Biosimilars have dominated the headlines in the U.S. with several FDA approvals, legal battles and questions around reimbursement, placing an increased focus on how to successfully navigate this relatively new pathway from end to end.
Starting with the regulatory environment to CMC bioanalytics and pharmacodynamics, learn how drug developers can understand regulatory differences and identify a fit-for-purpose program. We will also cover how to proactively identify key issues for both PK equivalence and Phase III equivalence studies, and initiate market access and commercialization approaches.
Opening an early dialogue
Regulatory guidance from EMA and FDA has become more harmonized, but the requirements continue to evolve. Regulatory authorities have outlined a stepwise approach designed to demonstrate biosimilarity on various levels. To meet agency standards, sponsors must devise carefully designed strategies for chemical, manufacturing and controls (CMC), non-clinical research and clinical development studies that are substantially different from the plan required for the originator drug.
The range of evidence needed to demonstrate biosimilarity includes: 1) the establishment of structural and functional similarity based on a battery of CMC characterizations and nonclinical evaluations and 2) demonstration of clinical biosimilarity through human studies designed to demonstrate similarity to the originator product based on pharmacokinetic (PK), pharmacodynamic (PD) and clinical immunogenicity assessments.
In determining what evidence is required, both agencies use a multistep, sequential process, involving analytical studies, as well as animal and human clinical data. A battery of analytical studies is followed by non-clinical in vitro and in vivo functional assessments that may also include toxicological comparisons. Finally, human clinical data are required from tests designed to show whether any of the differences detected in the prior testing result in clinically meaningful differences in either the pharmacokinetics, immunogenicity or efficacy of the biosimilar product compared to the originator product.
As a CRO reviewing many proposals for studies, we’ve noticed that sponsors often need guidance to understand the regulatory landscape and benefit from early engagement with regulatory bodies.
After proving biosimilarity with the same protein sequence and demonstrating potency by showing minor differences in post-translation modification, such as glycosylation, a sponsor could approach the FDA and discuss the similarity of the compound to determine if any gaps exist. At this stage of development, the biosimilar should have the same effector functions regardless of potential contribution of mechanism of action.
Comparing the need for nonclinical testing
After demonstrating a highly characterized and similar CMC bioanalytic, the next hurdle is to design a fit-for-purpose and cost-effective nonclinical testing program, a process that is highly tailored based on the molecule of interest. However, a common question arises in this stage – is toxicology testing necessary? In short, it depends on the regulatory body.
At one end of the spectrum, the EU indicates that toxicity testing is usually not recommended unless there is some particular signal in the comparative assessment of the CMC bioanalytical or if the PD data suggests potential issues. The FDA says testing can be discussed, and includes justifications for not doing some degree of toxicity studies. The WHO has some general regional guidelines, which are in the process of being modified, but currently request testing for at least one repeat dose toxicity.
Regardless, if sponsors are aiming for a global or more broad market, they should consider toxicology studies. Conversely, if strong comparability data in the CMC support the biosimilarity, then a minimalistic approach can be considered in this stage.
Transitioning from Phase I to Phase III
The Phase III pivotal study demonstrates that a biosimilar is highly comparable to the reference product, by showing minimal differences in terms of efficacy and safety. Regulators generally look for trials to establish equivalence rather than non-inferiority, unless there is some scientific justification for the latter. However, in the U.S. at least, there does appear to be more flexibility in setting upper bounds of equivalence to allow for potentially improved performance compared to the originator product. When designing a study, sponsors need to consider which desired therapeutic indication to target and identify a sensitive measure to determine the differences between the biosimilar and the reference product.
Factors to consider in this stage include the background therapy of the clinical subjects and the need for blinding or stratification. Sponsors also need to determine if any switching from the originator to the biosimilar product should take place in the later stages of this study along with the primary endpoint variable to use.
Other design issues include the choice of an equivalence or a non-inferiority design and determining the equivalence margin, which needs to be justified to gain regulatory acceptance, and also drives sample size. And, while there have been some recent considerations of alternative statistical approaches that might be more efficient, at this time regulators are mostly interested in classical inferential type of designs.
Incorporating Crucial Market Access Considerations
In many ways, the commercial path for biosimilars is as challenging as that for a unique innovator biologic. Facilitating market access for biosimilar products involves engaging in the full spectrum of market access and health economic planning activities as early as clinical development.
For example, reimbursement under Medicare Part B will remain a hot topic for biosimilars approved under the new abbreviated biosimilar pathway along with coverage by commercial insurers. Sponsors are wise to perform landscape assessments and primary research with stakeholders to gain a comprehensive understanding of the current policy and insurance environments. Other strategic approaches through reimbursement hotlines, patient assistance programs and provider-facing field teams can also help maximize the potential for commercial success in this rapidly growing market.