At the World Biosimilars Congress this month, we had the opportunity to sit down with Dr. Leah Christl, formerly one of the key scientists at the FDA’s Center for Drug Evaluation and Research. She was “present at the creation” of the FDA’s biosimilar approval pathway and in 2019 moved into her current position at Amgen. Our conversation ranged from topics involving biosimilar development and approval to the future pipeline.
Biosimilars Review & Report: Dr. Christl, you’ve recently transitioned from working at the Food and Drug Administration (FDA) to the private sector. Has your view of the biosimilar industry changed at all with that transition?
Leah Christl, PhD: There’s definitely a transition when moving from the FDA into the private sector, but I don’t think my view of the industry has changed at all. I’ve worked within the biosimilar space for over 11 years. Although my role at the FDA included setting up the internal biosimilar review process and working on policies associated with biosimilars, I had a great deal of external interaction as well. My job was to make the program work, which required efforts to reach out externally.
The biosimilar field represents a new industry. Some of the players are traditional innovative biologics firms, some are traditional generics manufacturers, and then others were created specifically for this space. At that time, the agency had to engage with those external stakeholders, to work with them in this new process.
Folks who are working in the biosimilar space are dedicated to being here and are really looking for success. Everyone shares that common goal—to make the biosimilar industry a sustainable success. There are some differences in opinion about how we might get there though…
BR&R: Looking back at your work in developing and implementing the analytical and evaluation policies for biosimilar approval, what do you believe the FDA really got right?
Dr. Christl: In terms of the analytical similarity assessment, the FDA was always focused on the science and in really doing a robust analysis. During my time at the FDA, one of our strengths was in focusing on comparability and then building on it. However, some folks want that space to just be about comparability, but we’re trying to show much more: We’re talking about a completely new manufacturing process. At the FDA, we recognized that. We thought very hard about what that analytical process should look like.
There may have been some missteps around the application of a statistical analysis, how rigorous that should be, and what was reasonable with regard to the variability of biotechnology manufacturing.
BR&R: As you mentioned this morning during your remarks, the FDA’s initial work built upon the European Medicine Agency’s (EMA’s) original work. Did the EMA do an adequate job of considering biosimilar manufacturing variability when developing its own pathway? How long ago did we fully understand the nature of variability in biologic production and its implications?
Dr. Christl: While I was at the FDA and the agency entered this space, we looked at it a little bit more robustly, a little bit differently. But one could say that there wasn’t really a good understanding in how to apply the statistical analysis for the analytical comparison.
At the FDA, we immediately implemented the “totality of the evidence” approach, where the foundation is the analytical comparison. We considered the concept of residual uncertainty, applying an approach of step-wise evidence development using the analytical underpinnings and expanding to considerations of what clinical data were needed to demonstrate biosimilarity. The FDA considered carefully the sensitivity of certain clinical endpoints and the use of pharmacodynamic evaluations. The EMA’s original approach, which evolved over time, included expectations of specific clinical studies with traditional hard efficacy endpoints.
On the other hand, the FDA had the ability to consider the evolution of the regulatory approaches over time. As a result, we had more of a scientific but flexible standard at the beginning, which has also been implemented by other regulators in this space. There is good scientific harmony among stringent regulatory authorities.
EVOLVING CLINICAL STUDY STANDARDS
BR&R: The flexibility has been a very intriguing aspect of the evolution of the biosimilar development and process. The FDA has been in constant contact with the manufacturers through its biosimilar clinical development program, consulting with them on the analytical, physiochemical, and clinical expectations for a successful BLA. To an extent though, this creates what appears to be a moving target. It’s sometimes difficult communicating that evolving expectation outside of the industry to payers, prescribers, and others. How are the payers specifically reacting to the requirement around the extent of clinical trials needed for approval of a specific product?
Dr. Christl: Yes, it was such a new paradigm. Getting prescribers, patients, and payers to understand the data that underpin those approvals was a problem earlier in my tenure at the FDA, and it continues to be a challenge. It can differ for two biosimilars to the same reference product. Two slightly different submission data packages could imply different levels of residual uncertainty.
Many payers are used to seeing a certain data set that is used to approve a product, including two adequate and well-controlled clinical trials. My thinking has evolved around that concept of comparative clinical studies. It can involve pharmacokinetic similarity, pharmacodynamic similarity, all the way up to what they consider a phase 3 study. These are comparative investigations and are not designed to demonstrate efficacy of the biosimilar independently. Again, we are seeking to evaluate similarity. People default to the language that they know and call it a phase 3 study, but it’s not demonstrating the same thing.
We talk a lot about the education needed to help gain the understanding and acceptance, and uptake of these programs. That continues to be a work in progress. I do think it’s very important to understand that any of those studies are assessing similarity and potential differences between the products. The studies then need to be designed to ferret that out. It’s the whole intent and purpose of it. Once this is understood, people can grasp why there’s a difference in the study design and the data package that underpins biosimilar approvals. And there’s more trust when the agency states, “We’ve looked at these data, and the biosimilars are safe and effective for those labeled conditions of use.”
MULTIPLE BIOSIMILARS FROM A PAYER’S PERSPECTIVE
BR&R: As far as payers are concerned, when they see multiple biosimilars approved for adalimumab, they will treat them as they are pretty much clinically equivalent to each other (not just to the reference product). Will it matter that technically, biosimilar A is not biosimilar to B or C, only to the reference product?
Dr. Christl: I believe it will matter. As with other abbreviated approval pathways, like for generic drugs and 505(b)(2) medications, these agents are compared with a reference drug, not each other. You’re right, those other evaluations haven’t been done.
BR&R: In a specific geographic area, you may have multiple health plans. Plan A has placed one biosimilar on its formulary, Plan B may cover a different biosimilar, and Plan C may decide to cover the reference product only. If a person needs to change plans (or the plan decides to change its formulary coverage) from year to year, this question becomes potentially relevant.
If the change is from one biosimilar adalimumab to another biosimilar adalimumab, that’s one thing. If you are changing coverage from one biosimilar to that interchangeable product, that’s again something else. Is there a scientific basis for concern in switching coverages like this?
Dr. Christl: I don’t think that question is answerable yet. We don’t have the data to say that it is or it isn’t. That may come out as we have more experience with these products, and more products with multiple competitors to a reference product. We’ll be able then to establish some real-world evidence, real-world data on that question.
We should be aware and cautious, and monitor patients. We need transparency for the prescribers and the patients, so people know when there’s been a change. We also need transparency in order to collect that information for monitoring purposes.
THE SPREAD OF GOOD MANUFACTURING PRACTICES
BR&R: Several manufacturers produce biosimilars in overseas production facilities. Have we obtained adequate harmonization of the US’s good manufacturing practices with those in other countries? Can we be confident that the overseas production is safe?
Dr. Christl: In the US, we have requirements or standards for good manufacturing practices. The EMA and Health Canada have similar requirements. When they approve a product, they inspect those production facilities, looking very carefully at the chemistry, manufacturing and controls. We have the expectation that the production facility meets those standards, regardless of where it is located.
That said, I don’t think the standards are the same in the some of the emerging markets. There is a big push around biosimilars especially to make sure that we are applying equivalent standards for all biologics, including biosimilars. We want to have a global definition of biosimilar, in terms of how it is compared with a reference product. We need to move in that direction, and make sure that those production standards are elevated globally. But I do think some work needs to be done in the emerging markets.
THE NEXT GENERATION OF BIOSIMILARS
BR&R: Amgen obviously has a long history of quality biologic manufacturing and a quality culture. Amgen has certainly taken the lead in launching the cancer-treating biosimilars of trastuzumab and bevacizumab. From a research and development perspective, what does the company believe will be the next important frontier in biosimilars?
Dr. Christl: Amgen’s present focus is on oncology, hematology, and the chronic inflammatory diseases. There is a pretty wide range of products in those spaces. Certainly, conversations have taken place at Amgen and within the industry as a whole about other opportunities outside of our standard therapeutic areas.
We need to look at where biological products are used. For the industry as a whole, those areas could include the orphan and rare diseases. Is there an opportunity there, not just from a business-case perspective? Can we say that we have a good platform to provide those products and create competition in those environments? Also, biologics used to treat neurological diseases, for example Parkinson disease or multiple sclerosis, may offer interesting targets. Certainly, in the oncology and the chronic inflammatory diseases, a wide range of products and diseases are waiting to be tackled.
BR&R: Well, yes, in the autoimmune category, it seems a new interleukin is introduced every couple of months.
Amgen, of course, is one of the few companies that can actually look at rare diseases from something other than an economic standpoint. You might not get a big return on investment on a biosimilar for an orphan drug. But without biosimilar competition, you risk drying up the supply chain for a specific drug, even an orphan biologic. Where do you think the biosimilar industry will be in 2025?
Dr. Christl: In 2025 in the US, we are going to have many more products approved and we are going to see many more new launches. Hopefully, we will be moving through some of the intellectual property (IP) issues. We’ve seen a lot of progress in that space, beginning with the interpretation of the BPCIA and what does it mean. All the conversations around the patent dance and whether it is mandatory or optional—and if it’s optional, then what does that mean?
Being a former regulator, I know that folks think that the regulatory process is slow—and it can be at times—but it’s also a necessary process. I don’t think that any of the IP issues are different. We need to work through them to build a foundation with understanding and transparency so that prospective biosimilar makers have confidence in their expectation of what their programs need to look like and what they will need to do to reach the market. That is really important for this industry. There will be more certainty in the regulatory space overall, and that will help this industry move forward.
Globally, I expect we’ll see in some of those emerging markets a real drive and desire to align with the stringent regulatory authorities. There will be movement toward true global development programs and a global definition of biosimilars.
BR&R: I’ll put you on the spot with this last question: By 2025, how many biosimilars (not which ones) will Amgen have?
Dr. Christl: We have four approvals now… we’ll go with eight or nine, I’ll say.
BR&R: Thank you, Dr. Christl.
