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Biologic Therapeutics Development, Part 2: Regulatory Pathways and Pharmacometric Analysis

Sponsors developing biologics must manage numerous scientific considerations specific to large-molecule products, including biochemical characterization studies to confirm structural identity, biological activity studies to confirm potency, and mechanism of action maintenance. Clinical trials of biologics are designed to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy. PK studies are used to confirm that dosimetry remains unchanged, and toxicology studies are needed to confirm that the therapeutic ratio and safety profile remain unchanged.

This second of two parts gives an overview of general clinical pharmacology considerations in biologics development. Part 1 focused on these products’ definition and distinct characteristics, and in Part 2 we cover regulatory pathways and pharmacometric analysis for biologics.

Regulatory considerations for biologics

The FDA’s Center for Drug Evaluation and Research (CDER) and its Center for Biologics Evaluation and Research (CBER) have regulatory responsibility for therapeutic biological products, which are subject to the federal Food, Drug, and Cosmetic Act and the Public Health Service Act. A biologics license application (BLA) is required for biological products subject to licensure under the Public Health Service Act, and FDA approval to market a biologic is granted by issuance of a biologics license. The regulations regarding BLAs for therapeutic biological products are included in 21 CFR parts 600601, and 610.

Section 351(a) is the traditional pathway for approving biologics under the Public Health Service Act. An application submitted under 351(a), also known as a standalone application, must contain all safety and effectiveness information for a biological product and cannot depend on any other biological product. A 351(k) application is a BLA process submitted by a manufacturer to get a product reviewed as a biosimilar or interchangeable, which is considered to be “highly similar” to an FDA-licensed reference product. A 351(K) application must include information explaining that the biosimilarity is based completely on the data related to animal studies, clinical studies, and analytical studies.

CBER regulates products under a variety of regulatory authorities:

Pharmacometrics for biologics


In the development of new biologics, pharmacometric analysis is necessary from the early stages of development up to BLA or biosimilar submission. Pharmacometrics is used to describe the early PK of a product in animal species, correlating with the relevant target biomarkers. The main objective of this early work is to identify the target doses and dosing regimen in humans, though the information is needed even before first-in-human studies. The target doses are first used in planning GLP toxicology studies, as incorrect dose selection for these animal studies may make a product appear more toxic than it is if the actual needed doses are lower than tested. This could lead to early and unnecessary attrition of the candidate. Conversely, a product may advance to clinical studies with insufficient safety information if higher doses than were tested properly in animals are required for efficacy.

Safety and efficacy evaluation

Pharmacometrics also allows parallel evaluation of exposure and response practically in real time to optimize study designs, augment efficacy in the treatment of patients, and detect potential safety issues as soon as they arise. This is done by watchfully monitoring exposure and relating it to any observed safety signals and efficacy outcomes. Searching for and correlating biomarkers also supports safety and efficacy and may additionally lead to the validation and qualification of surrogate biomarkers to reduce the duration of future efficacy trials. Use of PK and PD similarity data can remove the need for a comparative efficacy study for a biosimilar approval and lead to a more efficient, streamlined program.

Product type-specific analysis

The exact type of the biologic under consideration has tremendous impact on the analysis. Bispecific antibodies, antibody-drug conjugates, and gene therapies all have their own specific features that must be taken into account. One common characteristic of most if not all biologics is the triggering of an immune response or anti-drug antibodies. Though most biologics and even drug polymers can elicit immune responses, the consequences associated with those responses can vary vastly depending on the product type, so differing methods are required to detect and quantify them. Multiple modeling methods are available to incorporate these effects and evaluate their importance.

Analysis of biosimilars

The role of pharmacometrics for biosimilars is no less significant than for biologics. On the contrary, due to the complexity involved in comparing the structures of biologics, selecting the correct sampling times to prove bioequivalence for both PK and biomarkers is of primary importance. In some cases, the exact PD parameters for comparison need to be derived without availability of prior information. In the same way, sample size estimates may need to be simulated if such information about the originator product was not obtained through past development.

For example, the European Medicines Agency and other regulatory agencies recognize the importance of the C-terminal telopeptide (CTX) biomarker comparison between the osteoporosis treatment denosumab and its biosimilar candidates. The correlation between a decrease in CTX and the preservation of bone mineral density is well established, but criteria for correlation to efficacy and relevant clinical endpoints currently exist only for daily phosphonate treatments. The profile for twice-a-year denosumab injections differs significantly: CTX levels stay low, sometimes below the level of quantitation, for two or three months and only then start rise to back to baseline. Because of this significant difference, the profile requires different PD parameters for comparing the change from baseline CTX levels. Using the traditional AUE parameter over the complete dosing interval may miss fine differences in the pharmacodynamics and the correlation to clinical endpoints. Therefore, the comparison needs to focus on most sensitive areas of the PK-PD profile.

The importance of having an FDA-vetted regulatory strategy and of conducting pharmacometrics analysis at all stages of biologics development cannot be overstated. Premier Consulting can help you to move your biologic product through the development process with our high-science, creatively bold solutions. Contact us to learn how we can advance your program.


Agnieszka Marcinowicz, PhD
Manager, Pharmacokinetics

Stacey Ayres, PhD
Vice President, Regulatory and Strategy