requirements: Additional information may be found on the FDA website.
"Treatment Use" is described in the federal regulations to facilitate broader availability of promising new therapies to desperately ill patients as early in the development process as possible. Under these regulations, patients faced with a serious or life-threatening disease/condition for which no alternative exists may receive investigational therapy outside of the controlled clinical trial.
Treatment Use may be considered when:
- The drug/device is intended to treat or diagnosis a serious or immediately life-threatening disease or condition
- There is no comparable or satisfactory alternative drug/device available to treat or diagnose the disease or condition in the intended patient population.
- The drug/device is under investigation in a controlled clinical trial for the same use under an approved Investigational Device Exemption (IDE) or Investigational New Drug (IND) application, or all clinical trials have been completed; AND
- The sponsor of the controlled clinical trial is pursuing marketing approval/clearance of the investigational drug/device with due diligence.
Study Team Responsibilities
The Principal Investigator either through the sponsor or directly with the FDA must obtain a "Treatment Use IND/IDE"
- The Principal Investigator would then submit a new protocol application to the IRB-HSR following procedures outlined in Protocol Builder for a Full Board study.
- Two exceptions will be allowed for a Treatment Use protocol by the IRB-HSR:
o The IRB-HSR will allow concurrent review of the protocol by the PRC and the IRB-HSR.
o The investigator needs to answer the questions in protocol builder, however the he/she may submit the sponsors protocol in place of writing the protocol following the IRB-HSR protocol template. The consent form, however, must be written using the IRB-HSR template created with Protocol Builder.
THE IRB-HSR STRONGLY ENCOURAGES THE INVESTIGATOR TO CONTACT THE IRB-HSR STAFF PRIOR TO WRITING THE DOCUMENTS TO VERIFY THEIR PROTOCOL MEETS THE CRITERIA FOR A TREATMENT USE PROTOCOL.
FDA Requirements: Continued Access
Study Team Responsibilities:
Researchers wishing to open a continued access protocol may use a central IRB as the IRB of record for the trial. The PI will submit the appropriate paperwork to the central IRB and the IRB-HSR.
Investigators as Sponsors
If an investigator is the developer of the drug, biologic or medical device, and no commercial manufacturer is involved, then the investigator is also the sponsor for the purposes of designing and organizing clinical trials.
- When the principal intent of the investigational use of a test article is to develop information about the product's safety or efficacy, an Investigational New Drug (IND) or Investigational Device Exemption (IDE) may be required. If an IND or an IDE is required, it is the investigator's responsibility to submit the appropriate application to the FDA, obtain the necessary documentation, and provide this documentation to the IRB as a part of the approval process.
- An IND may not be necessary if all of the conditions stated in 21 CFR 312.2(b)(1) have been met. If the PI does not already have an IND , the PI will be notified in writing that IRB approval is pending receipt of an IND. If there is a debate regarding the need for an IND , the IRB will require that the PI contact the Food and Drug Administration (FDA) to obtain written documentation that an IND is not necessary.
- The IRB will review protocols involving investigational devices to determine if the device is exempt from IDE regulations. If not exempt, the IRB will then determine if the device is a “Significant-Risk device” (SR) or a “Non-Significant Risk”(NSR) device. If the IRB determines that the research involves a SR device, an IDE is necessary. If the PI does not already have an IDE, the PI will be notified in writing that IRB approval is pending receipt of an IDE.
Sponsors also have important administrative and reporting requirements above and beyond those of investigators. Faculty contemplating the dual role of sponsor-investigator should consult with the School of Medicine Clinical Trials Office (SOM CTO) about the additional responsibilities that entails.
The sponsor must declare any individual financial conflict(s) of interests in the research and develop a management plan that is approved by the University.
Multi site trials:
Should an investigator associated with the University of Virginia or the University sponsor a multi-site study, that investigator is required to meet all the responsibilities of a sponsor as determined by DHHS guidance.
At the time of initial review the IRB will require an approval from the SOM CTO who will assess the procedures for dissemination of protocol information (e.g. unanticipated problems involving risks to subjects or others, protocol modifications, interim findings) to all participating sites. In addition the UVA PI must ensure that investigators at other research sites submit and follow requirements directed by their local IRBs.
IRB policies and procedures from each approving institution will be followed by researchers at that site. All required reports will be provided to the local IRB as per their policy. The coordinating PI at the University of Virginia will be responsible for providing local information as well as unanticipated problems involving risks to subjects or others, protocol modifications, or interim findings that may affect the UVA IRB's continuing approval of the research.
The IDE application must contain sufficient data from animal and in vitro studies to demonstrate the likelihood that the product will be safe and effective for the purpose indicated. If the FDA agrees that the data are sufficient to support a decision to initiate clinical trials, and the proposed protocol is acceptable, the FDA will provide an IDE number to the protocol. Specific requirements for protocol design are set forth in FDA Regulations.
IDE: The investigator is required to wait for the FDA scientists to review the materials submitted, and if necessary request additional information, require modifications, and approve or disapprove the application before proceeding with the clinical trial. The IRB will not provide approval to enroll subjects in the study until the FDA has either provided an IDE number or advised the principal investigator that an IDE is not required.
Required Approval Process to Use a New Device at UVa Health System
No medical device ( supplies, accessories, or equipment), whether purchased, contracted, donated, loaned or for trial, may be used in the Medical Center for inpatient or outpatient care purposes without first being evaluated by Clinical Engineering.
The Food and Drug Administration (FDA) defines a medical device as any instrument, apparatus, or other article that is used to prevent, diagnose, mitigate, or treat a disease or to affect the structure or function of the body, with the exception of drugs. This means that the FDA classifies common hospital products such as catheters, thermometers, patient restraints and syringes as medical devices.
In order to obtain approval submit the New Medical Device Request From online at https://www.healthsystem.virginia.edu/newmedicaldevice/index.cfm?requestid=new.
If you have questions on how to complete the form call 434-982-2590
Device Summary Table