The regulator is clarifying the “principal factors” it will take into account with assessing the benefits and risks of IDE applications for human clinical study, and describing risk mitigation measures, in a bid to improve review process predictability and patient access to new devices.
The document Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device Exemptions (IDEs) is primarily aimed at spelling out the factors considered during the assessment of risks and anticipated benefits for IDE studies, and how to offset uncertainty using risk mitigation measures. According to the FDA, using the benefit-risk framework in an IDE application will make it easier to incorporate evidence and knowledge from different domains – clinical, nonclinical and patient – to support a “comprehensive, balanced decision-making approach,” as well as improve the predictability, consistency and transparency of the IDE application review process.
The guidance goes over the informed consent process and the standard for IDE decisions, calling the former a “key tenet” to the FDA’s IDE benefit-risk framework by way of being a key principle of human subject protection in clinical investigations. Regarding IDE decisions, the guidance further clarifies assessment of risks and benefits associated with a device use proposed in the application, and inadequacy or uncertainly about the data from prior studies; the proposed study; the manufacturing, transport and storage of the device; or monitoring of the study. With three main decision categories on IDE applications, the FDA may grant approval, approval with conditions or disapproval. The FDA also notes it will consider study design, which has a “direct bearing on the knowledge that can be gained from that study.”
The FDA also explains IDE application evaluation in the context of a device development pathway, stating that during IDE benefit-risk assessments, it considers the stage of device development, the maturity of the technology, and the availability of nonclinical testing to accompany or substitute clinical testing. Given that device investigations at different stages of developments are usually associated with different types of risks and levels of uncertainty, the assessment should be tailored to the device development stage. The guidance also states nonclinical data plays a key role in determinations throughout all stages of development, noting that in certain cases nonclinical testing can reduce the need for additional clinical testing.
As stated in the guidance, because IDE applications have a more limited level of evidence than do marketing applications, decisions related to the former are made in settings that involve greater uncertainty and less evidence. However, this uncertainty can be offset by tailored risk control/mitigation measures. In taking into account benefits of investigational research, the FDA weighs direct benefits to the subjects and benefits to others – either indirect benefits to subjects or the gain of important knowledge.
When the FDA assesses benefits and risks for an IDE application, it also considers the contextual setting in which the study is being proposed, including characterization of the disease or condition being treated or diagnosed, the availability of alternative treatments or diagnostics, and the risks associated with them. Information about subject tolerance for risk and perspective on benefit may also be useful in terms of context – when it’s available.
The FDA also dedicates a section of the guidance to outline its approach to assessing benefits and risks of IDE studies, recommending that sponsors include a summary of the key considerations. These are listed as patient preference as it relates to the participants in the study, and a description of the investigational device as well as a risk analysis related to its use. The risk assessment of IDE subjects should involve the description of the relationship between a hazard and harm, whose extent is determined by types of risks – including severity, likelihood or probability – and duration. Also considered are residual risk evaluation and risk management, with the FDA noting that risk controls that can be applied to IDE studies include safety by design, protective measures and communication of safety information.
The guidance also describes assessment of other risk considerations of investigational studies, including those related to study data, benefits of gained knowledge and risk to others, as well as of direct benefits to study subjects and to others. The FDA concludes with several appendices, including one that includes recommendations related to the benefit-risk summary and what it should address, one that provides hypothetical examples for illustrative purposes, one that goes over the investigational device description and one that provides a glossary of risk management terms.