Why should PD biomarkers be explored?
In the US, the 2009 enactment of the Biologics Price Competition and Innovation Act, established an abbreviated approval pathway for the licensure of biosimilar and interchangeable biological products. To have a biosimilar product approved, a stepwise approach must be followed. Firstly, the product must be analytically established as “highly similar”, then animal studies and clinical studies that assess safety/immunogenicity are carried out. Pharmacokinetic (PK) similarity and, when appropriate, PD similarity must then also be demonstrated. If the PK and PD data is sufficient, in some cases, biosimilars may be approved without a comparative clinical study with efficacy end point(s). Here, it is important to note that PD biomarkers used to measure PD response can be a single biomarker or a group of more than one PD biomarker, that together, effectively demonstrate the characteristics of the product's target effects. In the recent publication, it has been highlighted that, under some circumstances, PK and PD similarity studies can actually be more sensitive in detecting differences between biosimilars and reference products than clinical efficacy endpoint(s). For example, when comparing filgrastim products, the PD biomarker endpoint was found to be more sensitive than the clinical efficacy endpoint.

In light of this, PD biomarkers offer an opportunity to reduce the need for clinical trials when assessing biosimilars. As such, new PD biomarkers need to be identified and explored so that biomarker data can be used in clinical pharmacology studies. With this information, more biosimilar products that can be approved without requiring comparative clinical studies with biosimilarity demonstrating efficacy end point(s). This can reduce the time and cost of bringing a biosimilar product to market.

Action to explore PD biomarkers
FDA described five essential characteristics for PD biomarkers in their 2015 and 2016 guidances [2, 3]. These are:
• The relevance of the PD biomarker to the mechanism of action of the drug
• The sensitivity of the PD biomarker to the differences between the proposed biosimilar and the reference
• The analytical validity of the PD biomarker assay
• The time of onset of change in the PD biomarker relative to dosing and its return to baseline with dosing discontinuation
• The dynamic range of the PD biomarker over the exposure range to the biological product

These aim to assist companies planning to use PD biomarkers as a component of a biosimilar development programme. In 2018, FDA produced a Biosimilars Action Plan [4, 5], which includes aims to develop a framework to support the use of PD similarity studies in biosimilar development. This hopes to outline steps for companies to follow when developing PD similarity studies for biosimilar development, including the necessary data to demonstrate suitability of PD biomarker(s) and the study design (e.g. doses, study population).  

One strategy FDA is adopting to identify PD biomarkers and explore similarity study design characteristics involves collecting and summarizing existing information on potential PD biomarkers for different products. It is hoped that this can be used to advise biosimilar product developers/applicants on their development programmes. In addition,in silicomodels and simulations can correlate PK and PD responses with measures of clinical performance. These will be explored in an effort to increase confidence in relying on PD biomarkers in biosimilar assessments.

FDA is also planning pilot clinical studies with biologicals selected from three scenarios. These scenarios include:
• PD biomarker used as a surrogate endpoint for the reference product
• Known PD biomarker tied to the mechanism of action but not used as a surrogate endpoint for the reference product
• No existing well‐characterized mechanism of action and/or PD biomarker(s) for the reference product

These will allow considerable PK and PD biomarker data to be collected at different dose levels. The data can then be used in model‐based approaches to inform future clinical pharmacology PK and PD similarity studies.

These studies also offer an opportunity to investigate how new technologies can be used for the identification of PD biomarkers. For example, this may highlight the possible applications of using broad panels of PD biomarkers to capture multiple pharmacological effects

Conclusions
Overall, the recent study concludes that, to extend PD biomarker application beyond surrogate end point PD biomarkers, FDA must carry out all or some of the following: (i) invest in evaluating and synthesizing available information in the literature; (ii) conduct pilot studies; (iii) complete model‐based assessments using available data; and (iv) adopt other novel or emerging technologies.

In identifying more PD biomarkers to facilitate biosimilar similarity assessments, the time and cost of bringing a biosimilar product to market can be reduced. This will give patients faster access to affordable, safe, and effective treatments.

Related articles
Approval and launch dates for US biosimilars

Assessment of biosimilarity for monoclonal antibodies

References
1. Li J, Florian J, Campbell E, et al. Advancing biosimilar development using pharmacodynamic biomarkers in clinical pharmacology studies. Clin Pharmacol Ther. 2020;107(1):40-2.
2. U.S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.fda.gov/media/82647/download 
3. U.S. Food and Drug Administration. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.fda.gov/media/88622/download
4. U.S. Food and Drug Administration. Biosimilar Action Plan: balancing innovation and competition [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.fda.gov/media/114574/download
5. Kurki P. Potential changes to the FDA approach to biosimilars have a global impact. Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(2):53-5. doi:10.5639/gabij.2018.0702.011

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