Why pharmacists are concerned about the safety of biosimilars


Pharmacists and other healthcare professionals are looking to the FDA for more guidance on biosimilars and interchangeability with their reference products.

Pharmacists, physicians, and other healthcare professionals are rightly concerned about the safety and efficacy of biosimilar drugs. Because they are so new on the market-only two have been approved in the U.S. to date-their safety has not been proved.

In addition, healthcare professionals are looking to the FDA for more guidance. To date, the agency will only say that biosimilars are “highly similar” to their reference products. In other words, they are not completely interchangeable as generics are.

“Since a biosimilar drug is not identical to the reference innovator product, the efficacy and safety data generated for the latter cannot be directly and completely transferred to the biosimilar. Both its efficacy in various therapeutic indications and its safety profile in diverse risk populations may be different from that of the innovator,” said Suhasini Sharma, director of medical affairs for Sciformix Corporation, in the company’s white paper Pharmacovigilance and Risk Management for Biosimilars: Unique Challenges and Possible Solutions.

Biosimilars are “highly similar to an already FDA-approved biological product, known as the biological reference product (reference product), and have been shown to have no clinically meaningful differences from the reference product,” according to the FDA in its notice Information for Healthcare Professionals: Biosimilars. “Minor differences in clinically inactive components are allowed. But there must be no clinically meaningful differences between the biosimilar and the reference product it was compared to in terms of the safety, purity, and potency of the product.”

On the other hand, interchangeable products are both biosimilar to an FDA-approved reference product and can be expected to produce the same clinical result as the reference product in any given patient, according to the FDA. “An interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. In addition, for a biological product that is administered more than once to an individual, the risk in terms of safety or efficacy of alternating or switching between the biological product and the reference product will not be greater than the risk of using the reference product without alternating or switching.”

Before doctors will prescribe new biosimilars, they need assurances from the FDA that the drugs are substitutable, as is the case with branded versus generic drugs, said Robert T. Adamson, PharmD, chief pharmacy officer, corporate pharmacy, Barnabas Health, West Orange, NJ.


“Right now, FDA is just saying that the biosimilar for Remicade, for example, is ‘highly similar’. We are all waiting for some guidance from FDA that Drug A is completely substitutable for Drug B and vice versa,” Adamson said.

Sandoz’s Zarxio (filgrastim-sndz), for example, was not approved for all the same indications as its reference biologic product, so the uptick in use of the product is slower than for a generic. “There are a lot of clinicians who said, ‘I need to get more indications to get more comfortable,’” Adamson said.

“In our system, we saw a fairly good uptake of Zarxio: 80% of doctors prescribed it, while 20% didn’t feel comfortable using it.” The only reason 20% didn’t use the drug is that Zarxio lacks an indication for bone marrow transplant, so doctors didn’t feel comfortable switching some patients, according to Adamson.

Conversely, in Europe, biosimilars have been available for a few years, and for a few different disease states, without reports of negative safety or quality effects. “We can glean from the European market that biosimilars can be introduced, that there is no patient harm, and they do provide the same level of efficacy,” Adamson said.

FDA’s policy of naming biosimilars with the addition of a four-letter suffix has also been controversial among prescribers and others. “We have advocated for a prefix on biosimilar names because when you look at a screen and you have a drug name that is 10 to 12 characters long, they [prescribers and pharmacists] may just see the beginning of the name and not the suffix,” Adamson said.

However, the four-character suffixes are meant to improve safety, according to the FDA. “The goal of this naming convention is to help minimize inadvertent substitution. Inadvertent substitution may lead to unintended alternating or switching of biological products that have not been determined by FDA to be interchangeable,” FDA said in its draft guidance, Nonproprietary Naming for Biologic Products. “This naming convention may also facilitate pharmacovigilance for multiple biological products containing related drug substances when other means to track a specific dispensed product are not readily accessible.”

Safety solutions

To help prevent potential safety issues with prescribing and dispensing biosimilars, experts and organizations are working on several solutions. Here are two potential solutions:


Postmarketing studies and data collection are needed. Compared with generics, there is a greater need for strict postmarketing product vigilance and additional post-approval studies, according to Sharma. To detect possible differences between the reference and biosimilar products, it is crucial to compare the frequency and severity of known side effects of the reference product with that of the biosimilar. “Due to the limited size of studies required for approval, any difference in the safety profile or new side effects not yet observed with the reference product can only become apparent through the painstaking collection and evaluation of postmarketing data once the product is on the market,” said Sharma.

To have complete confidence in biosimilars, physicians will want to see critical, peer-reviewed, published evidence on their safety and efficacy, according to Murray Aitken, IMS Health senior vice president and executive director of the IMS Institute for Healthcare Informatics. “The more of that they can see, the more comfortable they will be in prescribing these drugs.”

However, the discussion is still open on what-if any-postmarketing monitoring and safety-related requirements should be imposed on biosimilar applicants (such as special requirements related to safety reporting and postmarketing studies, or on the information that must appear in labeling for physicians or patients), according to Sharma.

Examine Europe’s safety and efficacy data on biosimilar drugs. “The European experience with biosimilars is going to be relevant. The biosimilar for infliximab, for example, is well-established for well over a year in some of the European markets,” Aitken said.

Additional evidence and information being gathered now by European agencies will be relevant to help build the confidence of the FDA, physicians, and patients “around the safety and quality of the biosimilar drugs that are available,” Aitken said. When data on the biosimilar infliximab and other medications become available through sources such as the registry of patients in Norway, “We should be looking at the European experience, so we can benefit from observing their experience,” Aitken said.

Strict data collection is a very important part of developing confidence in adopting biosimilars, according to Aitken. “Adequate safety and tracking requires the names of the biosimilars to be captured in the data sets, so researchers or regulators can look at the safety profile of each of the biosimilars individually.”


Preventing biosimilar label confusion?

While some groups may be pushing for more FDA requirements on biosimilar labels to ensure safety, the FDA should not require a statement of biosimilarity on the products’ labels, a group of leading pharmaceutical supply chain organizations recently stated in a letter submitted to the agency.

That requirement will limit access to biosimilars, they argue.

“In most cases, the scientific information necessary to approve a biosimilar will primarily focus on establishing biosimilarity between the two products. This means that safety and efficacy information will come from studies of the reference product rather than the biosimilar,” said the groups, including the Generic Pharmaceutical Manufacturers Association, the Academy of Managed Care Pharmacy, and the American Pharmacists Association.

Including a biosimilar product’s biosimilarity data in addition to that of the reference product would only provide unnecessary information and create confusion for prescribers and patients, the organizations said.

“This differentiation between biosimilars and their reference products risks undermining the important provider education that is being done by the FDA today. Informing providers that ‘biosimilars have no clinically meaningful differences in terms of safety, purity, and potency (safety and effectiveness) from the reference product’ while requiring a differentiator on the labeling sends mixed signals to providers responsible for driving patient familiarity and comfort with these products,” the groups said.


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