Medical Device Clinical Trials
We conduct a large number of clinical trials for new medical devices, as well as pharmaceutical / drug trials. In general, the approach to testing devices is fairly similar to testing new drugs – there is a need for preclinical research, there are strict regulations, safety and ethical requirements, and the testing process is broken up into a series of phases/stages. Our previous article, “Introduction to Clinical Trials”, provides an overview of these topics and more. There are, however, some obvious differences when conducting clinical trials for medical devices, compared to pharmaceutical trials, which we will describe here.
Classification of Medical Devices
By definition, a medical device is any “article, instrument, apparatus or machine that is used in the prevention, diagnosis or treatment of illness or disease, or for detecting, measuring, restoring, correcting or modifying the structure or function of the body for some health purpose” (World Health Organisation). This includes something a simple as an adhesive bandage, artificial body parts (prostheses), any surgical, diagnostic or monitoring equipment/devices, as well as advanced, implanted devices such as pacemakers and neurostimulators.
Medical devices are classified based on their intended use, invasiveness, duration of use, and the risks and potential harms associated with their use. The following table provides an overview of the classes defined by the Therapeutic Goods Administration (TGA) Australia:
|IIa||Low to moderate||Maybe||
|IIb||Moderate to high||Maybe||
|AIMD||High (Active Implantable Medical Devices)||Yes||
When do Medical Devices Require Clinical Trials?
Not all medical devices will require clinical trials before they may be approved for market release. Class I devices are such low risk that they don’t require clinical trials. In Australia, however, all medical devices regardless of their class must comply with the Australian Regulatory Guidelines for Medical Devices (ARGMD), which includes requirements for device design and manufacturing, benefits that outweigh the risks, minimisation of risks and unwanted effects, and so forth. With the exception of Class I devices, they must also be registered with the Australian Register of Therapeutic Goods (ARTG). The approval process may require an audit and clinical evidence or data. Whether a device needs to undergo clinical trials relies on its class, whether it is substantially similar to or based on an already approved device, and/or whether significant clinical data to support the new device has already been published in the medical literature or not.
From Idea to Clinical Trials to Market
Idea & Prototype
The idea for a new medical device usually comes from the mind of a physician and/or an engineer, as opposed to a new drug, which usually comes from basic laboratory research. If the idea is determined to be workable and practical (proof of concept) an early design of the device, known as a prototype, will be built.
A prototype device will undergo a cycle of preclinical testing -> redesigning -> preclinical testing of the redesign -> and so forth, until the design has been refined and tested to a point that it is ready for production and testing in humans. Preclinical testing may involve the following:
- Bench testing – Laboratory / workshop testing to assess the performance and safety of the device and make sure that it does what it was designed to do.
- Technical testing – Engineering and quality testing of the materials and the electronic / mechanical elements of the device for accuracy and reliability. The prototype will usually be rebuilt using different materials.
- Computer simulations – By applying maths and scientific understanding of human biology and diseases, computers may be used to virtually model how a device should function in the human body. Computer simulations can provide accurate predictions about the device’s effects in humans and identify potential risks or unwanted effects that may be improved by redesigning the device.
- Animal studies – If appropriate, a device will be tested in animals to assess its biocompatibility, toxicology and other potential safety concerns. Efficacy testing may be performed in animals but is not always possible because of anatomical and biological differences, particularly if the device is intended for complex or rare human diseases.
Regulatory & Ethics Review
Before a clinical trial involving a new device (or drug) may begin, the proposed study and device must undergo a review and notification process for the purpose of ensuring the safety of study participants:
- The study (protocol + consent form + other study documents) must be reviewed and approved by a Human Research Ethics Committee (HREC) (or an Institutional Review Board (IRB) in the U.S.). They will also continue to monitor the trial.
- The site(s) at which the trial is proposed to take place at will perform a Site Assessment or a Research Governance review, in order to decide if the study is appropriate for the site to conduct (e.g. in terms of the site’s policies, capabilities, etc).
- If the device is new (unapproved) or is to be tested for an unapproved use, then the sponsor (who is usually the company behind the new device) must notify or submit an application (CTN/CTX scheme) to the TGA (Australia) before clinical trials can be conducted. If the device is already approved and will be used as per its approved use, then neither of these is required. Whether the CTN or CTX scheme is appropriate relies mostly on the availability and quality of preclinical safety data for the device.
- The CTN (Clinical Trials Notification) Scheme involves notifying the TGA of the intention (via an online form) to use the new device and paying a fee. The TGA records, but does not assess preclinical data, the trial design or risks vs harms etc – that is up to the HREC.
- The CTX (Clinical Trials Exemption) Scheme involves an initial evaluation process, whereby an application is submitted and a fee is paid to the TGA before using the device. The TGA will review technical device information and any preclinical or early clinical data, and the HREC will do the rest. This scheme is generally required for high risk devices or new technologies where there is limited or no safety data. Once approved, the device may undergo any number of clinical trials without the need for further TGA evaluation.
Medical Device Clinical Trials
Phases vs Stages
In our previous article, “Introduction to Clinical Trials”, we talked about how clinical research is broken up into a series of “phases”, each with a different distinct purpose, beginning with (though not always conducted) pilot studies, then safety testing, then efficacy testing, then clinical efficacy, and, if approved for market release, post-market monitoring. New pharmaceuticals/drugs all undergo this clinical trial phase sequence. For medical devices, the sequence is fairly similar, and some devices do go through a clinical trial phase process, however, most medical devices will go through clinical trial “stages”, instead of phases. The table below provides a side by side comparison of pharmaceutical trial phases versus medical device trial stages.
|0 Pilot / Exploratory||10 - 15||
||Pilot / Early Feasibility / First-in-Human||10 - 30||
|I Safety & Toxicity||10 - 100||
||Traditional Feasibility||20 - 30||
|II Safety & Efficacy||100’s||
|III Clinical Effectiveness||100’s - 1000’s||
|IV Post-Market / Surveillance||1000’s||
The gold standard of study design for clinical trials is a randomised controlled trial, preferably with blinding and a placebo as the control. To recap on this terminology:
- Controlled means that there is a control group of participants who receive no treatment, a placebo, or some other treatment (comparison study);
- Randomised means that trial participants are randomly assigned to either the treatment group or the control group;
- Blinding means that participants don’t know which treatment they are receiving (single-blinded), and in some studies, neither do the doctor(s)/study coordinated (double-blinded).
This study design is often much more difficult or not possible to implement for medical devices, however. A well-controlled study design is generally acceptable. The table below compares study design elements between pharmaceutical and medical device trials:
Placebo / Sham
There is a lot of controversy surrounding the use of a placebo for surgical / implanted devices because the standard placebo would be a sham surgery or implantation of a sham device. Sham procedures are high risk and may be considered unethical. Without this kind of control, however, there is no sure way of knowing whether the device is providing real clinical benefit or if the benefit experienced is due to the placebo effect. It is the job of the ethics committee to determine if the risks associated with a sham surgery outweigh the risk of mistaking clinical benefit for a placebo effect.
For implanted devices that don’t induce any physical sensations (e.g. neurostimulators that don’t produce paraesthesia / “pins and needles”), the issue of a placebo may be balanced by implementing a crossover study design. An example would be a study in which all patients receive the implanted device, however, the patients in the control group don’t have their device switched on (activated) until the crossover point, at which point device activation/deactivation would be reversed between the groups. This kind of study could be blinded, although double-blinding may be difficult as someone would have to activate/deactivate the devices.
Health Professionals Involved in Device Trials
Along with the standard list of health professionals involved in clinical trials, such as the study doctor(s) / investigator(s) and clinical trial coordinator(s), patients in medical device trials will usually see the following additional health professionals:
Device Technicians / Programmers
For trials involving implanted devices or devices that require regular check-ups, maintenance and/or programming, patients will typically be seen by a representative of the device company. This person may also be known as a technician or programmer. They will usually be present at the implant surgery and will meet with the patient during their post-op visit to check on and activate the device.
For neurostimulators and other programmable devices, the programmer will spend time with the patient while they tweak the device’s program settings in order to suit the patient’s individual needs. There is rarely a one-size fits all approach to programmable devices, and so this visit may take much longer than standard study visits. Multiple programming visits are often required, whether on a regular or an as-needed basis, in order for the programmer to optimise the device and address any potential unwanted effects or adverse events.
For surgical/implanted devices, patients will be seen by a nurse. Advanced devices such as neurostimulators may also require a patient education session, which may be led by a nurse. Nurses may perform post-operative wound checks and phone calls to check on patients, however, the study coordinator will remain the primary contact person for study patients.
Many device trials will involve medical imaging staff, either for screening / diagnostic purposes (including x-rays, CT-scans, MRI scans) and/or to check the anatomical placement of an implanted device. Other health professionals that may be involved include pathology staff (i.e. for blood tests), psychologists, physiotherapists, and so forth, depending on the device and trial design.