Unknowns of interchangeability likely not problematic with monitoring, FDA guidance

Robert M. Rifkin, MD, FACP
Robert M. Rifkin

As more biosimilars are approved by the FDA, and with more in the development pipeline, the issue of interchangeability is raising red flags and causing concern among physicians about the future of biosimilars.

For a biosimilar to be considered interchangeable, it must not only meet the same basic standards set for biosimilarity, but also undergo additional testing. Further, it must produce the same clinical result as the reference biologic in any given patient, and when given more than once must carry no greater risk to safety or efficacy if switched with the reference product vs. using the reference product without switching, according to the FDA.

“Interchangeability means different things to different people,” Robert M. Rifkin, MD, FACP, medical director of biosimilars at McKesson Specialty Health, The US Oncology Network, told Healio. “... [It] is something that goes beyond the test of biosimilarity, and the term is unique to the United States regulatory environment. Interchangeability, in the biosimilar regulatory context, sets a higher bar than the test for biosimilarity, and it requires more data.”

There are currently no FDA-approved biosimilars designated as interchangeable. However, in January 2017 the FDA Center for Drug Evaluation and Research issued draft guidance on the topic.

The guidance includes information on the type and quantity of evidence needed to demonstrate interchangeability of a proposed therapeutic protein product; how switching studies or other studies to support interchangeability should be designed; how reference products should be used in switching studies; and how to develop presentations for proposed interchangeable products.

Concerns over communication

More details are now available from the FDA, and the agency has made clear that pharmacists can switch a patient from a biologic to an interchangeable biosimilar without prior approval from the prescribing physician. This lack of communication and loss of control has left many in the medical community feeling uneasy.

Dennis R. Cryer
Dennis R. Cryer

“As physicians who prescribe biologic drugs, we worry about medications being switched without our knowledge or without us knowing soon thereafter. If a patient who has been stable develops a problem, and we don’t know their medication has been changed — a major new piece of clinical information — we’re at a loss to explain it,” Dennis R. Cryer, MD, co-convener of the Biologics Prescribers Collaborative and chief medical officer at CryerHealth, told Healio. “Therefore, data required for interchangeable status must be robust and risk-based, especially since these products may be substituted for the reference product without intervention from the prescribing health care provider,” he said.

But while at the federal level the pharmacy will have the power to make the switch, each state will ultimately decide whether such a switch can occur without the patient or physician’s knowledge, according to Rifkin.

To date, 35 states and Puerto Rico have considered or enacted bills relating to interchangeability. Some, like Massachusetts, have mandated that pharmacists make a note in patient records, available to the prescribing physician upon request, when biosimilars are substituted for their reference products. Others, like Arizona, have ruled that patients must be notified of a switch and a specific record must be kept.

Vibeke Strand, MD
Vibeke Strand

Vibeke Strand, MD, adjunct clinical professor in the division of immunology and rheumatology at Stanford University, told Healio she is hopeful that a communication breakdown will not occur.

“The fact of the matter is it is highly unlikely such a thing would happen, and the reason I say that is because we are going to get a substitution period,” Strand said. “As soon as biosimilars lower costs, managed care will likely mandate ‘non-medical switching,’ and at that point we will know what the patient is getting.”

To determine whether a biosimilar can be substituted for its reference product, companies will need to perform “switching” studies where patients are switched between both products multiple times, which Strand said will be costly trials.

“When tocilizumab and abatacept went from [IV] to [subcutaneous], [researchers] had to study some 3,000 patients, two different trials, back and forth switching between IV and [subcutaneous] and examining immunogenicity,” Strand said. “Based on what is required for interchangeability, I do not know that a biosimilar company will actually want to spend the money for these more expensive clinical trials.”

Expensive clinical trials that would essentially subvert the intention of the abbreviated approval pathway for biosimilars — to save time and resources and avoid unnecessary testing.

Biosimilars around the world

The first biosimilar to receive approval in the European Union was Omnitrope, a biosimilar somatropin for the treatment of pituitary dwarfism, Prader-Willi syndrome and Turner syndrome, in 2006. Though a total of 23 biosimilars have since been authorized in the EU, interchangeability remains a concern.

Peter D. Higgins, MD, director of the inflammatory bowel disease program at the University of Michigan, told Healio that physicians in Europe have been researching interchangeability for the past 3 years, which has led to positive outcomes in terms of both clinical results and cost-effectiveness.

According to Rifkin, “there have been 400,000,000 patient-days in Europe without an incident, meaning no immunogenicity, none of the bad stuff that you read about.”

One of the largest trials on interchangeability is the NOR-SWITCH study — a randomized, double blind trial conducted in 40 sites across Norway designed to evaluate the effects of switching patients once from Remicade (infliximab, Janssen) to the biosimilar Remsima across six inflammatory diseases, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis and plaque psoriasis. Researchers randomly assigned 481 patients who were stable on the original biologic to either remain on Remicade or switch to Remsima. After 1 year, patients would be eligible to roll over into a 6-month open extension study where everyone received the biosimilar, ensuring each patient switched medicines at least once during the study. Researchers collected blood samples at each patient visit to evaluate whether the switch to the biosimilar stimulated a patient’s immune system, as well as whether the immune system was activated to neutralize the drug. Researchers analyzed the effects of the switch on disease worsening, disease-specific outcomes, safety, immunogenicity and cost-effectiveness.

Data presented at United European Gastroenterology Week 2016 showed that Remsima was not inferior to continued treatment with Remicade, with comparable efficacy and safety demonstrated between the two groups. Additional data presented at the meeting showed Remsima and Remicade were associated with comparable remission rates among patients with Crohn’s disease and ulcerative colitis.

Jorgen Jahnsen, MD, PhD
Jorgen Jahnsen

“The data show that safety and efficacy are maintained post-switch and should give confidence to physicians looking to move their patients onto biosimilar infliximab for non-medical reasons such as cost,” Jørgen Jahnsen, MD, PhD, professor of gastroenterology at the University of Oslo, Norway, and co-author of the NOR-SWITCH study, said in a press release.

Tracking, education needed

Most experts agree: Tracking the switch from reference product to biosimilar is of utmost importance, and patients and physicians must be informed when these decisions are made. However, according to Higgins, as long as this tracking occurs and biosimilars are monitored when prescribed, interchangeability may not be as problematic as expected.

“To some extent every new biosimilar needs to be watched and monitored, and we absolutely need some way to track when a patient’s medication is changed. [We need to know] which one they are on and the [biosimilars] need to be clearly named. ... It will need to be recorded somewhere in the medical record because if something does go wrong, the only way we will know and [be able to] track it is to have that information available and know exactly what dates the patient was on [which drug],” Higgins said.

According to Strand, interchangeability may not be as big of a concern as originally perceived.

“For now, we really do not know what interchangeability is going to mean,” she said. “... It is better not to be fearful of the unknown if actually the unknown does not seem like it is going to occur.”

Either way, as increasingly more biosimilars receive approval here in the U.S., education is essential — both for physicians and patients.

“[Physicians] need overall general education; interchangeability is not auto-substitution, but it is a regulatory term just like biosimilars. They need to understand that you need to meet the higher bar to be granted interchangeability,” Rifkin said. - by Casey Tingle and Stacey L. Adams

Disclosures: Higgins reports consulting for AbbVie, Johnson & Johnson and UCB. Strand reports consulting for Celltrion, Merck, Pfizer, Samsung and Sandoz. Cryer and Rifkin report no relevant financial disclosures.

Robert M. Rifkin, MD, FACP
Robert M. Rifkin

As more biosimilars are approved by the FDA, and with more in the development pipeline, the issue of interchangeability is raising red flags and causing concern among physicians about the future of biosimilars.

For a biosimilar to be considered interchangeable, it must not only meet the same basic standards set for biosimilarity, but also undergo additional testing. Further, it must produce the same clinical result as the reference biologic in any given patient, and when given more than once must carry no greater risk to safety or efficacy if switched with the reference product vs. using the reference product without switching, according to the FDA.

“Interchangeability means different things to different people,” Robert M. Rifkin, MD, FACP, medical director of biosimilars at McKesson Specialty Health, The US Oncology Network, told Healio. “... [It] is something that goes beyond the test of biosimilarity, and the term is unique to the United States regulatory environment. Interchangeability, in the biosimilar regulatory context, sets a higher bar than the test for biosimilarity, and it requires more data.”

There are currently no FDA-approved biosimilars designated as interchangeable. However, in January 2017 the FDA Center for Drug Evaluation and Research issued draft guidance on the topic.

The guidance includes information on the type and quantity of evidence needed to demonstrate interchangeability of a proposed therapeutic protein product; how switching studies or other studies to support interchangeability should be designed; how reference products should be used in switching studies; and how to develop presentations for proposed interchangeable products.

Concerns over communication

More details are now available from the FDA, and the agency has made clear that pharmacists can switch a patient from a biologic to an interchangeable biosimilar without prior approval from the prescribing physician. This lack of communication and loss of control has left many in the medical community feeling uneasy.

Dennis R. Cryer
Dennis R. Cryer

“As physicians who prescribe biologic drugs, we worry about medications being switched without our knowledge or without us knowing soon thereafter. If a patient who has been stable develops a problem, and we don’t know their medication has been changed — a major new piece of clinical information — we’re at a loss to explain it,” Dennis R. Cryer, MD, co-convener of the Biologics Prescribers Collaborative and chief medical officer at CryerHealth, told Healio. “Therefore, data required for interchangeable status must be robust and risk-based, especially since these products may be substituted for the reference product without intervention from the prescribing health care provider,” he said.

PAGE BREAK

But while at the federal level the pharmacy will have the power to make the switch, each state will ultimately decide whether such a switch can occur without the patient or physician’s knowledge, according to Rifkin.

To date, 35 states and Puerto Rico have considered or enacted bills relating to interchangeability. Some, like Massachusetts, have mandated that pharmacists make a note in patient records, available to the prescribing physician upon request, when biosimilars are substituted for their reference products. Others, like Arizona, have ruled that patients must be notified of a switch and a specific record must be kept.

Vibeke Strand, MD
Vibeke Strand

Vibeke Strand, MD, adjunct clinical professor in the division of immunology and rheumatology at Stanford University, told Healio she is hopeful that a communication breakdown will not occur.

“The fact of the matter is it is highly unlikely such a thing would happen, and the reason I say that is because we are going to get a substitution period,” Strand said. “As soon as biosimilars lower costs, managed care will likely mandate ‘non-medical switching,’ and at that point we will know what the patient is getting.”

To determine whether a biosimilar can be substituted for its reference product, companies will need to perform “switching” studies where patients are switched between both products multiple times, which Strand said will be costly trials.

“When tocilizumab and abatacept went from [IV] to [subcutaneous], [researchers] had to study some 3,000 patients, two different trials, back and forth switching between IV and [subcutaneous] and examining immunogenicity,” Strand said. “Based on what is required for interchangeability, I do not know that a biosimilar company will actually want to spend the money for these more expensive clinical trials.”

Expensive clinical trials that would essentially subvert the intention of the abbreviated approval pathway for biosimilars — to save time and resources and avoid unnecessary testing.

Biosimilars around the world

The first biosimilar to receive approval in the European Union was Omnitrope, a biosimilar somatropin for the treatment of pituitary dwarfism, Prader-Willi syndrome and Turner syndrome, in 2006. Though a total of 23 biosimilars have since been authorized in the EU, interchangeability remains a concern.

Peter D. Higgins, MD, director of the inflammatory bowel disease program at the University of Michigan, told Healio that physicians in Europe have been researching interchangeability for the past 3 years, which has led to positive outcomes in terms of both clinical results and cost-effectiveness.

PAGE BREAK

According to Rifkin, “there have been 400,000,000 patient-days in Europe without an incident, meaning no immunogenicity, none of the bad stuff that you read about.”

One of the largest trials on interchangeability is the NOR-SWITCH study — a randomized, double blind trial conducted in 40 sites across Norway designed to evaluate the effects of switching patients once from Remicade (infliximab, Janssen) to the biosimilar Remsima across six inflammatory diseases, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis and plaque psoriasis. Researchers randomly assigned 481 patients who were stable on the original biologic to either remain on Remicade or switch to Remsima. After 1 year, patients would be eligible to roll over into a 6-month open extension study where everyone received the biosimilar, ensuring each patient switched medicines at least once during the study. Researchers collected blood samples at each patient visit to evaluate whether the switch to the biosimilar stimulated a patient’s immune system, as well as whether the immune system was activated to neutralize the drug. Researchers analyzed the effects of the switch on disease worsening, disease-specific outcomes, safety, immunogenicity and cost-effectiveness.

Data presented at United European Gastroenterology Week 2016 showed that Remsima was not inferior to continued treatment with Remicade, with comparable efficacy and safety demonstrated between the two groups. Additional data presented at the meeting showed Remsima and Remicade were associated with comparable remission rates among patients with Crohn’s disease and ulcerative colitis.

Jorgen Jahnsen, MD, PhD
Jorgen Jahnsen

“The data show that safety and efficacy are maintained post-switch and should give confidence to physicians looking to move their patients onto biosimilar infliximab for non-medical reasons such as cost,” Jørgen Jahnsen, MD, PhD, professor of gastroenterology at the University of Oslo, Norway, and co-author of the NOR-SWITCH study, said in a press release.

Tracking, education needed

Most experts agree: Tracking the switch from reference product to biosimilar is of utmost importance, and patients and physicians must be informed when these decisions are made. However, according to Higgins, as long as this tracking occurs and biosimilars are monitored when prescribed, interchangeability may not be as problematic as expected.

“To some extent every new biosimilar needs to be watched and monitored, and we absolutely need some way to track when a patient’s medication is changed. [We need to know] which one they are on and the [biosimilars] need to be clearly named. ... It will need to be recorded somewhere in the medical record because if something does go wrong, the only way we will know and [be able to] track it is to have that information available and know exactly what dates the patient was on [which drug],” Higgins said.

PAGE BREAK

According to Strand, interchangeability may not be as big of a concern as originally perceived.

“For now, we really do not know what interchangeability is going to mean,” she said. “... It is better not to be fearful of the unknown if actually the unknown does not seem like it is going to occur.”

Either way, as increasingly more biosimilars receive approval here in the U.S., education is essential — both for physicians and patients.

“[Physicians] need overall general education; interchangeability is not auto-substitution, but it is a regulatory term just like biosimilars. They need to understand that you need to meet the higher bar to be granted interchangeability,” Rifkin said. - by Casey Tingle and Stacey L. Adams

Disclosures: Higgins reports consulting for AbbVie, Johnson & Johnson and UCB. Strand reports consulting for Celltrion, Merck, Pfizer, Samsung and Sandoz. Cryer and Rifkin report no relevant financial disclosures.

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