Ahead of the Curve
by Sarah Stone Wunder
April 2008
As a follow-on biologics pathway inches closer to reality, interested companies must consider biologics’ unique characteristics when preparing to enter the game.
Photography by Colin Cuthbert/Photo Researchers, Inc.
On March 13, 2008 U.S. Rep. Anna G. Eshoo (D-California) introduced the “Pathway for Biosimilars Act,” the latest legislation in a nearly decade-long attempt to create a regulatory pathway for the U.S. Food and Drug Administration (FDA) approval of “biosimilars” or “follow-on biologics” (FOBs).
The introduction of the bill is the first step in what could become landmark legislation regarding the manufacture of follow-on biologic drugs. The bill’s introduction also signals what many in the industry have come to accept—that FOBs are no longer a question of if, but when.
Companies looking to develop FOBs in the future need to consider some of the unique characteristics—and challenges—inherent in biologics manufacturing versus traditional small-molecule generics, says Kamali Chance, Ph.D., RAC, director of global regulatory strategy at Quintiles, in Durham, N.C., USA.
“The company needs to be aware from the onset that FOBs will be much more costly to develop than small-molecule generics,” she says. The reason FOBs will be more expensive to produce is because, unlike small molecules, biologics will need to demonstrate comparability to the innovator drug at preclinical, chemistry, manufacturing and controls (CMC), and clinical levels. As a result, FOBs will require more trials and studies than small-molecule generics. The industry uses the term “comparability” because FOBs can never be identical to the innovator drug, Chance says.
“Biologicals are unique compared to small molecules in that sometimes, even when comparability can be shown based on CMC data with the originator product, due to biological variability between sources of starting material and even minor differences in manufacturing processes, the end product may show significant differences in the clinical setting in bioactivity and immunogenicity potential,” Chance says.
“Due to the limitations of the applicability of non-clinical data, the immunogenic potential of FOBs is not known until tested clinically. So, unlike small-molecule generics, the FOBs will need to go through much more rigorous [clinical and non-clinical] testing to convince regulatory authorities of the comparability of their product with the innovator product.” Although this testing likely will not be as rigorous as trials for innovator drugs, they will be much more involved than small-molecule generics bioequivalence studies.
“Extensive characterization of a candidate FOB will be needed to support a regulatory conclusion that the FOB is essentially the same as the innovator protein and that new clinical outcome studies are not needed,” says Paul Aebersold, Ph.D., senior director of global regulatory strategy at Quintiles, in Rockville, Md., USA.
“Potential FOB companies are going to have to characterize their product up one side and down the other and compare that to characteristics of the innovator product,” he says. “The better the data are to support that a FOB is essentially the same protein as the innovator drug, the less likely there’s going to be any perceived need for new clinical outcome studies.”
That question, along with industry groups on both sides of the equation, will come into play when the United States and other countries consider FOB legislation.
Finding Comparability
According to Chance, the comparability exercise for FOBs involves showing comparability in terms of quality, safety and efficacy. The clinical comparability exercise is a stepwise procedure that generally involves the following:
- Comparability in Phase I studies in terms of pharmacokinetics (PK) and pharmacodynamics (PD) of the FOB relative to the innovator product;
- Comparability in Phase III study or studies in the safety and efficacy profiles of the FOB relative to the innovator product;
- Immunogenicity comparability in the Phase III study (which is generally part of the safety and efficacy study) and the Phase IV study, if requested by regulators, (general commitment to do the study as part of approval) with the innovator product. Immunogenicity testing also requires a validated antibody neutralizing assay as part of the program. “In addition, if the immune response for the FOB differs from that of the reference product,” Chance says, “further studies are required to characterize the antibodies and their implications for safety and efficacy.”
As the United States considers establishing a pathway for FOBs, it will most likely look to the European Union’s (EU) current process. Currently, the guidelines in the EU require comparability of the FOB to the innovator product in the clinical setting in terms of strength, route of administration and pharmaceutical form, Chance says.
Generally, separate studies are required for different indications for the same drug. However, extrapolations sometimes are granted if it can be proven that all indications rely on the same mechanism of action, Chance says. The reference product must be authorized in the EU and the same reference product has to be used in all comparability exercises. For efficacy trials, clinical comparability margins need to be pre-specified and justified. In addition, the company developing the FOB needs to ensure that the proposed bioassays are sensitive.
According to Chance, there is leeway in EU guidelines for confirmatory comparative PK/PD studies between the FOB and the innovator product, if the following conditions are met:
> The reference product PK is well characterized.
> PD properties of the reference product are well understood, including binding of target receptor(s) or the mechanism of action, especially if it is disease-specific.
> The reference product dose response curve is sufficiently characterized.
> At least one PD marker is accepted as a surrogate marker for efficacy and the relationship between dose/exposure to the product and this surrogate marker is well known. Justification is required for the choice of surrogate marker in PK/PD studies.
The EU has also established clinical safety and pharmacovigilance requirements for all biosimilars. The adverse effect profiles of the FOB and reference product in a sufficient number of patients has to be proven to the European Medicines Agency based on type, severity and frequency of the adverse events. The risk management plan has to comply with the EU legislation and pharmacovigilance guidelines, Chance says.
Looking Ahead
As FOB companies gear up for a new regulatory landscape in the United States, they will need to know in detail how FDA reviews comparability study results, via consultants if the requisite expertise does not reside in-house, Aebersold says.
Within the FDA, two centers have regulated protein products that may be candidates for FOBs: The Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER). In the past few years, the regulatory oversight of a number of these protein products was transferred from CBER to CDER.
“Now that [some of] the protein drugs that are candidates for FOBs have moved over to CDER, comparability has became an agency-wide issue rather than a center-wide issue,” Aebersold says. “People like myself at Quintiles who have background at CBER know exactly what CBER and CDER are looking for when they look at comparability.”
According to Aebersold, the FDA will look for biophysical, biochemical and perhaps even pharmacology data to support a conclusion that the FOB is essentially the same as the innovator product and thus the clinical safety and efficacy are expected to be the same.
“We can advise people on the kinds of studies that they need to undertake with the protein drugs. We can help them in assessing the outcomes of the studies and writing up those reports,” he says. “They’ll need to discuss any differences between the FOB and the innovator and explain why such differences would not be expected to make a clinical difference.”
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