The FDA's approval in March of the first biosimilar drug for the US market has aroused much concern among physicians.
Melissa Dillmon, MD
The FDA’s approval in March of the first biosimilar drug for the US market has aroused much concern among physicians, who fear that these complex drugs will not be perfect substitutes for the branded drugs they will replace and who insist that certain standards be attached to their approval and distribution.
“There is no doubt that biosimilars will play a large role in the future treatment of our patients, and hopefully that they will fulfill their goal of bioequivalence and decreased cost,” said Hillary Hahm, MD, a medical oncologist with Northwest Georgia Oncology Centers and also a board member of the Georgia Society of Clinical Oncology (GASCO). “However, there need to be safeguards concerning the development and clinical use of each of agents, so that our patients are assured the best possible treatment from both an efficacy and safety standpoint.”
Georgia is one of at least 23 states so far whose legislatures have considered regulating the prescription, doctor and patient notification, recordkeeping, and approvals of biosimilars. GASCO has sought to block legislation in Georgia that would allow Georgia pharmacists to dispense biosimilar drugs as a substitution for brand name drugs without physicians being informed about the substitutions.
Melissa Dillmon, MD, president of GASCO and a medical oncologist at the Harbin Clinic in Rome, Georgia, is pushing for a requirement that pharmacists notify physicians and patients about potential biosimilar substitutions. “The patient has to know they are not getting the same thing, and the physician has to be notified,” said Dillmon, adding that the US has no track record on researching the safety and efficacy of biosimilars.
Biosimilars—complex molecule drugs that are administered intravenously—have been marketed in Europe since 2007, and they are now entering the US via a pathway established by The Biologics Price Competition and Innovation Act of 2009, as part of the Affordable Care Act.1 The first FDA-approved biosimilar is Zarxio (filgrastim-sndz), a Sandoz drug that can boost white blood cell counts for cancer patients whose immune systems have been weakened by chemotherapy. The drug would compete with Amgen’s Neupogen, whose patent expired in December 2013.
There are legal obstacles to overcome before Zarxio is offered for sale. Amgen has challenged the sale of the drug, saying it was not given sufficient notice by Sandoz that the company was about to launch a biosimilar that would compete with Neupogen. In late March, a federal judge in San Francisco dismissed Amgen's claims, which led to an appeal in the US Court of Appeals for the Federal Circuit in Washington. This decision, which was handed down on May 5, blocked Zarxio from entering the market until oral arguments could be heard. The next court date is scheduled for June 3, 2015.
In granting approval, the FDA stated that Zarxio would not be regarded as “interchangeable” with Neupogen, despite its close similarity and “biosimilar” status.2 This means it cannot be substituted for Neupogen without the involvement of the prescribing physician. Much of the controversy surrounding biosimilars has to do with the variability of the manufacturing process of these large molecule drugs, which vary slightly from one batch to another in the same factory and also among batches produced by brand name manufacturers.
Many more biosimilars from Sandoz are on the way. Those that are undergoing or have completed clinical trials and are in line for FDA consideration include pegfilgrastim (comparable to Amgen’s Neulasta) for chemotherapy-induced febrile neutropenia; rituximab (comparable to Rituxan/MabThera) for patients with rheumatoid arthritis and follicular lymphoma; epoetin alfa (comparable to Johnson & Johnson’s Procrit and Eprex) for patients with anemia associated with chronic kidney disease; etanercept (comparable to Amgen’s Enbrel) for patients with plaque psoriasis; and adalimumab (comparable to AbbVie’s Humira) for patients with plaque psoriasis, according to Sandoz.
An Ongoing Review of Pharmacy Laws
In contrast to generics, biosimilars aren’t perfect copies of brand name drugs, and as a result “all 50 states either have or will be reviewing their pharmacy laws about how to offer substitution,” predicts Mark Fleury, the policy principal of emerging sciences for the American Cancer Society Cancer Action Network (ACS CAN), a Washington, DC, group that advocates on behalf of patients. “Because all the existing laws are written for small molecules, not biosimilars, you can’t just apply the same law. The drugs are highly similar but may not be exactly the same. It boils down to the issues of consent and notification and what is considered interchangeable, and each state has to figure out how they want to handle it,” Fleury said.
ACS CAN is optimistic that biosimilars, like generic medications, could reduce the cost of potentially lifesaving therapies and make them easier to access for patients. The group wants the FDA “to quickly finalize guidance on naming, labeling, and interchangeability criteria, so that biosimilars’ development can move forward and patients are assured of transparency and safety.”
When it approved Zarxio, the FDA gave it the nonproprietary name filgristim-sndz, which differs from the Neupogen version in that the suffix “sndz” is attached. This is intended to distinguish it as a biosimilar, but the FDA said it continues to work on an acceptable labeling system for biosimilars. GASCO contends that biosimilars should stay off the US market until such issues are fully resolved.
“The FDA must complete their work in approving and classifying the new biologicals as either biosimilar or interchangeable before the physicians can use them in this country,” said GASCO Director Karen M. Beard. “They are not the same as generics where the generic manufacturer uses the same active chemical ingredients after a drug comes off a patent. The biosimilar and interchangeable drugs are more complex structures derived from many sources of molecules, including human, animal and microorganisms, such as bacteria or yeast. The sources may be natural or synthetic. Physicians and patients must be assured by the FDA that it produces the same results as the original drug with no adverse side effects.”
Both the FDA and Sandoz say that the approval of Zarxio was based on a thorough review of clinical safety and effectiveness data. Sandoz currently markets the non-US version of Zarxio, called Zarzio, in 40 other countries, and used “a comprehensive package of analytical, nonclinical and clinical data, which confirmed that Zarxio is highly similar to Neupogen,” Sandoz said in a written statement. “We also presented results from post-marketing studies, and post-marketing pharmacovigilance data from use of the product in Europe and other markets. Taken together, these data provided the totality of evidence necessary to establish biosimilarity” of Sandoz’s filgrastim biosimilar to Amgen’s Neupogen, the company said.
“Just as it does for other drugs, the FDA undertakes a rigorous and thorough evaluation to ensure a biologic’s safety and effectiveness before it is approved,” FDA spokesman Kristofer Baumgartner said in a written statement. Biosimilar products can only be approved if they have the same mechanism(s) of action, route(s) of administration, dosage forms and strengths as the reference product, and only for indication(s) and condition(s) of use that have been previously approved for the reference product, he added.
Different Names Are Possible Source of Confusion
Potential problems abound in the choice of nonproprietary names that are assigned to biosimilar drugs. Both the FDA and drug manufacturers rely on what are called “spontaneous report adverse event reports,” submitted by physicians, pharmacies, or patients, to report any adverse effects from using Zarxio or any other medications, said Greg Daniel, PhD, a fellow and managing director at the Center for Health Policy at the Brookings Institution based in Washington, DC. “Because many of these reports do not include unique codes to identify the specific drug, [the] FDA and manufacturers often have to rely on the drug names listed in the report when analyzing spontaneous report databases.”
With the subtle differences between biosimilar drugs and their brand name counterparts, even from batch to batch, Daniel speculated, it will be especially important to distinguish each product in the safety reports once they are in use in the US. With nonbiologic small molecule drugs, such as Tylenol, Lipitor or Advil, the chemical structures of the drugs are identical between brand and generic versions, and the need to distinguish between products isn’t as critical from a safety perspective, said Daniel.
Hospira, a drug company that markets biosimilars in Europe, argued in a recent position paper that allowing identical nonproprietary names for biosimilars would enable physicians to more easily recognize similar drugs and would simplify reporting on adverse events and other issues.3 “Adding prefixes and suffixes to biologic products historically means that something is clinically different with a drug. That is not the case with biosimilars, which are approved by regulatory agencies to have similar clinical results as a brand name biologic drug,” Hospira wrote.
One concern with having a different generic name for a biosimilar product, compared to its reference product, is that it might signal to providers and patients that the biosimilar drug is somehow inferior, because it’s perceived as less effective or less safe, said Daniel. “This could unnecessarily slow the uptake through less utilization of the product, which could happen if people perceive the original reference product as being better," he added.
“If there is less utilization of biosimilars than there really should be, the potential for large savings to patients and the health care system as a whole might not be as great,” said Daniel. “There are a lot of dollar savings that can be brought into the healthcare system.”
Generic medications cost about 80-90% less than the name brand drugs, while most people are expecting a 20-40% discount on biosimilars, as compared to the brand name drug, Fleury said. “The intrinsic cost to manufacturers for biosimilars is higher, while with generics, when you strip away the research and development costs, it may only cost a few pennies per pill to make,” he said.
Because biosimilars aren’t yet available in the US, it’s still unclear how pricing will work. Sandoz would not disclose details about how Zarxio will be priced once it is available. And insurers and pharmacies may also play a role.
“What you may see is pharmacy benefit manufacturers pitting manufacturers [of biosimilars] against each other in order to drive costs down,” said Fleury. “It could be that unless you provide a low-enough price, a health insurer may not put that version of a biosimilar on the formulary.”
According to research published in 2013 by the pharmacy benefits manager Express Scripts, if the 11 likeliest biosimilars enter the market over the next decade, biosimilars could help save $250 billion in healthcare costs by 2024.4 Similarly, the research organization the Rand Corporation in 2014 predicted a more modest but still notable healthcare savings of $44 billion over the same period.5
An Advantage for Doctors
Though they are concerned about drug performance, physicians do have a measure of control in that Zarxio and other potential cancer biosimilars are administered intravenously, and are typically taken episodically, as opposed to over-the-counter medications that patients will pick up at the pharmacy themselves. “These are all injectibles that are given in a hospital or at a physician’s office, or infused like chemotherapy,” said Dillmon. In these cases, the physician is more likely to be able to speak directly with a pharmacist before the biosimilar is used by the patient, so that the physician can speak about their concerns about safety and other issues.
Dillmon said that it’s very important to her to be able to weigh in on whether a biosimilar is going to be used in treatment of one of her patients. “I would personally have to have a discussion with the insurance company about my preferences as a physician,” she said.