FDA releases draft guidance on use-related risk analysis for combo products

The US Food and Drug Administration (FDA) has released a draft guidance outlining the purpose and content of a use-related risk analysis (URRA) for drug- and biologic-led combination products.

The URRA draft guidance is relevant for drug- and biologic-led combination products, as well as human nonprescription drug products that are part of an investigational new drug application (IND), a new drug application (NDA), or a biologics license application (BLA) or supplements to IND, NDA, or BLA applications. “A URRA is important to help identify use-related hazards associated with the user interface design of the combination product, as well as to characterize risks so they can be mitigated (such as through risk controls) or eliminated through improved product user interface design,” FDA said.

While FDA said the process of creating and analyzing a human factors (HF) study is beyond the scope of the draft guidance, they explained that URRA can be used during a product’s development phase with other information to identify HF data needs as well as provide support in a marketing application.

“The URRA, along with other information, such as comparative analyses, can help inform whether the sponsor should submit HF validation study results for Agency review as part of the marketing application,” the agency said. “The URRA is also a key component in developing an HF validation study protocol and informing the acceptability of residual risks.”

FDA noted that an URRA should be considered while creating a risk management framework for a product, should cover the entire human factors engineering process, and may be present in every phase of a medical product’s lifecycle. URRAs should be created early in a product’s development and updated as needed during that product’s lifecycle.

Key components of an URRA include a “comprehensive list” of required tasks for a product related to its use, documentation of potential errors and harms that could take place when completing required tasks, noting what tasks are critical, any risks controls for the reduction of errors associated with product use, and methods for evaluating risk control effectiveness.

When identifying intended product uses, sponsors need to consider both physical as well as knowledge-related tasks associated with the product, such as interpreting the information on the label for a product. When describing potential errors, FDA said documenting “what use errors can be reasonably expected to occur” is sufficient, and sponsors can draw on information from their experience with the product, literature reviews, adverse event reports, product safety communications, or similar products in the market to identify potential use errors.
“For each potential use error, the sponsor should consider the potential harms and clinical impact. Clinical impact may vary greatly depending on the disease condition and severity, whether the medication has a narrow therapeutic index, dose frequency, treatment urgency, and magnitude of potential underdose or overdose, and other factors,” the agency said.

Sponsors also need to consider the potential impact associated with a single use error or repeated use errors. “These and other considerations are important for understanding the clinical impact of any use errors and the acceptability of the residual risk,” they wrote.

In implementing risk controls for products, FDA said the focus should be on risk controls that eliminate or mitigate risks for combination products at the design level instead of through labeling or training. “Once the risk controls have been identified, sponsors should include specific details about how they have evaluated or intend to evaluate the risk controls,” the agency said. “For example, sponsors may indicate that a particular risk control will be evaluated as part of a specific task in the proposed human factors validation study protocol.”

Sponsors can submit URRAs with other supporting information to signal to FDA that a product does not need HF validation study results. Supporting information could include comparative analyses with a similar combination product and would depend upon the regulatory pathway used. “If the sponsor determines that differences (if any) identified in the comparative analyses do not warrant submitting HF validation study results to the marketing application, the sponsor should submit the URRA and any other supportive information, such as comparative analyses, together with the justification for not submitting an HF validation study for review under the IND,” the agency said.

Another use for an URRA is to design an HF validation study with appropriate risk control strategies for a particular product. “It is important to note that there is a connection between the tasks and risk controls in the URRA, the labels and labeling, and the HF validation study protocol,” FDA wrote. “For example, critical tasks identified in the URRA often use the labels and labeling as one aspect of risk control, and the sponsor should evaluate these risk controls in the HF validation study.”

Draft guidance

FDA releases draft guidance on use-related risk analysis for combo products

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