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Perspectives in Febrile Neutropenia: Q&A With Gary Lyman, MD, MPH

There are many solutions to this, but they are all difficult. One, of course, would be to improve insurance coverage. The Affordable Care Act attempted to do that by trying to help uninsured patients become insured. Another strategy lies in the G-CSF agents. These myeloid growth factors are biologic substances, not small chemicals like antibiotics or pain medications. They are synthesized in living cells and then purified and packaged and delivered. But, because they are made in living organisms, unlike small-molecule drugs, you cannot replicate them identically. To develop competitors as the patents expire on these biologic agents, one can’t replicate the drug exactly. However, once the patent expires there’s the capacity to develop very similar systems and synthesize biologic agents that are highly similar to the original drug, and that is called a biosimilar. Therefore, the biosimilar is not an exact copy of the originator, but it has to meet certain FDA criteria both in terms of its molecular makeup and structure, as well as how it behaves in animal and in human studies. 

The patents for these new biologic agents have begun to expire, so they are open to competition from biosimilar companies. In fact, there are biosimilars available in the United States that are G-CSF molecules. The first one that was an official biosimilar is filgrastim-sndz, but there’s a whole line-up of companies that have applied to be approved by the FDA [with] biosimilar G-CSF forms. Therefore, we are very likely over the next year to have multiple potential agents. There’s another drug that has approval as a biosimilar in Europe but received approval in the United States through the traditional pathway, tbo-filgrastim, and that’s available now. Therefore, there are 3 forms of filgrastim available in the United States: the originator, which is Neupogen, and then 2 that are essentially biosimilars. The interesting thing about biosimilars, based on the FDA approval process, is that they don’t need as much clinical trial data as the originator drug. The first biologic for a condition has to provide not only the preclinical data, but also the extensive clinical data demonstrating efficacy and safety. If we required the same amount of preclinical and clinical data of the next generation, the biosimilars, the development cost would be prohibitive, and we would not have companies pursuing that, or if they did, the pricing would be no less than what the originator required. The rules that have been promulgated and are now in place require much less clinical data, with the presumption that if the molecule has the same components and the same structure and behaves the same in preclinical studies, some limited clinical data should be sufficient to justify approval as being highly similar to the originator. 

The other thing that makes clinicians uncomfortable is that the approval of that biosimilar based on the clinical data provided will be extended or extrapolated to all indications that the original drug has been approved for based on larger amounts of clinical data. So, this extrapolation beyond what the studies have previously justified makes some providers nervous; however, the experience in Europe is far ahead of the experience here in the United States. In Europe, where biosimilars have been approved for well over 5 years, no major safety concerns have emerged through this process of extrapolated approval. The hope is that with increased competition, prices will be driven down. 

There are a couple of challenges, 1 of which is that these agents are still expensive to produce. They’re biologics produced with a living organism. It’s very sophisticated technology. There’s that bottom-line cost that you can’t go below in developing these drugs, and even with not requiring so much clinical trial data to get approval, the experience has been that you don’t experience the huge price reduction that you see with generic drugs, which drops upwards of 80% of the cost of the brand name chemical agents. In the biologic area, because of the complexity and the high development cost of a biosimilar, it’s expected that, and the European experience would suggest, we might see about a 20% drop in price, with no more than a 30% drop. Any reduction is good if we want to improve access, and the rising healthcare cost could go down because of competition; however, it will not be as dramatic as with generics. 

There’s 1 remaining issue around biosimilars, which is the proposed FDA criteria for approval as an interchangeable biosimilar, which providers and professional organizations as well as [individual US] states are trying to tackle. ASCO is representing the oncologist and the patient, and wants to make sure that everyone is educated about what is good and what is to be concerned about with the introduction of biosimilars in the oncology setting. Right now, there are some provisions in the draft guidance around the interchangeability of a biosimilar drug. If a drug is to be given the designation of interchangeable, you can switch from the brand name, or the originator, to the biosimilar, back and forth without any concern about safety and efficacy. It’s a higher bar than just giving a designation as a biosimilar because you have to demonstrate through studies that you can go back and forth without any safety signals emerging or a loss of efficacy. This issue is discussed at length in a recent special issue of the ASCO Journal of Oncology Practice on biosimilars from September.

The regulations around interchangeability are out for public comment, and they have not been finalized yet. I think that among the concerns the clinicians have is a provision that the patient’s treatment could be switched from the brand name agent that we’ve had for decades and that various oncologists are very comfortable with, to the biosimilar, without the physician or patient being aware of the change. In other words, the pharmacy could switch a drug to the lowest- costing agent, and this has been a concern for many people. In fact, we now have 35 US states that are attempting to preempt these rules through legislation that the prescribing physician needs to be notified if such a switch is going to occur. So, although the FDA approval and CMS may try to impose the switching without notification, these states have decided they want to make sure that patients and physicians know if a drug has been switched to a biosimilar. I think that’s reasonable, and until we have more experience with these agents with longer-term follow-up, we want to make sure that there are not any rare or delayed [adverse] effects that didn’t show up in the limited data provided. This is a work in progress, and the FDA hasn’t issued the final ruling, but ASCO and others want to make sure that they’re at the table during the discussions to ensure that these are best implemented in the coming years. 

The next level of concern relates to biosimilars that are specifically cancer treatments and not supportive care, such as G-CSF, which helps enable patients to tolerate chemotherapy. The Oncology Drug Advisory Committee [ODAC] has recommended approval for trastuzumab, which is a biosimilar form of Herceptin, prescribed to women with breast cancer. The ODAC has also recommended and the FDA has recently approved bevacizumab, the biosimilar version of Avastin, which is used to treat several types of cancer. Therefore, we have, for the first time in the United States, a biosimilar approved for cancer treatment. That’s why it’s important to educate physicians and patients on how this will be done, what this means, what are the safety and efficacy issues, and how these will get integrated into guidelines. 

Certainly, for G-CSF we have reviewed all the data with the ASCO guidelines and NCCN guidelines, and have recommended that the approved biosimilars can be used equally with the original G-CSF based on the data provided. However, the concern rises to another level when talking about cancer treatments and biosimilars for those treatments, and not just supportive-care drugs. A lot is happening and a lot will change in the coming months and years in the world of biologic agents. Clinicians and patients need to know as much as possible about what’s coming. 

AJMC®: What are some ways that insurers can partner with cancer institutions to enable more effective or more appropriate evidence-based treatments that adhere to guidelines for FN, and what would be the most important take-away for managed care?

Lyman: I’m a strong proponent of clinical practice guidelines, and I believe that insurers and managed care organizations should do what they can to improve adherence to guidelines. Having said that, as I mentioned earlier, there are some gray areas in the guidelines, where a decision on, for instance, G-CSF use is left to the discretion of the clinician, who knows the patient the best. I think it will be important to have the flexibility to allow the clinician to make a judgment call about whether a specific patient is high risk or not and to use growth factor support accordingly. However, our studies have demonstrated both underuse and overuse of these agents in actual practice. I think adherence to guidelines is important, and anything we can do to improve that adherence will be important not only to the quality of patient care, but also in terms of cost and making sure the value of care is optimal. When it comes to biosimilars, we hope there will be a lower price tag, and with competition, this may bring down the price of the brand name product, although, again, it will probably be more modest than what we see with generic chemical molecules. Nonetheless, I think the introduction to biosimilars is reasonable, and based on the FDA criteria for approval, it’s reasonable to include those as options for physicians to use in supporting patients receiving cancer chemotherapy. 

The next generation of G-CSF biosimilars that will be forthcoming will be for long-acting G-CSFs, so that the patient doesn’t have to receive injections every day, but instead once per treatment cycle every couple of weeks. What’s currently on the market is pegfilgrastim or Neulasta administered as an injection or using an on-body injector as a single injection each treatment cycle. Although this is currently the only option for the long-acting form, there are a couple of companies that have developed the long-acting competitor biosimilars going through the FDA process, but they probably won’t be approved until next year. However, eventually there will be competitors for the long-acting product that patients prefer over the daily injections administered for 7 to 14 days. I think that for insurers and for managed care, cost is an issue, but patient adherence and satisfaction, and the full patient experience, have to be very strongly considered. There will still be pressure for patients to get these long-acting products. Of course, when the competitors come along, there will be more options available there and hopefully costs will come down.

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