With industry interest in biosimilars continuing to grow, top officials at the US Food and Drug Administration (FDA) are urging sponsors to leverage agency advice and follow best practices to ensure the timely success of their biosimilar development programs.
The regulators' advice comes as the agency and industry prepare for the next era of FDA's biosimilars program under the second Biosimilar User Fee Act (BsUFA II).
According to Leah Christl, associate director for therapeutic biologics at FDA's Office of New Drugs, there are currently 66 biosimilar products for 20 reference products in development in the US, with ten publicly announced 351(k) applications submitted to the FDA from seven different sponsors.
Speaking at the Drug Information Association's Biosimilars Conference in Washington, DC, on Thursday, John Jenkins, Director of the Office of New Drugs at FDA reminded the audience that the key advantage to biosimilars is that they are approved via an abbreviated pathway.
However, Jenkins said that biosimilar developers sometimes lose sight of the abbreviated nature of the 351(k) pathway and end up doing more work than necessary.
According to Jenkins, some sponsors have difficulties separating biosimilar development from traditional drug development: "This is intended to be an abbreviated program, not one that's supposed to replicate every study that the reference product ever conducted," he said.
Figure 1. Stand-Alone vs Abbreviated Development Programs
For biosimilars, Jenkins said, the foundation for approval is built on robust analytical data demonstrating the similarities between the reference and biosimilar molecules.
"This concept can be very challenging for stakeholders to understand. Biosimilar extrapolation is about extrapolating from what you know about the reference product to the biosimilar product based on all the available data. It is not about extrapolating from the indication that was studied from the biosimilar product to the other indications," Jenkins said, warning that "there are significant consequences to this lack of understanding about extrapolation."
For instance, Jenkins said that sponsors could end up conducting unnecessary comparative clinical studies beyond what's necessary to demonstrate biosimilarity.
For patients, healthcare providers and payers, these additional studies could lead to delayed access for biosimilars, Jenkins warned.
Because of the greater emphasis on analytical data for biosimilars, Jenkins said that sponsors should look to develop new and innovative approaches to studying their products.
"Biosimilar development programs are complex, and they often involve novel approaches trying to demonstrate biosimilarity, and we actually encourage the use of novel methods and study designs, such as different endpoints, different patient populations, to increase the sensitivity to detect potential differences to support that demonstration of biosimilarity," Jenkins said.
However, Jenkins noted that it takes a considerable amount of effort by FDA to review these novel approaches.
"For example, a biosimilar program may focus heavily on the [pharmacokinetic and pharmacodynamic] PK/PD comparisons in normal volunteers, and not compared in clinical trials. However, these novel approaches must be justified and supported by adequate data and information and they require extensive internal FDA scientific, regulatory and legal discussions to reach agreement that we can support such novel programs, and these are very resource and time consuming for us," Jenkins said.
Meetings and Advice
Jenkins also encouraged developers to leverage the resources offered by FDA, such as formal meetings with the agency.
FDA currently offers biosimilar developers five different types of meetings to discuss their products with the agency: an initial advisory meeting unique to biosimilars, and the four biological product development (BPD) meetings available to all biologics developers (BPD Types 1-4).
"Incomplete applications waste our resources and they cause delays for you and your development program," Jenkins said, adding that companies should make sure they schedule their meetings with enough time to act on FDA's advice. "We've seen situations where companies have the BPD Type 4 meetings and turned around and submitted their application very, very soon thereafter, before they even got the meeting notes," he added.
Lastly, Jenkins said that companies need to be ready for an inspection when they submit their applications.
"Make sure that your facilities are ready for inspection when you submit your application. When we go out for inspection, the facilities need to be actively manufacturing your commercial product so we can inspect it. Not somebody else's product, not somebody else's monoclonal antibody, but your monoclonal antibody that's the subject of your application," Jenkins said.
Global Development Considerations
According to Christl, sponsors should plan their biosimilar development programs with the global regulatory landscape in mind to maximize the return on their efforts.
Most importantly, Christl says companies should seek advice from all the regulators they plan to file with early on.
"The importance of the feedback at a specific stage might be a little bit variable, but if you want to support a global development program you have to think about the fact that if you're going to seek approval in the EU now, and in three or four years come to FDA … but you don't interact with FDA while you're doing your development program, you lose the opportunity to maximize the data that you're getting," Christl said.
While there are many similarities across biosimilar regulations in many of the major markets, Christl warned that the scientific advice companies get from regulators won't always match up. In those cases, Christl said, companies should have a plan to address those differences.
"If you don't get that advice and integrate it into your program," Christl said, "it increases the risk that you're going to have to provide additional data."