The promise and pitfalls of biosimilars
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Dermatologists laud potential cost savings, urge measures to protect patients

No one disputes the appeal of the best-case scenario for biosimilars: the marketing of a new class of agents, developed to mimic the biologic drugs used to treat psoriasis and other disorders, that achieve an equivalent safety and efficacy profile at a significantly lower cost to patients. But dermatologists who rely on biologics to treat selected patients with moderate to severe psoriasis have voiced concern about the myriad questions that still surround biosimilars’ path to the market: Who will manufacture the biosimilars? What testing will the Food and Drug Administration require before deeming a biosimilar “interchangeable” with the reference drug? How much cheaper will the biosimilars actually be? Finally, will pharmacists be allowed to substitute a biosimilar for a reference drug without notifying the physician or patient?

Biologics now account for about one quarter of the $320 billion Americans spend annually on drugs, according to a report from research firm IMS Health, cited in the New York Times (“Biotech Firms, Billions at Risk, Lobby States to Limit Generics,” Jan. 28, 2013). Even with health insurance, out-of-pocket costs to patients can reach thousands of dollars. “I think the economic pressures to develop biosimilars are so large that they will happen,” said Alice B. Gottlieb, MD, PhD, professor of dermatology at Tufts University School of Medicine and chair of the department of dermatology at Tufts Medical Center. “Even a 10 to 20 percent saving will mean significant savings to our health care system. So I think it will happen; it’s only a question of when.”

Alluding to the difficulty of creating a drug equivalent to a large molecule biologic, Craig L. Leonardi, MD, associate clinical professor of dermatology at St. Louis University Medical School, remarked, “This is as complex as it gets; there might be some ramifications for health and safety, and there may not be. We won’t know until we try. But something has to be done, because the costs [of biologics] are mind-blowing.” [pagebreak]

FDA draft guidelines issued

A confluence of factors, in addition to the high cost of biologics, has given rise to the drive to create biosimilars. The Patient Protection and Affordable Care Act, signed into law in March 2010, created an abbreviated licensure pathway for biological products that are “demonstrated to be biosimilar’ to or interchangeable’ with an FDA-licensed biological product,” according to the FDA website. In the meantime, the “patent cliff” loomed for some of the leading biologics — the patent on Amgen’s Enbrel (etanercept), for example, was set to expire in 2012, though it has since been extended until 2028 (see sidebar).

Draft guidelines issued by the FDA in February 2012 address the agency’s “current thinking on scientific considerations in demonstrating biosimilarity to a reference product and quality considerations in demonstrating biosimilarity to a reference protein product.” In a February 2013 address to the Generic Pharmaceutical Manufacturers Association, Margaret A. Hamburg, MD, the FDA’s top official, said the agency is in the process of finalizing the guidelines and had just issued another draft guidance on how to study whether patients are at risk of having an unintended immune response to a biological product, and if they do, how to evaluate the impact of that response. She noted that the FDA has already received 14 Investigational New Drug applications for biosimilar development programs. [pagebreak]

The draft guidelines state that the FDA will take a “totality-of-the-evidence” approach to reviewing applications for biosimilars, and that “the type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis.” While most dermatologists believe some clinical testing will be required, “the question I keep asking is whether the biosimilars will be tested in dermatologic disease appropriately,” said Kenneth B. Gordon, MD, professor of dermatology at Northwestern University Feinberg School of Medicine. “If you’re dealing with a biosimilar anti-TNF, for example, and it’s tested in rheumatoid arthritis, there’s no guarantee it’s going to work the same way in psoriasis. I think a lot of it has to do with speed and expense; if a company’s going to do a full-scale testing program in psoriasis, there’s an expense associated with that.”

Dr. Leonardi said dermatologists “may end up having to live with the knowledge that the biosimilar works in rheumatoid arthritis as [the reference drug does], and we might have to go forward in treating patients with this drug. It’s going to be a leap of faith, and we’re going to have to keep our eyes open, and we need to report things that we see through whatever mechanism of reporting exists.”

Complex manufacturing

The expense of manufacturing a biosimilar may limit the savings that are realized once the new products reach the market, said Dr. Leonardi. “It’s not going to be dollars vs. thousands of dollars. The manufacturing facilities can’t take shortcuts in making these drugs, and it represents a huge investment in equipment, manpower, and the nature of the facilities. They’re very expensive to build, and the workers have to take multiple precautions to prevent contamination.” [pagebreak]

A commentary entitled “Biopharmaceuticals and biosimilars in psoriasis: What the dermatologist needs to know,” co-authored by Dr. Leonardi and published in the Journal of the American Academy of Dermatology (2012;66(2):317-22), explains why the manufacture of biosimilars is so much more complex than the creation of generics for small molecule drugs. While small molecule drugs (compounds of low molecular weight) and their generic equivalents are based on medicinal chemistry and are chemically synthesized and purified, biologics are “biopolymers of organic molecules that are manufactured in living systems.” They can never be exactly replicated, and every step in the manufacturing process has the potential to change the characteristics of the biosimilars relative to the original biologic. In one plant Dr. Leonardi visited, he was told that “not every run is successful; about one out of every seven batches is contaminated and cannot be used.”

Even minute variations from the reference drug can have clinical implications, explained Mark G. Lebwohl, MD, professor and chair of the department of dermatology at Mount Sinai School of Medicine. “This is a huge molecule, so if it differs by even one little bit, it could make the efficacy worse, the safety worse — or it could make them better. But we won’t know until we have years of data and thousands of patients.”

Reports that some of the leading manufacturers of biologics are said to be pursuing the development of biosimilars for their competitors’ drugs came as welcome news to the psoriasis experts. In a February meeting with analysts, Amgen Inc. said it expected biosimilars to be a multibillion-dollar opportunity for the company and announced plans to launch six biosimilars, beginning in 2017: four cancer drugs and two rivals to its own Enbrel (etanercept), AbbVie’s Humira (adalibmumab) and Janssen’s Remicade (infliximab), according to (“Amgen biosimilar push takes aim at blockbusters,” Feb. 7, 2013). “I would like to see them manufactured by a company with experience in marketing biologics,” Dr. Gottlieb said. “I know they know how to do it and I know the FDA has looked at their manufacturing headquarters and has blessed them, so to speak. I do not want to use a biosimilar made in China or Venezuela.” Dr. Leonardi concurred, noting that “Amgen knows how to make biologic drugs. I don’t have to worry about melamine being introduced into the drug.” [pagebreak]

Dermatologists confront tiering

Estimates of the likely cost of biosimilars vary. According to pharmaceutical industry newsletter FiercePharma (“How much cheaper will biosimilars be?,” March 2, 2012), biosimilars were initially expected to cost 30 percent to 40 percent less than the reference drug. However, “as the complexity of bringing biosimilars to market continues to be discussed, more recent data suggest that most payers anticipate a biosimilar will come in between 10 percent to 20 percent less than the cost of the branded manufacturer. In Europe, we know that biosimilars have often been just a 10 percent discount from the brand.”

If the cost savings are only modest, the introduction of biosimilars may not improve patient access to biologics to the degree that the health care community initially hoped. “You take a drug that costs $15,000 and you make it $12,000, that’s still out of reach of a lot of people,” Dr. Lebwohl said. Access to affordable care “is a huge issue for our patients,” said Leah McCormick Howard, director of government relations and advocacy for the National Psoriasis Foundation. “If biosimilars are going to give us safe and effective treatment in the same way that biologics are working today for our patient population, we absolutely want to see them on the market in a way that patients can afford them but it’s not clear at this point what the savings will be.”

Even patients with health insurance can have difficulty obtaining biologics, as insurers place onerous restrictions on which patients can receive the drug and/or require higher co-pays, a process known as tiering. Dr. Lebwohl called the tiering of biologics by insurers “a problem across the country. You may know what’s going to be best for your patient, you may have a very clear, coherent reason why they should get drug A rather than drug B, but the insurance company has decided they’re going to determine who gets drug A vs. drug B, and they usually do it on the basis of cost.” Dr. Gordon said he’s experienced “tremendous pushback” from insurers. “There’s the useful and the absurd. The main pushback is the amount of paperwork that’s put in front of us, and much of that is used to delay the prescriptions. It’s really an attempt to get doctors and patients to give up.” If cost savings related to biosimilars are only in the 20 to 25 percent range, “my concern is that we’re still going to have poor access for patients, and on top of it, have less information on the medicines we’re using for those patients who can get the medicine.” [pagebreak]

And it’s not only drugs that are tiered. Physicians, too, are sometimes penalized by insurance companies for prescribing too many biologics and other costly drugs. “It’s euphemistically called pay for performance,’” Dr. Gottlieb said. “Physician tiering uses claims databases and some quality measures, but it’s very much cost-driven. You are supposedly compared to your peers, but whether you’re in a tertiary care center is not taken into account, nor is your case mix or patient outcomes, because that’s not in the claims database.” The quality measures don’t address psoriasis, but rather, “do you write for Lotrisone, and do you have pregnancy on Accutane,” Dr. Gottlieb said. “I see the the most severe, recalcitrant psoriasis and psoriatic arthritis patients, and I’m compared to the doctor who, basically, gives topical steroids to the most severe of his psoriasis patients. So the irony is that the doctors who see the sickest patients are penalized, and that penalty is that all my patients — not just the psoriasis patients — pay a higher co-pay to see me. The result is that it’s very hard for a sick psoriasis patient to find good care in this state.”

The politics of substitution

The issue of when and if a pharmacist can substitute a biosimilar for a branded product, once biosimilars are available, is drawing attention from drug companies, insurers, state regulators, physicians, and patient advocacy groups. In at least eight states, bills have been introduced that would expand substitution laws to include biosimilars but place restrictions on biosimilars that do not apply to generics, according to the New York Times article. For example, the laws would require that the FDA find a biosimilar “interchangeable” with the reference drug in order for the biosimilar to be substituted. To meet that standard, the FDA says, the manufacturer “must show that the proposed interchangeable product is expected to produce the same clinical result as the reference product in any given patient. When a product will be administered more than once to an individual, the manufacturer must also demonstrate that the risk in terms of safety or reduced effectiveness of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” Some of the bills place further restrictions on substitutions, requiring, for example, that the patient consent to the switch or that the pharmacist notify the physician. These additional requirements would put the state laws in conflict with the 2010 federal law, which states that once the standard of interchangeability is met, a pharmacist may substitute without consulting the physician. [pagebreak]

In its Position Statement on Generic Therapeutic and Biosimilar Substitution, the AADA stipulates minimal thresholds that must be met before a biosimilar should be substituted for a reference drug. (The full position statement is available online at One is that the biosimilar has a unique, nonproprietary name; another is that the prescribing physician provides explicit permission for substitution, and that both the physician and patient are notified if a substitution occurs. Dr. Gordon pointed out that with generic drugs, a pharmacy might substitute one generic one week and a different one the next — “whatever they got a better deal for that day. That’s not going to be the way you can do it with biosimilars. I don’t mean to be a naysayer on biosimilars. The problem is you need to do it right, and I think the fear of all of us who work in this area is that there’s a huge impulse to do things cheaply and not well. Doing this well and doing it right and actually saving some money would be great.”

Editor’s note: Dr. Gordon has served as a consultant to AbbVie (formerly Abbott), Amgen, and Centocor, the original innovator of Stelara. Dr. Gottlieb has served as consultant to AbbVie, Amgen, and Janssen. Dr. Lebwohl has served as consultant and investigator for Amgen and Centocor and a consultant to AbbVie. Dr. Leonardi has served as investigator, speaker, and advisory board member for Abbott and Amgen and as investigator and advisory board member for Centocor. [pagebreak]

Biologic patent expiration dates

AbbVie Inc.
Humira (adalimumab)
Janssen Biotech, Inc. (division of J&J)
Remicade (infliximab)
Janssen Biotech, Inc. 
Stelara (ustekinumab)
Janssen Biotech, Inc.
Simponi (golimumab)
Enbrel (etanercept)
2028 (extended from 2012)

Information supplied by the manufacturers.



Biologic patent expiration dates