From The Editor | August 31, 2017

The Evolving Landscape Of Biosimilar Risk Management Programs

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By Anna Rose Welch, Editor, Biosimilar Development
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In any industry, there are buzzwords that arise seemingly on a daily basis. Though these concepts can be easily defined and, over time, become more actionable and less theoretical, it’s easy to rattle them off without putting much thought into what they actually mean for the industry. In the biosimilar space, we’re all familiar with a handful of these terms/phrases. These include biosimilarity, switching, interchangeability, extrapolation, immunogenicity, and, who could forget, “totality of evidence” and “no clinically meaningful differences.” However, there are a few terms that, though they’re not exclusive to the biosimilar industry, have also earned their place on the biosimilar buzzwords list, including risk management and pharmacovigilance.

In the past, I’ve written a number of articles focused specifically on real-world evidence (RWE) and the role it will play in boosting biosimilar uptake. I’ve written about the mission of the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC), along with a series of articles on the complexity of gathering RWE and the challenges of interpreting that data. The ongoing release of study data, for instance the NOR-SWITCH study in Norway, goes a long way to familiarizing patients and physicians with key concepts like extrapolation, and, in turn, establishing biosimilars’ safety and efficacy profiles.

But before a company can even gather data and interpret it, they need to have a proper monitoring and risk management process in place. In a presentation at the 2017 World Biosimilars Congress, Asif Mahmood, disease area safety and strategy lead at Pfizer, shed more light on global risk management strategies and the challenges of launching these programs.

Comparing EU And U.S. Risk Management Protocols

There are a few differences between the U.S. and EU regulators in terms of risk management plans. Any company wishing to approve and launch a drug in the EU is required to submit a risk management plan (RMP) to the European Medicines Agency (EMA). The EMA explains that the purpose of the RMP is to “document the risk management system considered necessary to identify, characterize, and minimize the important risks of a medicinal product.” When establishing an RMP, the sponsor must provide information on a medicine’s safety profile; risk-prevention or minimization tactics; post-marketing studies to understand safety and efficacy; and methods to measure how effective risk-minimization measures have been. These RMPs remain “living” programs, and are regularly adjusted throughout each drug’s lifetime.

Biosimilars are as “identical” to their reference products as any biologics can be. Therefore, it only makes sense that safety concerns or risk-monitoring being carried out on the originator would translate over to its biosimilar. As Pfizer’s Mahmood emphasized throughout his presentation, the EU RMP for a biosimilar is expected to take into account any identified or potential risks being covered in the RMP of the reference product. Similarly, should a new safety concern arise and be integrated into the biologic’s RMP, it will be imperative that this be adequately addressed in the biosimilar’s RMP.

“Risk minimization activities in place for the reference product should be included in the risk minimization plan of the biosimilar until or unless you have a solid justification for no longer needing to carry out a certain part of that plan,” Mahmood described. For instance, given the length of time between the market launches of the reference biologic and the biosimilar, plenty of data may be attained which negates a particular risk, and it may no longer be necessary for a biosimilar to carry out that particular aspect of the risk management plan.

In contrast, the EU RMP is much wider in scope than the Risk Evaluation and Mitigation Strategies (REMS) program in the U.S. (which, on a slightly unrelated note, are also likely known because they can be a key hurdle in biosimilar development.) Unlike the mandatory RMP in the EU, REMS programs are created by the sponsor at the request of the FDA, either pre- or post-approval. This program may require healthcare providers and distributors to follow certain safety procedures in prescribing, shipping, or dispensing the drug. REMS could also require patient monitoring to ensure the drug does not lead to a specific safety issue. Mahmood stated that, much like the RMP in the EU, a biosimilar REMS program in the U.S. will closely resemble that of its reference product.

“You are not going to be adding or deleting anything because you are not trying to prove a new safety profile,” he described. “You are just proving biosimilarity.” That said, however, there is still a great need to discuss risk management in meetings with the FDA, given the agency’s interest in biosimilar post-marketing strategies and registry enrollment.

Regulator Demands For RMP Spreading Globally

It’s interesting to look at the EU and U.S. risk management strategies in a global context. I’ve spent some time this summer writing about a few different countries and their experiences with biosimilars, both on a regulatory and market uptake level. Many of the biosimilar regulatory guidelines being released in non-EU nations have closely adapted a majority, if not all, of the EMA’s (and the WHO’s) guidance on biosimilar regulation. When looking at other regulators’ RMP requirements, it seems the same trend is occurring: though presenting an RMP upon filing for drug approval is optional in certain nations, the format for the RMP often closely resembles that of the EU.

Take, for instance, the systems being established in Canada and Japan. Starting in 2013, Japan’s Pharmaceutical and Medical Devices Agency (PMDA) made it mandatory for companies submitting novel and biosimilar drugs to provide a RMP. (Though, I was somewhat humored to notice the Japanese guidance uses the phrase “shall file,” which, as we all know by now, led to a few delightful legal twists in the U.S. this year.) Though there may be differences in the RMP format, the requirements are essentially based on the EU’s RMP. The PMDA RMP requires safety specifications, for instance notice of dangerous adverse drug reactions; pharmacovigilance activities carried out post-marketing; and risk minimization activities.

Mahmood also called attention to Health Canada’s RMP, which was established in 2009 and should be included with a biologic and biosimilar application. The Canadian RMP also takes after the EU’s format, however, it could include some additional considerations for Canadian populations.

A common theme throughout this industry is “one size does not fit all.” This motto can be applied to anything from reimbursement and discounting to regulatory affairs. Naturally, the same motto applies to pharmacovigilance practices. However, there are some efforts underway to streamline the submission of RMPs as countries begin to add risk management to their list of requirements for new drugs and biosimilars. For instance, companies have begun to develop a global RMP, which is closely based on the EU format, but can be altered to match local requirements. The “global RMP” strategy could be an important option for companies that may have sought biosimilar approval only within the U.S. These companies would not have an EU RMP on hand if they wished to extend their products’ reaches globally.

The Importance Of Working With Regulators On An RMP

In the U.S., especially, one-on-one scientific meetings between industry and the FDA have become common and highly emphasized. But there is also growing emphasis on closer collaboration between the drug sponsor and the regulatory authority in the EU and elsewhere. Mahmood pointed out the importance of remaining in communication with regulators about their post-marketing plans, especially for biosimilars. After all, a biosimilar is following in the footsteps of a successful biologic, which has been closely monitored for years by the innovator company. As such, there’s always a chance the biosimilar company might be able to work with a regulator to eliminate certain duplicate efforts.

“It is important that a biosimilar manufacturer work with the FDA and other agencies early in their development program to discuss their risk management approach,” he described. “It is quite possible you may be asked to participate in the ongoing efforts of the innovator. But if one of these activities was imposed 10 or 20 years ago, biosimilar makers might not need to go into these details in their own RMP because the reference product has a known safety profile, and the issues associated with long-term use are more clearly understood.”

One area in particular Mahmood touched upon that is likely to be different is in the administration of the biosimilar. One way companies can differentiate their products is through the device or different routes of administration — for instance, subcutaneously or intravenously. As such, it can be possible for a biosimilar company to identify the risk minimization activities linked to the innovator’s device and work with regulators to justify why those activities are not relevant for the biosimilar’s RMP.

A biosimilar company is also likely to face challenges should there be any changes to the innovator’s RMP. As Mahmood explained, this will be particularly difficult for a biosimilar company because it does not have immediate access to the innovator’s RMP. For instance, “You can apply to the EMA for the innovator’s RMP, but it can take a minimum of six months to a year to receive it — if not longer,” he said. “So whatever has been changed in the innovator RMP cannot be added to the biosimilar’s RMP until you have formally received the innovator’s RMP from the EMA.”

Throughout his presentation, Mahmood highlighted the importance of maintaining “the right balance” in a biosimilar’s development program. It’s important for biosimilar makers to have “just the right amount” of data for approval that doesn’t push development costs to an unsustainable level. This is where post-marketing efforts come in. It’s clear the ongoing release of RWE is not only an important addition to a biosimilar’s abbreviated development pathway, but it will also be the way to continue familiarizing all stakeholders with biosimilars. But in order to get there, you have to know and plan where exactly to look.