UVA HRPP SOP: Section 13:  FDA Regulated Research

See the UVA Human Research Protection Program (HRPP) Standard Operating Procedure (SOP) Section 13 titled FDA Regulated Research for additional information.

 BACKGROUND

This guidance is intended to assist investigators in meeting the FDA requirements when investigating medical devices in clinical research and in some treatment situations. Federal regulation 21 CFR 812 defines the requirements for clinical investigations of medical devices.

All clinical investigations of devices must have an approved IDE (Investigational Device Exemption) from the FDA or be exempt from the IDE regulations before beginning a clinical investigational of a significant risk device. 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. 

DEFINITIONS

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)).

Investigational device means a device, including a transitional device, that is the object of an investigation. A medical device is considered investigational if either condition applies:

• The device is not approved for marketing in the United States or
• The device is approved for marketing but is being clinically evaluated for a new indication.

Investigational device exemption (IDE) IDE refers to the regulations under 21 CFR 812. An approved IDE means that the IRB (and FDA for significant risk devices) has approved the sponsor’s study application and all the requirements under 21 CFR 812 are met.

Significant risk device means an investigational device that:

(1) Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;

(2) 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;

(3) 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

(4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

A Non-significant Risk (NSR) device study is one that does not meet the definition for a Significant Risk device study.

IDE Exempt means a study that is exempt from the requirements of regulations under 21 CFR 812. Two common investigations of medical devices that are exempt from the requirement for an IDE include:

• Investigations conducted with legally marketed devices used according to labeling.
• Studies using in vitro diagnostic devices labeled “for research purposes only” may be IDE-Exempt as per regulations if the testing: 
  • Is noninvasive;
  • Does not require invasive sampling procedures that presents significant risk;
  • Does not introduce energy into a subject; and
  • Is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure

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. 

STEPS TO DETERMINE IF AN IDE IS REQUIRED FROM THE FDA

1. Determine if something is a medical device according to the federal definitions.

Review the definitions of device/medical device above to make this determination.

It is important to remember that apps may be considered a device. See additional information under Exemption.  

2. If the device is determined to be a medical device according to the federal definitions, 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 include: 

1. a legally marketed device when used in accordance with its labeling  
    
2. 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.
   • 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.
3. 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; 
    
4. a device intended solely for veterinary use;  
    
5. 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."  
    
6. a custom device ** 
   • (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.
7. 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
8. Medical Mobile Apps: Mobile medical applications (apps) may be considered a device. See examples below.

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.
• Apps that use patient-specific parameters and calculate dosage or create a dosage plan for radiation therapy;
• Computer Aided Detection software (CAD);
• Image processing software24; and 
• 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. 

• Body Mass Index (BMI)
• Total Body Water / Urea Volume of Distribution
• Mean arterial pressure
• Glasgow Coma Scale score
• APGAR score
• NIH Stroke Scale
• Delivery date estimator

For additional information see:

• FDA Guidance on Mobile Medical Apps- 9-23 13 
• Guidance on Electronic Storage of Highly Sensitive Data Policy

3. If the medical device is determined to NOT be exempt from the requirement for an IDE: 

The IRB will determine at a convened meeting if the investigational device is a significant risk (SR) or non-significant risk (NSR) device based on the information in the application.

• If the IRB agrees that the device is NSR, an IDE from the FDA will not be required.
• If the IRB determines that the device poses a SR, an IDE from the FDA will be required.

ADDITIONAL INFORMATION

Investigator Responsibilities for Investigational Devices

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.

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.

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.

When is an IDE from the FDA required?

Studies involving unapproved devices that are considered to be significant risk: An IDE from the FDA is required to perform clinical research using an unapproved device that poses a significant risk to subjects. Typically, these studies are conducted to collect safety and effectiveness data used to support Premarket Approval (PMA) applications submitted to the FDA.

Studies involving an approved device being tested for a new indication: IDE regulations also apply to significant risk studies testing an FDA-approved device for a new indication.

Example: Significant risk (SR) studies involve implantable devices such as cardiac pacemakers, orthopedic implants, and stents. SR studies can also involve products not introduced into the body, such as computer software used for prenatal risk evaluation. Each of these studies would require an IDE. For more information, see FDA guidance on Significant and Non-Significant Risk Medical Devices.

Example: A legally marketed coronary stent would be considered an investigational device and would require an IDE if used as part of a study to collect safety and effectiveness data for treating occlusions of other vascular sites.

When is an IDE from the FDA not required?

Studies involving devices that are considered to be non-significant risk (NSR): An IDE from the FDA is not needed for research when the sponsor provides a brief explanation of why the device is NSR and the IRB agrees with the sponsor’s explanation.

The following guidance includes examples of significant-risk devices and NSR devices: Significant and Non-significant Risk Medical Devices.

Process for obtaining an IDE

• Pre-IDE Process: Investigators considering submitting an IDE application to the FDA should communicate with the reviewing division of the Office of Device Evaluation (ODE) prior to the submission of an IDE application. See the FDA IDE Approval Process website for details.
• The IDE Submission: The IDE submission to the FDA and the IRB application should be initiated at the same time. The FDA has 30 days to review the IDE application. Likewise, the IRB typically reviews an application within a 30-day window, but it may take longer to secure approval. Subjects may not be recruited or enrolled before FDA and IRB approval.

IDE Letter and Detailed Description of the Device

For all investigational devices, you must submit detailed information about the device, similar to an Investigator’s Brochure.

For research involving a significant risk device, investigators must submit an IDE approval letter from the FDA with the application for initial review. If the sponsor has not yet received the approval letter, the IRB will review the study and may approve it with the condition that the study cannot start until the investigator submits a copy of the IDE approval letter to the IRB and the IRB acknowledges receipt.

Control of Investigational Devices

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:

• Ensuring that the investigational device is used only as described in the IRB approved protocol, the signed agreement, the investigational plan and applicable FDA regulations.
• Providing the investigational device only to participants under the investigator’s direct supervision or under the supervision of a sub-investigator responsible to the investigator.
• Supplying the investigational device only to persons authorized to receive the device.
• Maintaining accurate, complete, and current records relating to the investigator’s participation in an investigation, including records of receipt, use or disposition of a device that relate to: 
  • The type and quantity of the device, 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.
• Returning any unused devices or following the sponsor’s requirements for disposition of unused devices if the investigation is terminated, suspended, discontinued, or completed. See Sample Investigational Device Accountability Log.

Importing Medical Devices

A complete overview of medical device import/export regulations is provided by the Center for Devices and Radiological Health (CDRH). Clinical investigators should be aware that the FDA does not recognize regulatory approvals from other countries. Therefore, an imported medical device must meet all FDA requirements.

• The IDE sponsor must be located in the United States.
• Anyone who intends to import an investigational device takes on the responsibilities of a sponsor.

Drug-Device Combination Products

If an investigator is interested in investigating a combination product, the following links may be useful:

• The FDA’s Office of Combination Products (OCP) was created in 2002 to facilitate the review process for combination products by coordinating interactions between reviewing branches.
• The OCP provides applicable guidance documents for combination products.
• Some recent combination product approvals include: 
  • Drug-eluting coronary stents;
  • Spinal fusion putty; and
  • An influenza vaccine administered via an intranasal delivery device.

Device Classifications

The level of regulatory controls placed on a medical device is determined by the risk classification. Most research reviewed by the IRB involves significant risk, Class III devices. To help determine device classification, regulatory controls, and exemptions, the CDRH maintains:

• A searchable classification database containing information about all approved Class I, Class II, and Class III devices.
• A listing of Class I and Class II devices deemed exempt from Premarket Notification 510(k) regulations.

Required Approval Process to Use a New Device at UVA Health

No medical device (supplies, accessories, or equipment), whether purchased, contracted, donated, loaned or for trial, may be used at UVA Health 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 Form online at https://www.healthsystem.virginia.edu/newmedicaldevice/index.cfm?requestid=new

• FDA References 
  • Device Advice: Comprehensive Regulatory Assistance
  • Significant Risk and Non-significant Risk Medical Device Studies
  • Expanded Access to Unapproved Medical Devices
  • Guidance for Humanitarian Device Exemptions
• FDA Regulations: 
  • Investigational Device Exemptions: 21 CFR 812
  • Premarket Approval of Medical Devices (includes HUDs): 21 CFR 814
  • Medical Device Classification Procedures: 21 CFR 860
  • Requirements for Device Registration and Listing: 21 CFR 807
  • Electronic Records; Electronic Signatures: 21 CFR 11
  • Financial Disclosure by Clinical Investigators: 21 CFR 54
  • Quality System Regulation: 21 CFR 820