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MedPage Today – Interchangeability of Biosimilars Under Review

MedPage Today – Interchangeability of Biosimilars Under Review

As biosimilars enter the pharmaceutical market, physicians will have to decide whether to prescribe these potentially lower-cost drugs for their patients instead of the originator drug or biologic. In some cases, their own recommendation may not even matter.

Physicians, pharmacists, patient advocates, and industry experts spoke of the challenges facing a healthcare system focused on curbing costs while maintaining access to safe and effective drugs for patients at a panel discussion on biosimilars here on Tuesday hosted by the advocacy group Friends of Cancer Research and the Duke Margolis Center for Health Policy at Duke University.


The half-day forum was titled “The Future of the U.S. Biosimilars Market: Development, Education, and Utilization.”

Biologics are large complex molecules that include a broad array of vaccines, blood components, somatic cells, and gene therapies. Biologics have been used as treatment for cancer, rheumatology, and inflammatory bowel disease. Unlike small molecule drugs, which can be chemically synthesized, biologics must be produced in living organisms.

Biosimilars, according to the FDA, are drugs that are “highly similar” to their reference products that demonstrate “no clinically meaningful differences” related to safety, purity, and efficacy.

In 2010, the Biologics Price Competition and Innovation Act allowed the FDA to develop an abbreviated approval process for biosimilars. Under that law, biologics are given 12 years of exclusivity before biosimilars can be approved and compete in their market. In 2015, the FDA approved its first biosimilar, Zarxio (filgrastim-sndz) manufactured by Sandoz — a biosimilar to the reference product Neupogen, manufactured by Amgen.

Three more biosimilars were approved this year and 66 are currently under development, noted Mark McClellan, MD, PhD, director of the Duke Margolis Center for Health Policy and a former administrator for the Centers for Medicare and Medicaid Services.


As the landscape of available treatment begins to change, a core question facing physicians and their patients now relates to the interchangeability of these drugs — trading a biologic for a biosimilar or vice versa.

“A lot of how these drugs will ultimately be deployed in clinical practice will be determined by the level of confidence that a physician has that a product is safe and effective and that it truly represents an acceptable alternative … and that there is not a clinically meaningful difference,” said Richard Schilsky, MD, chief medical officer for the American Society of Clinical Oncology.

As an example, Schilsky cited the difficulty he might have in deciding whether to give a patient trastuzumab (Herceptin), a drug that oncologist have used for a quarter century, with a competing biosimilar for which there is far less long-term data regarding adverse events. Schilsky said that beyond safety he is even more concerned about possible differences in efficacy: “At what point does the doctor or the patient acquire that confidence to make the switch?” he asked.

That the clinical evaluation process for biosimilars, an accelerated pathway, specifically de-emphasizes clinical evaluation and focuses instead on analytical studies to determine the level of similarity is a stumbling block for Schilsky: “You can get down to the last angstrom, on whether or not the molecule has the same turn in its helix, compared with the reference product, but the real issue is going to be to determined with confidence whether there is a clinically meaningful difference between the originator product and the biosimilar.

“Establishing that confidence to the satisfaction of doctors and patients is going to be important,” he said.


Leah Christl, PhD, of the FDA’s Center for Disease Evaluation and Research, who spoke on an earlier panel, explained that unlike in traditional drug applications, where the weight of the approval decision rests largely on pivotal clinical trials, biosimilars undergo a different review process, which relies more heavily on analytical studies. Comparative clinical trials are thus necessary only if there are “residual uncertainties about whether there are clinically meaningful differences,” based on the available data, including data that assesses structural and function similarity to the reference product, animal testing and pharmacokinetic studies, and possibly pharmacodynamics studies.

Schilsky also pondered another important question aloud: “What level of control will the doctor actually have in determining what drug they can actually prescribe?”

Earlier Christl explained the distinction between a drug that has biosimilarity and one that has interchangeability: The FDA can deem a biological product “interchangeable” if a sponsor demonstrates that one can expect that drug to produce the same clinical result as the reference product.

What worries many patients and some doctors is that once deemed “interchangeable,” these drugs can be substituted for a reference product by a pharmacist without a physician’s knowledge.

Draft guidance regarding the issue of interchangeability has not yet been provided by the FDA.


Asked what impact these substations have had in Europe, where biosimilars have been available for the last decade, Carlos Sattler, vice president of clinical development and medical affairs for Sandoz, said, “there haven’t been any unexpected untoward experiences” when decisions have been based solely on cost and not on clinical decisions.

However, Emily Alexander, senior director of biologics strategic development for AbbVie, pointed to an abstract from the American College of Rheumatology’s annual meeting which looked at 792 patients in Denmark who switched from infliximab (Remicade) to biosimilar Remsima. “The authors conclude that for many patients the switch was without problems, but a little over 10% of patients within 3 months have loss of effectiveness or have an adverse event,” she said.

Patients should be notified if they receive an interchangeable drug, particularly if there is a change in the cost, said another speaker, Kristen Santiago, senior director for policy and advocacy for the Cancer Support Community.

“I don’t think they have any clue that any of this goes on,” she said.

One patient however was very aware of such problems.


During a question-and-answer session, Kathleen Arntsen, president/CEO of the Lupus and Allied Disease Association, who has lupus and is blind in her right eye, partially due to an allergy she has to the inactive ingredients in certain eye drops, said she is “terrified” of nonmedical switching. Arntsen was forced to fill two prescriptions for eye drops against her doctor’s advice. “Long story short, it caused me to downward spiral, and I’m now blind in my right eye,” she told MedPage Today.

To the panel, she said, “I’m part of my treatment team. I’m educated and empowered and I want to be in charge of my healthcare.”

Arntsen is now lobbying the New York state legislature to reform what is known as “step therapy” in which patients must first fail to improve on a less expensive treatment before an insurer will reimburse a more costly one.

According to the National Conference of State Legislatures, 36 states have considered another type of bill focused on establishing state standards for substitution of biosimilars for a biologic product.