Bridging and Extrapolation Approaches

A modeling technique called extrapolation (also known as “bridging”) is used throughout drug development and can be particularly useful to accelerate your program and fill certain regulatory requirements or “gaps.” In some cases, bridging data can even be used to avoid a new clinical trial altogether. In these situations, preexisting data can be leveraged to support new formulations, dosage forms, dosing regimens, routes of administration, and more, without having to conduct new studies. Extrapolation using modeling and simulation approaches is used to support 505(b)(2) applications and support pediatric drug development (as illustrated below) and has been applied to many drug development strategies harnessing data for the efficient development of medicines for patients who need them.

505(B)(2) Pathway

The 505(b)(2) pathway is a streamlined NDA process in which the applicant relies upon one or more investigations conducted by someone other than the applicant. In other words, the 505(b)(2) pathway enables investigators and/or manufacturers to apply for regulatory approval without having to repeat all the drug development work done for an innovator drug, offering tremendous opportunity for sponsors.

When planning your 505(b)(2) development program, you must determine how the new drug product is different and similar to the innovator drug. From there, you can leverage all information relevant to the new drug product by creating a “bridge” linking the in vivo performance of the new drug product to that of the innovator drug product (e.g., establishing a strong PK/PD relationship, matching PK exposure and time course for the reference product, using a defined therapeutic index to assess clinical impact, and more efficient confirmatory studies). Understanding how to best link the two products is an essential step in maximizing the full streamlining capability of the 505(b)(2) approach and requires experts in these techniques to be successful.

Pediatric Drug Development

Extrapolation approaches are regularly used to assist in pediatric dose selection and to optimize trial design. For pediatrics, extrapolation aims to scale the previously established model describing the adult data to children based on body size, physiological differences, ADME, and disease features, as appropriate. This modeling approach provides a rationale for the doses by size and age to achieve similar efficacy or efficacy targets in adults. In addition, you can avoid testing uninformative and unnecessary dosing regimens in pediatric patients.

The information gained from bridging/extrapolation using modeling and simulation can lead to conducting efficient (i.e., parallel, fewer and/or shorter) pediatric studies by optimizing sampling and maximizing the information collected on a drug’s PK and PD in this population.

Bridging and Extrapolation Services: 

• New formulations, dosing regimens, routes of administration, fixed dose combination formulations, dose and device combinations, etc.
• 505(b)(2) applications
• Pediatric dosing and development
• Biosimilars
• Leveraging mechanistic and competitor data
• Other specific populations such as pregnant and breast-feeding women, elderly, patients with renal impairment or hepatic impairment, and more.
• Over the counter products
• Ethnopharmacology bridging