Future Bisomilars: Pros and Cons

Note: This story was originally published in the January 2016 issue of BioSupply Trends Quarterly. It can be read in its original format here.

By Meredith Whitmore
In this brave new world of medicines, more and more physicians are prescribing a biologic. Perhaps they have even witnessed a patient’s remarkable transformation thanks to biologics such as Humira, Enbrel and Remicade. After months or years of debilitating chronic illness, the patient is now going back to work, experiencing less pain and
even exercising again.
But maybe physicians have also seen the strain on a patient’s face when he or she describes the cost of such life-changing drugs. Copays can cost $1,500-plus out of pocket each month. What if, during an appointment, the patient finally asks if there’s a less-costly but equally effective treatment? What’s the answer for a patient who needs the higher quality of life that biologics provide, but without the devastating expense?
According to Industry Standard Reports, 46 percent of U.S. consumers have never heard of biologic medications, and only 38 percent know whether their prescription is a biologic or a chemical medication. That means they rely on their physicians to guide them through the maze of biopharmaceuticals. Unfortunately, 54 percent of primary health providers and 78 percent of pharmacists can’t yet define “biosimilars.”¹

What Are Biosimilars?

Biosimilar medications, sometimes called follow-on biologics, are considered the cost-effective alternative to biologics. They are roughly analogous to generic drugs in that they are a nonproprietary alternative to a name-brand medication. Unlike generics that are identical chemical formulations of the original medication, however, a biosimilar, due to its complex proteins, is highly similar to but not exactly the same as its reference biologic product.
While such medications have been available and successfully used in Europe and other parts of the world for at least nine years,² only one biosimilar, Zarxio (filgrastim-sndz), is available in the United States to date. But that will change. More and more biosimilars are lining up to be approved by the U.S. Food and Drug Administration (FDA). And while FDA develops guidances for biosimilars, these drugs remain a heated topic of debate. As such, physicians are wise to educate themselves about these medications now since they pose unique safety and legislative concerns.

Potential Pros of Biosimilars

Price. Perhaps the most anticipated advantage of a biosimilar is its lower cost, which ExpressScripts predicts will be at least 20 percent to 30 percent less than the cost of reference biologics. By 2024, biosimilars in the United States are predicted to save$250 billion. Currently, Zarxio (manufacturered by Sandoz) costs 15 percent less than its reference product, Neupogen.^3,4
Some are skeptical of the potential savings, however. Among them is Frank Kopenski, principal actuary at Milliman actuarial group. “For a 10,000-lives employer with 2019 commercial healthcare expenditures of $81.5 million, the 2019 total estimated savings is just $635,925 or 0.8 percent of total healthcare spend assuming 30 percent total market penetration and 30 percent lower pricing of biosimilars,” says Kopenski in a December 2011 study projecting biosimilar cost savings to employers. “The overall savings as a percentage of total healthcare costs resulting from biosimilars is likely to be small (i.e., less than 1 percent) given the relatively small frequency of members with high-cost conditions. At this level of savings potential, it is unlikely that employers will change benefit provisions to incent the use of biosimilars over biologics.”⁵
Still, Julianna Reed, president of the Biosimilars Forum, says people must remember that biosimilars are not generic drugs. “It’s important for physicians and patients to know how different biosimilars are and how much more rigorous the science is in their development. The cost of developing a biosimilar is so much higher than that of a generic – between $100 million and $200 million – that, initially, the first few products in the United States will not be the current generic model discount. That’s what we’ve seen in Europe for the past nine years,”⁶ explains Reed. “Patients in the United States won’t see great discounts until more and more biosimilar competitors come onto the market. This is exactly how the generic industry also started in its first years. It’s important for folks to understand biosimilars are the very beginning of a very different pathway.”
Availability and options. In some cases, biosimilars could offer greater availability than a reference product. If a biologic faces a shortage due to high demand or a lack of active ingredients, biosimilar manufacturing could alleviate the biologic’s scarcity. Besides this, physicians want more options for patients, not fewer. Having biosimilars available, properly tested
and used gives everyone more choice.

Potential Cons of Biosimilars

The drawbacks of biosimilar medications depend largely on what FDA’s final guidances will be. Depending on the guidances’ stringency, the cons could be devastating, hence the heated debate from numerous patient interest groups. If guidances are adequately strict, however, and clinical testing is effective, the risks will diminish significantly. It all remains to be seen, but most patient groups and physicians are hopeful despite the following concerns.
Nomenclature. Biosimilar names, if not unique and nonproprietary, could be confusing for physicians and, as a result, harmful to patients. In the event of adverse reactions to drugs, biosimilar names that are too similar to a reference product could cause an inability to determine which biosimilar is problematic. “For example, ibuprofen, a generic of Motrin, is called only ibuprofen, without a unique name. If it caused adverse reactions in patients, how would we know if the problematic ibuprofen is from Walgreens or Sam’s Club or CVS?” explains Lawrence LaMotte, vice president of public policy for the Immune Deficiency Foundation (IDF). That’s a simple but clear analogy for a potentially serious problem. “We at IDF believe that labels must indicate that a drug is a biosimilar, and should indicate what the reference product is, at the very least. A biosimilar will not only not be identical to a reference product but will also not be similar to other biosimilars of the same reference product.”
Many patient interest groups, including Lamotte’s, are thankful that FDA has begun to consider nomenclature more seriously. In its recently released guidance on nonproprietary naming, FDA states that distinguishable names, including four-letter suffixes based on the manufacturer’s name, will help in product identification, prescribing and dispensing. A manufacturer-specific suffix such as Zarxio’s -sndz (which stands for its manufacturer, Sandoz) not only ensures that doctors and pharmacists will know the products are not interchangeable, but makes drug companies accountable.
Extrapolation across indications. Just because a biologic is said to be effective in treating five different diseases does not mean that its biosimilar will be also. That assumption is dangerous for patients, many of whom have a 30 percent chance of experiencing adverse effects when taking any new biologic,⁷ let alone a drug that is merely similar to their biologic. “The idea that a similar drug, not an identical drug such as a generic, but a similar drug like a biosimilar, would be given indication extrapolation is dangerous,” says Dr. David Charles, chairman of the Alliance for Patient Access. “Just imagine if you test the biologic in a condition like inflammatory bowel disease – do you really know it’s going to have similar efficacy in a condition like rheumatoid arthritis? No. The patient groups that are treated with biologics are so different that indication extrapolation is a concern. I think the FDA has a long way to go to offer more clarity.”
Katie Verb, associate director of policy and government relations at the Hemophilia Federation of America, agrees. “Our main concern with the FDA guidance is how it treats extrapolation across indications. A lot of biologics are approved to treat multiple diseases, and those approvals are based on clinical trials within each disease group,” says Verb. “The FDA seemed light on whether they would do that for biosimilars. The FDA guidance in 2012 took the patients’ safety into account more seriously. That guidance said more about extrapolation, and that there would need to be clinical data for each disease group. The 2015 guidance lightened up on that considerably, however. The 2012 guidance pointed out that there should be caution when it comes to extrapolation, and that caution indication for industry was taken out of the 2015 guidance.”
“You just can’t make that leap and assumption [of extrapolation across indications],” adds Lamotte. “That is an issue that needs to be better defined, and it has not yet been by the FDA. The scientific community and patient organizations have issues with that policy.”
Efficacy. At least one report has illustrated that biosimilars might not be as efficacious as their reference products. An Irish study on Inflectra, a biosimilar used to treat irritable bowel disease, found that 29 percent of patients who took it required surgery versus 0 percent of patients who took Remicade (infliximab), its reference biologic. In addition, 80 percent of the Inflectra group required hospital readmission versus 5 percent of the Remicade group. And 93 percent of the Inflectra group showed an increase in C-reactive protein (CRP), while 100
percent of the Remicade group had a decrease in CRP.⁸
Still, Dr. Charles is hopeful for the efficacy of future biosimilars. “How do we know, without clinical trials, that a biosimilar may not actually be better than its biologic? Some people are coming to the table as if the biosimilar will be only ‘just as good,'” he says. “Actually, they’re different products, and it’s possible that some biosimilars will have a better profile than the original. Maybe the biosimilar will treat the condition better, and maybe it has fewer side effects. But how do we know that? We will never know that unless these drugs are properly tested in clinical trials. I think we should come to the table with the notion that the biosimilar product is not the same and it may be better. It’s certainly possible. Why would we assume that the biosimilar is going to be merely the same or worse?”
Safety. In August, Indian pharmaceutical and biotechnology firm Intas Biopharmaceuticals stopped distribution of its injectable biosimilar, Razumab, after only two months on the market.⁹ Used to treat macular degeneration, the drug caused adverse reactions such as inflammation in patients’ eyes. LaMotte expresses related concerns in the United States: “The question for us was: Does the FDA have enough inspectors around the world to inspect all these different manufacturers and get the required data in order to approve a biosimilar? There still isn’t a good answer to this question.”
Pharmacists’ responsibilities and substitutions. Though laws differ from state to state, in many states, pharmacists may switch a drug to a generic instead of dispensing a name brand, and they may do so without informing physicians and patients. Because biosimilars are not identical to their reference biologics, switching from a biologic to a biosimilar, or vice versa, could pose considerable problems. Doctors must remember to write prescriptions clearly, blocking such substitutions by stating: “Dispense as written.” Many patient interest organizations believe FDA must address this issue further.
Interchangeability. To be considered interchangeable, a biosimilar must be able to produce the same clinical result as a biologic in all patients without increasing the risk of side effects or lowering efficacy. There are currently no biosimilars that are interchangeable.
Considering that what is true of a biologic will likely be true of a biosimilar, however, Verb of the Hemophilia Federation of America says, “there’s a really high immunogenicity portion of our patients. About 30 percent of our population develops an inhibitor while using a biologic. That means their bodies are basically eating their coagulation factor. There are a lot of issues for us, even in switching current FDA-approved biologics. There’s anecdotal data in the community that switching drugs leads to a higher inhibitor development rate, so it becomes increasingly important for our population that they’ve got biologics that have gone through all these clinical trials and have gone through this huge approval system. Now there will be follow-on biosimilar products that might not be tested to the same strengths, so that for us is what causes a lot of the debate and the concern.”
Today, there is no way to guarantee that a highly complex biosimilar will act exactly as its reference product biologic. Yet Dr. Charles remains hopeful that someday less complex biosimilars might be duplicated and considered interchangeable. “I don’t think every biosimilar is so complex that there couldn’t be one that is duplicable,” he says. “But how would you know that it’s interchangeable? With detailed clinical trials to demonstrate that interchangeability, not just the assertion that it’s interchangeable.”

Time Will Tell

The pros and cons of biosimilars are still somewhat hypothetical, but significant, and as FDA irons out safety concerns, the future of the U.S. drug market will gradually emerge. New biosimilars under FDA review include Hospira’s version of Amgen’s Epogen, Celltrion’s version of Remicade and Apotex’s version of Neupogen.¹⁰ It is exciting to think of having more options for patients, but patient interest organizations remain hesitant with good reason.
“I think there’s hope for biosimilars, and the community is looking forward to them, but a couple of things have to happen to ensure their safety,” says Verb. LaMotte agrees: “We would love to have drugs on the market that cost less, because we’re talking about expensive drugs. But we also want those drugs to be safe and effective, and that requires some assurance on the part of the regulatory body, and the drugs are going to be watched carefully. That is the FDA’s number one concern, and they are raising these issues because they want safety and efficacy to be the number one priority.”

MEREDITH WHITMORE is an English professor and freelance journalist in the Northwest.
References
1. ISR Reports. Biosimilar Education: Who Knows What About Biologic Generics and How Are They Making Decisions? Accessed at www.isrreports.com/wp-content/uploads/2013/09/ ISR-biosimilar-consumer-infographic-printer_friendly.pdf.
2. Generic Pharmaceutical Association. Biosimilars in the EU. Accessed at www.gphaonline.org/ gpha-media/gpha-resources/biosimilars-in-the-eu.
3. ExpressScripts. The $250 Billion Potential of Biosimilars. Accessed at lab.express-scripts.com/ insights/industry-updates/the-$250-billion-potential-of-biosimilars.
4. Novartis Launches First U.S. ‘Biosimilar’ Drug at 15 Percent Discount. Reuters, Sept. 3, 2015.
Accessed at www.reuters.com/article/2015/09/03/us-novartis-drug-idUSKCN0R30C220150903.
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Milliman, April 6, 2012. Accessed at milliman.com/insight/health/Understanding-biosimilars-and-projecting-the-cost-savings-to-employers.
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9. Dandekar V. Intas Cuts Razumab Supplies After Adverse Eye Reactions. The Economic Times, Aug. 21, 2015. Accessed at economictimes.indiatimes.com/2015-08-21/news/ 65706153_1_cold-chain-lucentis-inflammation.
10. Stanton D. Biosimilars Land in the US as Sandoz Launches Zarxio. BioPharma Reporter, Sept. 3, 2015. Accessed at www.biopharma-reporter.com/Markets-Regulations/Biosimilars-land-in-the-US-as-Sandoz-launches-Zarxio.