Guidance Breakdown: Purpose and Content of Use-Related Risk Analyses for Drugs, Biological Products, and Combination Products
The FDA outlines a comprehensive approach to identifying and mitigating use-related risks for drugs, biologics, and combo products throughout product lifecycle.
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The FDA has issued new draft guidance on conducting use-related risk analyses (URRAs) for drugs, biologics, and combination products. The guidance, titled "Purpose and Content of Use-Related Risk Analyses for Drugs, Biological Products, and Combination Products," provides detailed recommendations for identifying, analyzing, and mitigating potential hazards associated with product use throughout the entire product lifecycle.
This draft guidance applies primarily to drug- and biologic-led combination products with device components submitted under INDs, NDAs, and BLAs. It may also be relevant to certain standalone drug and biological products.
At its core, the URRA is presented as an essential component in ensuring product safety and effectiveness. It guides manufacturers in anticipating how their products might be used — or misused — in real-world settings, covering everything from initial design considerations to postmarket surveillance. The FDA emphasizes the importance of integrating URRA development early in the product lifecycle and maintaining it as a living document throughout all development and marketing stages.
Who should pay attention to this guidance
Entities impacted by this guidance and who should thoroughly understand it include:
Pharmaceutical Companies: Those developing drug products, both prescription and nonprescription; as well as entities involved in NDAs and INDs.
Biotechnology Firms: Companies developing biological products and those submitting BLAs and related supplements.
Medical Device Manufacturers: Manufacturers of combination products that involve drugs or biologics.
Regulatory Affairs Professionals: Individuals responsible for preparing and submitting regulatory documents to the FDA.
Human Factors Engineers and Usability Specialists: Professionals involved in the design and testing of user interfaces for drugs, biologics, and combination products.
Risk Management Teams: Teams responsible for identifying, analyzing, and mitigating use-related risks in product development and post-market phases.
Clinical Research Organizations (CROs): Organizations conducting clinical trials and human factors studies for drug and biologic products.
Quality Assurance and Compliance Teams: Professionals ensuring adherence to FDA regulations and guidance throughout the product lifecycle.
Consultants and Regulatory Advisors: Experts providing guidance and support to companies in preparing URRAs and other regulatory submissions.
Purpose and Scope
The draft guidance provides comprehensive information on the purpose, content, and utilization of URRAs throughout the product development lifecycle and as supporting documentation for marketing applications. This guidance is primarily aimed at drug- and biologic-led combination products that include a device constituent part. Specifically, it applies to products that are the subject of INDs, NDAs, or BLAs, as well as supplements to these applications.
The scope of this guidance extends beyond just combination products, however. In certain cases, it may also apply to standalone drug and biological products. This includes human prescription drug products, including biological products, that are the subject of INDs, NDAs, or BLAs and their supplements. It also covers human nonprescription drug products subject to INDs or NDAs and supplements for these applications.
The guidance serves multiple purposes within the product development and approval process. During product development, URRAs are intended to identify use-related hazards associated with product use and outline the measures implemented to reduce those risks. They are meant to support the entire human factors (HF) engineering process and should be considered part of an overall risk management framework.
In the context of marketing applications, URRAs and other supporting information, such as comparative analyses, can be used to justify whether or not human factors validation study results need to be submitted for Agency review. They are also a key component in developing HF validation study protocols and informing the acceptability of residual risks.
Furthermore, the guidance emphasizes that URRAs should be initiated early in product development and updated in all product lifecycle phases. This includes updates as the product design changes or as new risks are identified during development or post-marketing.
It's important to note that while this guidance provides recommendations on URRAs, it does not describe the methods used to design, conduct, or analyze HF studies, how to conduct comparative analyses, or how to submit HF protocols or study results. (The FDA recommends that sponsors refer to other relevant guidance documents related to product design and HF for these aspects.)
The guidance also clarifies that it does not apply to medical products submitted under ANDAs, although ANDA applicants may find a URRA helpful in their development process.
The URRA Development Process
The URRA development process outlined in the guidance puts the components into a systematic and iterative process that forms a critical part of product development and risk management.
The FDA guidance outlines a structured approach consisting of seven key steps, each building upon the previous to create a thorough understanding of use-related risks and appropriate mitigation strategies.
Let’s break it down:
Identify all user tasks (physical and knowledge-based). The process begins with developing a comprehensive and systematic list of all tasks involved in product use. This includes both user tasks (related to the physical use of the product) and knowledge tasks (involving assessment of information provided in labeling). Tasks can be identified through methods such as task analysis or contextual inquiry. The sponsor should consider all intended uses of the product, potential users, likely use environments, and the entire product lifecycle (from acquisition to disposal), as these factors may impact product design, user tasks, and subsequent risks.
Identify potential use errors for each task. For each identified task, the sponsor should determine what use errors can be reasonably expected to occur. This includes considering reasonably foreseeable misuse, including product use by unintended but foreseeable users. Simple examples include task omission, but more complex errors should also be considered. Tools like FMEA or fault tree analysis can aid in this identification. Sponsors should also draw from their experience with the proposed product (e.g., during clinical trials), literature reviews, adverse event reports, and product safety communications. For products similar to marketed ones, the FDA recommends analyzing postmarket safety databases and other sources (e.g., the FDA Adverse Event Reporting System, ISMP newsletters).
Determine potential harms and clinical impacts. The sponsor should consider each potential use error's potential harms and clinical impact. The FDA says it’s crucial to consider both one-time errors and the impact of repeated errors, as in some cases, a single error may not have a significant clinical impact, but repeated errors could. This assessment should take into account factors such as:
disease condition and severity;
whether the medication has a narrow therapeutic index;
dose frequency;
treatment urgency, and
the magnitude of potential underdose or overdose.
Categorize tasks as critical or non-critical. Each task should then be categorized as either critical or non-critical. For combination products, critical tasks are defined as "user tasks which, if performed incorrectly or not performed at all, would or could cause harm to the patient or user, where harm is defined to include compromised medical care." This categorization should help prioritize risk mitigation efforts and inform the design of human factors validation studies.
Identify risk controls for each potential error. For each potential use error, the sponsor should identify risk controls to either reduce or remove the associated risk and potential harm. Risk controls should be implemented following a priority order:
(1) inherently safe design and manufacture;
(2) protective measures in the product itself, and
(3) information for safety (such as labels and labeling) and, where appropriate, user training. The emphasis should be on eliminating or mitigating risks through device design when feasible rather than relying on labeling or training.
Specify evaluation methods for risk controls. Once risk controls have been identified, sponsors should include specific details about how they have evaluated or intend to evaluate these controls. This could involve indicating that a particular risk control will be evaluated as part of a specific task in a proposed human factors validation study protocol or through other appropriate evaluation methods.
Update URRA throughout the product lifecycle. The URRA should be updated in all phases of the product lifecycle. This includes updates as the product user interface or risk controls change or as new risks are identified during development or post-marketing. For combination products, sponsors should consider HF principles when making design changes, as outlined in relevant FDA guidance documents.
Submitting a URRA
The guidance outlines two primary scenarios where the URRA is particularly valuable in submission: justifying the absence of HF validation study results and developing protocols.
The guidance emphasizes the URRA's importance in both scenarios. It also highlights the interconnected nature of the URRA, product labeling, and HF validation studies in the overall risk management strategy for the product.
Justifying that HF validation study results do not need to be submitted
The URRA, along with other supportive information such as comparative analyses, can be used to justify why HF validation study results are not necessary for Agency review in the marketing application.
If the same or similar combination products exist, sponsors may conduct comparative analyses, which include: