FDA outlines benefit-risk approach to drug or biologic product quality assessment

The publication outlines the benefit-risk principles applied by the US Food and Drug Administration (FDA) when conducting product quality-related assessments of chemistry, manufacturing, and controls (CMC) submitted for FDA assessment as part of original new drug applications (NDAs) or original biologics license applications (BLAs).

Industry has until October 7, 2022 to submit comments on the draft document​​.

The agency describes how the product quality assessment determines whether an applicant’s product development studies, manufacturing process, and control strategy will consistently result in a finished product of acceptable quality when manufactured at the facilities named in the application.

For biological products, a product quality assessment may examine the expression system used, the quality of the production cell banks, the manufacturing process, control of any microbial contaminants, and potential process-related impurities as well as product-related variants, outlined the US regulator.

When determining whether a drug or biological product meets the standard for approval, the FDA conducts an overall benefit-risk assessment that “takes into account the extensive evidence of safety and effectiveness submitted by a sponsor . . . as well as many other factors affecting the benefit-risk assessment.”​

Residual risk​

When a regulatory decision regarding the approval of an NDA or BLA is made, the agency said it also assesses any residual risk related to unresolved product quality issues, adding that, under most circumstances, when unresolved quality issues remain, it would not approve the application.

“However, in rare circumstances, an application may meet the standard for approval despite the presence of certain unresolved quality issues, as determined by the agency. In such a case, the residual risk posed by the unresolved quality issue may be outweighed by the benefits of the product and of having the product on the market more quickly,” ​reads the guidance.

In situations like this, the FDA said it might allow certain information to be submitted post approval. It gave examples of where this might be the case, such as where it determines it is not feasible for the product quality issue to be resolved before approval and it can be addressed post approval without an unacceptable level of risk.

“This could be the case when there is an unmet medical need, such as a serious disease or condition for which there is no available therapy. An unmet medical need may also exist where there are available therapeutic options but an additional clinically important benefit (such as superiority over current treatment options or comparable efficacy with a more favorable safety profile) has been observed. In these instances, the overall benefits observed (with the associated uncertainties) would need to outweigh the overall risks, including the residual risk, and this would be considered on a case-by-case basis; the more significant the residual risk the greater the benefit would need to be to outweigh that risk.”​

In such cases, FDA may use a quality post marketing agreement (QPA) for a product quality issue. 

Review challenges 

The agency said it may also need additional or new information to better understand potential risks previously not known or considered.

“These considerations may raise additional or new product quality issues and concerns. For example, a novel combination of a drug or biological product with another medical product, such as a medical device, or the introduction of a novel technology in the manufacturing process or analytical testing methodology could introduce additional complexity to the decision-making process by adding new risks and uncertainties relating to product quality.”​ ​