Although I have experience in drug and in-vitro diagnostic clinical trial, I am also familiar with medical device as in-vitro diagnostic products are regulated under the same regulation as medical devices.
So what is a medical device? Medical device is an instrument or reagent that is used to diagnose or treat disease without chemical action within the body. Due to the broad definition, medical devices can vary in complexity and application. In United States under FDA’s definition, medical devices can be categorized into the following three categories:
Class I – General Controls
Class I medical devices are subject to “general controls”, which are the basic rules to ensure safety and effectiveness. General controls include rules that regulate adulteration, misbranding, device registration and listing, premarket notification, banned devices, notification, including repair, replacement, or refund, records and reports, restricted devices, and good manufacturing practices.
Class I medical devices have the least harm to the user and thus, have the least amount of regulatory control. Example of class I medical devices include bandages, gloves, tongue depressors, and arm slings. Most class I medical devices are exempt from the 510(k) clearance and premarket approval (PMA) process. Some class I medical devices are also exempt from current good manufacturing practices (cGMP) requirements.
Class II – General Controls + Special Controls
Class II medical devices require special controls in addition to general controls above to ensure safety and effectiveness. Special controls include special labeling requirements, mandatory performance standards, post market surveillance, and FDA medical device specific guidance. Class II medical devices have greater potential risk to the user and thus, have greater amount of regulatory control than class I medical devices. Examples of class II devices include physiologic monitors, X-ray machine, infusion pumps, acupuncture needles, and powered wheelchairs.
Class II medical devices usually require FDA 510(k) clearance submission. Section 510(k) of the Food, Drug, and Cosmetic Act requires device manufacturer to notify FDA at least 90 days prior to marketing a device. This is called Premarket Notification – also known as PMN or 510(k). Upon notified FDA will determine whether the device is equivalent to previously approved devices and allow the device to be sold. There are some class II medical devices that are exempt from the 510(k) process. Below is a link to FDA’s webpage for a list of 510(k) exempted devices. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.cfm
Class III – General Controls + Premarket Approval
Class III medical devices usually support or sustain human life and therefore present significant risk to illness and injury. Class III devices require the most regulation, specifically general controls and premarket approval. FDA requires a premarket approval application (PMA) to be submitted for most Class III devices. FDA reviews PMA in a similar way to the new drug application (NDA) for new drug to ensure safety and effectiveness. Thus, class III device under PMA will need to perform clinical trial in human to show safety and effectiveness. Examples of class III medical devices include HIV diagnostic tests, pacemaker, silicone gel-filled breast implants, and drug eluting stents.
Medical Device Clinical Trials
Clinical trials for class III medical devices fall under FDA 21 CFR 812 regulation. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=812
Similar to clinical trials for new drug, clinical trials for new PMA required devices require IRB review and oversight and appropriate monitoring to ensure patient safety. Animal studies are usually conducted as needed prior to human clinical trial.
Unlike drug trials, medical device trials do not have phases. Medical device trials usually have pilot and pivotal trial, both in patient population with the disease or condition the medical device is intended to treat. Pilot study usually is done in smaller number of patients and pivotal trial is done with larger number of patients. Often, the results from both pilot and pivotal trial are combined for analysis.
In addition, post-market studies are also often done after marketing approval to learn more about the safety and effectiveness of the device in larger population.
Significant Risk, Non-Significant Risk, and Exempt Studies
Regardless of the regulatory approval route a medical device will go through (510(k), PMA, etc.), an Investigational Device Exemption (IDE) is needed for an investigational device to be used in a clinical study to evaluate safety and effectiveness. One exception to this is for exempt studies which will be discussed below.
Three types of medical device studies are:
- Significant risk (SR)
- Nonsignificant risk (NSR)
- Exempt studies
Significant Risk (SR)
FDA 21 CFR 812.3(m) defines significant risk (SR) device as 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 use 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.
Nonsignificant Risk (NSR)
A nonsignificant risk device is an investigational device that does not meet the SR requirement above. Sponsors are responsible for making the initial determination whether the device under study is SR or NSR and present it to the Institutional Review Board (IRB). FDA may also be available to help the sponsor, clinical investigator, IRB in determining the risk of the device.
Differences Between SR and NSR Device Studies
Differences between SR and NSR studies are:
According to FDA 21 CFR 812.2(c), an IDE exempt study involves:
- A device in commercial distribution on or before May 28, 1976.
- A device that FDA deemed substantially equivalent to a device in criteria 1 above, and that is used following indications in the labeling FDA reviewed under subpart E of part 807 in determining substantial equivalence.
- A diagnostic device, if the sponsor complies with applicable 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 of the diagnosis by another, medically established diagnostic product or procedure.
- A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, 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 on or with laboratory animals and labeled in accordance with 21 CFR 812.5(c).
- A custom device as defined in 21 CFR 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.
If one of the above is met, then the device study is IDE exempt and can be carried out under IRB approval and review without FDA notification.
Below is a diagram summarizing specific clinical study pathway for significant risk, nonsignificant risk, and IDE exempt devices.
Differences Between Drug and Medical Device Clinical Trials
In addition to the difference in trial phases as described above, below are some more differences between drug and medical device clinical trial.
FDA requires agreement between sponsor and investigator for both drug (21 CFR 312.56) and medical device trial (21 CFR 812.46). The difference is that drug trial uses FDA form 1572 while medical device trial uses an agreement called “Investigator’s Agreement.” No specific format is given by the FDA for this agreement. However, the agreement should specify investigator’s:
– Commitment to conduct the study following regulations
– Supervision of the trial
Caring Physician’s Involvement
The level of care or hand on treatment to patient from caring physician is different between drug and medical device trial. In drug trials, the caring physician would give consultation and monitor the health of the patient throughout the study. Supporting staff such as nurses can help with some of the tasks, such as giving dosing instruction and dispensing study drug. For medical device trials, often the skills of the caring physician or surgeon can be critical to the success of the trial. For example, placing a drug eluting stent inside vascular vein requires highly skilled vascular surgeon. Thus, the level of direct or hand on treatment by caring physician can be different between drug and medical device trials.
Most investigational drugs for clinical trial use are provided to investigator as part of the conduct of the trial. For some medical device trials, investigators are charged for the devices and are then reimbursed by insurance company or by government program such as Medicare.
Adverse Events Data Collection
For drug trials, all adverse events are usually recorded and evaluated for relationship to the drug given. This is different for medical device trial. Due to local effect of device, not all adverse events may need to be collected and evaluated for relationship to the medical device inserted into the patient. For example, a rash on a patient’s foot may not be recorded or evaluated for association with the pacemaker inserted into the patient. Also, the terms used for adverse events are different between medical device and drug trial. Unanticipated adverse device effect (UADE) is used for medical device trial. Serious adverse event (SAE) is used for drug trial.
Number of Subjects
As new drug go through the later phases of development (Phase II and III), the number of subjects needed for these trials can range from several hundreds to thousands. Not so for medical device trials. Pivotal trials for medical devices are generally done in hundreds but not in thousands.
Reporting of Serious Adverse Events
For drug trials, sponsor has 15 calendar days to report to FDA a serious and unexpected adverse drug event. For medical device trials, sponsor has 10 business days to FDA an unanticipated adverse device effect.
Picture Credit: DSC_3892, by Philip Dean, flickr