Which factors should medical device manufacturers take into account when trying to determine whether an investigational device is suitable to begin testing in humans? The US Food and Drug Administration (FDA) has some thoughts on the matter, contained within a new draft guidance document released on 17 June 2015.
The guidance, Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device Exemptions (IDEs), relates to the clinical trial process for medical devices.
When a medical device manufacturer wants to begin testing a device in human patients, it must apply for an IDE from FDA. In literal terms, an IDE is an application to be exempted from federal interstate commerce laws, which otherwise prohibit any unapproved devices from being sold or transported. In practical terms, however, an IDE simply acts as an application to begin testing a device and explains the rationale for why a device will likely be safe and effective in human patients with a particular condition.
The contents of an IDE are regulated under 21 CFR 812, Investigational Device Exemptions, and include elements such as an investigational plan, a report of prior investigations and FDA actions and an explanation of how the investigational device will be used.
A core component of the IDE review process involves weighing the expected benefits and risks of a device against each other, as well as in relation to the needs of the patient. As the IDE regulation explains, the expected benefits of the device must outweigh the anticipated risks in order for a study to go forward.
But as FDA implies in its new guidance document, sometimes that determination is easier to determine in theory than in practice.
Its new guidance document is therefore aimed at providing "greater clarity for FDA staff and IDE sponsors and sponsor-investigators regarding the principal factors that FDA considers when assessing the benefits and risks of IDE applications for human study."
Two elements should be at the core of any IDE application, the regulator notes: Certainty and risk mitigation. In early-stage testing, FDA says, sponsors may be largely uncertain about the risks or benefits attributable to an investigational device. Sponsors may become more certain about a device's benefits and risks through further study. In either case, companies will need to take steps to mitigate the risks to patients enrolled in a study. "For proposed IDE studies, at earlier stages of device development, FDA considers appropriate mitigation measures for anticipated possible risks and unanticipated risks, whereas in later stages risk mitigation focuses increasingly on the most probable risks," FDA wrote.
Another element that should be considered is informed consent: The concept that all patients should be made aware about the potential benefits and risks of participating in a clinical trial, as well as the limitations of a sponsor's certainty about those benefits and risks.
The crux of FDA's guidance, however, focuses on the establishment of a basic benefit-risk "framework … used both for supporting IDE decision-making, as well as decisions related to marketing submissions."
"FDA intends to permit appropriate latitude for the conduct of IDE studies within the boundaries of applicable laws and regulations. In considering whether risks outweigh the anticipated benefits to the subjects and the importance of the knowledge to be gained, absence of definitive evidence of benefit or the presence of purely hypothetical risks are not sufficient justification, in and of themselves, to disapprove an IDE application," FDA wrote.
The key, FDA said, will be in tailoring the risk mitigation efforts in each study to what is known about the device.
"Given the more limited level of evidence typically associated with IDE applications compared to marketing applications – especially for earlier stages of investigation – decisions about IDE applications are made in settings involving relatively greater uncertainty and a lower level of evidence," FDA's guidance explains. "The inherent uncertainty present in clinical investigations can often be offset by appropriately tailored risk control / risk mitigation measures which can assure appropriate patient and research participant protections in investigational research settings."
In addition, companies should take into account patient preferences, including a patient's tolerance for risk. Some patients with serious illnesses may be more accommodating to risk, while other patients with less serious illnesses may be less accommodating. "It may be appropriate to approve an IDE application where only a subset of the eligible study subject population would accept the risks as weighed against the benefits, provided there is enough information and an adequate informed consent process in place for study patients to make informed decisions," FDA wrote.
Companies will also have to compile an in-depth analysis of all risks and hazards the devices might present to patients, including the likely severity of those risks and hazards and how best to mitigate them and communicate them to patients.
Those risks must be weighed against the expected benefits, including the type of benefit(s), the magnitude of the expected benefits, the probability of the benefits and the duration of effect of the benefits.
Companies must also take into account the severity of the disease their device is intended to treat, existing treatments, the quality of prior clinical investigations and the proper design of studies.
FDA is accepting comments on its guidance document for the next 90 days.
Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device Exemptions (IDEs) (FR)