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‘Educational curve’ required before biosimilars are fully embraced in cancer treatment armamentarium

When the Affordable Care Act established an abbreviated licensure pathway for biosimilars in the United States, development of the agents accelerated at a staggering pace.

A Biotechnology Information Institute report released last year identified more than 650 biosimilars in the pipeline in the U.S. and Europe, 380 of which were under investigation for cancer-related indications. Nearly two dozen biosimilar products had advanced to clinical trials in the United States by mid-2014, and more than 40 others were the subjects of development-phase meetings.

However, only one biosimilar has received FDA approval. That agent, filgrastim-sndz (Zarxio, Sandoz Biopharmaceuticals), primarily will be used to reduce incidence of infection — manifested by febrile neutropenia — in patients with nonmyeloid malignancies who receive myelosuppressive anticancer drugs.

The FDA’s decision in March to approve filgrastim-sndz sparked a contentious debate about the potential role for biosimilars — copies of originator, or “reference,” biologic medical products manufactured by different companies — in the treatment of patients with cancer.

Biosimilars and their reference biologic products both are made from living cells, tissue or blood. Because biosimilars often are considerably cheaper, proponents tout them as a cost-effective alternative that may dramatically expand patients’ access to treatment.

However, unlike generic medications, biosimilars are not precise copies of branded biologics because living organisms cannot be copied exactly. Given the potential that biosimilars may differ from their reference products, questions have emerged about their safety and efficacy profiles. The lack of consensus about what biosimilars should be called — and the potential for confusion between them and their reference products — has contributed to the controversy.

“As traditional biologics rapidly approach the end of their commercial patents, the development of biosimilar products will likely become a more common occurrence,” Luis H. Camacho, MD, MPH, medical director of the Center for Oncology and Blood Disorders in Houston, told HemOnc Today. “As with any other new products in the market, the approved biosimilars will have to gain the trust of their consumers in the community and satisfy the financial needs of large medical practices.”

HemOnc Today spoke with several experts about the implications of the FDA’s decision to approve the first biosimilar for use in the United States, whether safety and supply concerns might make clinicians hesitant to prescribe biosimilars, and the need for specific naming guidelines.

‘Functionally identical’

Unlike chemical drugs, biologics long enjoyed regulatory protection in the United States because they were not included in the Hatch-Waxman Act, a federal law passed in 1984 that established a pathway for low-cost generic versions of small molecule drugs.

That changed in 2010 with the adoption of the Affordable Care Act, which established an approval pathway for biologic products determined to be biosimilar — or interchangeable — with previously approved biologics. Biosimilars contain a version of the active substance in their reference product, and they must demonstrate comparable efficacy and safety to receive FDA approval.

In summer 2014, Sandoz Biopharmaceuticals — a Novartis subsidiary — became the first company to seek approval for a biosimilar in the United States. The company contended filgrastim-sndz was biosimilar to filgrastim (Neupogen, Amgen), a biologic response modifier that was licensed in 1991 and came off patent in 2013.

In January, the FDA’s Oncologic Drugs Advisory Committee (ODAC) unanimously recommended approval of filgrastim-sndz, and the agent received full FDA approval in March. However, a U.S. appeals court in May granted Amgen’s motion for an injunction that temporarily blocked the sale of filgrastim-sndz pending resolution of the company’s legal dispute with Sandoz. The matter had not been resolved by press time.

To receive regulatory approval, biosimilars must be shown to be highly similar to an already-approved biologic product. The biosimilar must demonstrate it has no clinically meaningful differences in terms of safety and effectiveness from the reference product, and only minor differences in clinically inactive components are allowed.

Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology in the department of medicine at Duke University, and colleagues evaluated filgrastim-sndz in the PIONEER study.

The randomized, double blind, multicenter phase 3 study included 218 patients with breast cancer who underwent treatment with myelosuppressive chemotherapy. Researchers divided patients into four groups. One group received reference filgrastim only. A second group received the biosimilar only. Patients in the other two groups received both agents in alternating sequences.

Results — published in 2014 in Blood — showed incidence of febrile neutropenia during six cycles of chemotherapy was low in all cohorts, including among women who received filgrastim-sndz alone (5%) and those who received reference filgrastim alone (0%). Severe adverse events occurred in five women (9.4%) who received the biosimilar alone and two women (3.8%) who received the reference product alone; however, none of these adverse events were considered related to the study drug.

Based in part on these data, the FDA approved filgrastim-sndz for the same indications as its reference product. They include patients with cancer who receive myelosuppressive chemotherapy or undergo bone marrow transplantation; those with acute myeloid leukemia who receive induction or consolidation chemotherapy; patients with severe chronic neutropenia; and those who undergo autologous peripheral blood progenitor cell collection and therapy.

“A biosimilar, by definition, has a molecular biological profile that is functionally identical to the originator compound,” Louis M. Weiner, MD, director of Lombardi Comprehensive Cancer Center at Georgetown University, said in an interview. “The big difference between biosimilars and originator compounds is that when the originator compounds are developed, a disproportionate amount of the cost and time spent in drug development is devoted to the clinical evaluation to demonstrate that there is, in fact, a value related to its use in a particular disease setting. The primary evaluation of the biosimilar compound is to determine whether the biosimilar is structurally similar and functionally similar to the originator compound.”

‘An educational curve’

Although ODAC unanimously supported the approval of filgrastim-sndz, it may take time to build consensus in the clinical community that biosimilar medicines offer a safe, effective alternative to their reference products.

The Alliance for Safe Biologic Medications conducted an Internet-based survey of 376 U.S. oncologists and other prescribers. Results showed 85% of respondents would prefer to have the authority to specify that a biologic should not be substituted for a biosimilar without physician approval.

Luis H. Camacho, MD, MPH

Luis H. Camacho

“This [finding] will indeed be important for policymakers at a state level,” Camacho said. “Nonetheless, I can see these numbers changing as providers become more familiar and comfortable with the new products.”

An unscientific poll conducted in March on Healio.com/HemOnc asked clinicians whether they would feel comfortable prescribing an FDA-approved biosimilar to their patients. More than one-third (35.5%) of respondents indicated they would not.

Their reluctance may be due to the recency of their approval in the United States, despite the fact biosimilars have been marketed in Europe since 2006.

“Unlike generic drugs, biosimilars are more complex, larger and [more] sensitive agents to manufacture, store and handle,” Camacho said. “Moreover, there could be immunogenic factors affecting their biological behavior. Nonetheless, I believe these [survey] numbers reflect an initial reaction to novelty, and time will allow these compounds to find their place in our cancer armamentarium.”

The novelty may be particularly important for oncologists.

Maurie Markman, MD

Maurie Markman

“There are a lot of physicians who are not sure what everything means when it comes to biosimilars,” Maurie Markman, MD, president of medicine and science at Cancer Treatment Centers of America’s Eastern Regional Medical Center and a HemOnc Today Editorial Board member, said in an interview. “Concern has been raised in the oncology community by the companies that produced the branded drugs informing clinicians that these drugs are not the same. This is something more complicated than what we’ve seen.”

Greater understanding of the scientific development of biosimilar medicines compared with brand-name drugs and generics also may lead to a greater acceptance of their efficacy among physicians, Blackwell said.

“There’s going to be an educational curve,” Blackwell told HemOnc Today. “As someone who just recently entered the world of biosimilars, I can say that the biology and the chemistry behind this are really tremendous. Most practicing clinicians may not necessarily understand the rigor that goes into making therapeutic proteins, whether they be antibodies or granulocyte colony–stimulating factor. It’s probably worth taking 5 minutes to understand the policies or the guidance on biosimilars.”

This understanding may play a role in how often biosimilars are prescribed.

“Without firm knowledge of the composition of biosimilars, one would naturally be concerned,” Markman said. “But that doesn’t necessarily mean that one wouldn’t use a biosimilar — just that they want to understand the evidence that is going to be required.”

Scott Soefje, PharmD, MBA, BCOP

Scott Soefje

It is possible that a learning curve will lead to a stronger understanding of both the biology and practical uses of biosimilar medicines, Scott Soefje, PharmD, MBA, BCOP, director of pharmacy at University Medical Center Brackenridge in Austin, Texas, and president of the Hematology/Oncology Pharmacy Association’s board of directors, told HemOnc Today.

“It is important to remember that generics were not immediately accepted by all when they were first introduced,” Soefje said.

The price of treatment

The introduction of biosimilars to the U.S. market has the potential to drive down health care costs through competition.

A Congressional Budget Office analysis estimated the introduction of biosimilars would reduce health care spending by $25 billion over 10 years. This reduction would save the federal government approximately $6 billion.

A report from the RAND Corporation predicted even greater cost savings. In that report, Mulcahy and colleagues estimated the introduction of biosimilar medicines to the U.S. market could lead to a $44.2 billion reduction in spending on biologic drugs between 2014 and 2024, or the equivalent of 4% of the total spending on biologics.

The reduced cost of biosimilars may increase access to treatment, according to Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke University.

The reduced cost of biosimilars may increase access to treatment, according to Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke University. “What my hope would be is that the projected cost savings … will have direct implications and trickle down to benefitting our patients,” Blackwell said.

Source: Photo by Shawn Rocco/Duke Medicine

“Even if the savings were one-tenth of that, a lot of people would be pretty happy,” Blackwell said. “Biosimilars will have a societal benefit, and they will benefit the individual patients who are making tough decisions about cancer drug costs.”

The RAND Corporation estimate was based on several factors, such as the impact of biosimilar availability on European markets and the role the availability of generic medications has played since they were introduced.

“I would really love [for these cost-saving estimates to be] accurate, but we just don’t know yet,” Soefje said. “It’s an estimate based upon our belief that the biosimilars are going to be about 10% to 20% cheaper than the originator products, given the volume of the originator product.”

Generic drugs typically cost anywhere from 3% to 40% of the price of brand-name drugs, but the savings can be as great as 70%, Soefje said. Still, this cost reduction does not occur immediately with the availability of a generic.

“As we see different biosimilars entering the market, we do not know if it is going to stay at that 10% to 20% or go higher,” Soefje said. “However, considering everything, [a $50 billion reduction in biologics spending] is probably a good estimate.”

A major factor in the potential financial benefit is the reduced costs associated with biosimilar development compared with originator drugs. A lower manufacturing cost could lead to lower prices for patients.

Camacho and colleagues conducted a literature review — published in 2014 in Cancer Medicine — that showed the development of a biosimilar may cost an estimated $100 million to $200 million, whereas the development of reference biologics is estimated to cost $800 million.

“Based on that experience, it is expected biosimilars would decrease the cost of therapy with a parental drug by perhaps 25% to 35%,” Camacho said.

Any reduction in cost may improve patient access to treatments.

“By lowering drug costs, it makes it easier to offer the drugs to more people,” Weiner said. “This leads to the possibility of greater and more appropriate utilization. Just by definition, these drugs are likely to cost less than their originators.”

Because high drug costs have been linked to patients skipping or rationing treatment, reduced costs with biosimilars may improve patient adherence and, thus, treatment outcomes.

“What my hope would be is that the projected cost savings, whatever those may look like, will have direct implications and trickle down to benefitting our patients,” Blackwell said. “Every day I face the task of helping my patients make the decision about whether it’s worth making another trip back to the cancer center to avoid a $100 co-pay. The payers who will see the direct cost savings in the biosimilars will hopefully extrapolate those cost savings in a way that will make it cheaper for the patients to receive biosimilars.”

The name dilemma

Because generic drugs have the same active ingredients as their reference products, there is little to no risk of one product producing different adverse events. Pharmacists filling prescriptions often substitute a generic for a brand-name drug — due to their reduced costs and proven efficacy — unless the prescribing physician specifies otherwise.

Biosimilars could potentially be used in a similar manner in cancer treatment.

If so, a lack of direction about what biosimilars should be called — specifically whether they should include the same name as their reference product — could be a source of confusion.

To date, the FDA has not formally issued a recommendation about whether biosimilars will be permitted to share international proprietary names with their originator drugs. However, the FDA in May added biosimilar naming guidance to its 2015 agenda.

The Hematology/Oncology Pharmacy Association has advocated for a specific naming policy for biosimilars.

“Because of the complexity of the preparation of the agents, we need some method to track the efficacy and the toxicity of the biosimilars,” Soefje said. “Our concern is that if we started to see trends toward a decrease in efficacy or increase in toxicity in the age of electronic databases, it would be difficult to tease out whether it was an effect of the biosimilar, the originator drug, or if those products just don’t work anymore if the drugs all had the same generic name. [A naming policy] will give us a solid way to track efficacy, toxicity and even patient cost, and a good way for people to understand the differences between biosimilars, generics and originator drugs.”

European regulators never developed specific guidelines for naming and tracking biosimilars in contrast to generics and brand names.

“This issue is particularly important when developing pharmacovigilance guidelines,” Camacho said. “I see the importance of having a specific nomenclature to better identify a compound as a biosimilar. This is just another issue that will be identified and implemented with time. It has not been the case with EU approvals, but a prefix such as bio-XXXX would be a possibility.”

A survey conducted by Fernandez-Lopez and colleagues — published in March in Journal of Managed Care & Specialty Pharmacy — showed 74.6% of pharmacists would be confident or very confident substituting a biosimilar for its reference product if both shared the same active ingredient or nonproprietary name. Further, 25.3% of pharmacists reported they would confidently substitute even when the nonproprietary name is not shared with the biologic, and 37.3% expressed confidence substituting when the biologic and biosimilar product did not share the same nonproprietary name due to a prefix or suffix.

To provide safe and accurate care, any potential confusion regarding biosimilars vs. originator products based on naming should be diffused, Markman said.

“Naming is becoming very complicated, because there have been lots of drugs and lots of names,” Markman said. “Companies are trying to come up with names that are both distinctive and unique. It becomes very confusing to physicians. As the person who is going to be trying to figure out what I’m giving and I’m saying ‘What does that name mean?’ I would think there should be some kind of established convention.”

The next chapter

A market date for filgrastim-sndz had not been determined by press time due to the injunction granted by the U.S. Court of Appeals for the Federal Circuit. A court hearing had been scheduled for early June.

Sandoz currently markets two other biosimilars outside the United States and has five biosimilars in its R&D pipeline that either are undergoing or are about to undergo evaluation in phase 3 clinical trials. Many other pharmaceutical companies, including Amgen, have developed or are in the process of developing their own biosimilars.

The potential for future development is vast, Blackwell said.

“The next chapter in the story will really be what I consider the more important one: the therapeutic biosimilars, and in particular, antibody therapies whose prices continue to be astronomical,” Blackwell said. “In the therapeutic world, this development will broaden practicing oncologists’ ability to make good choices in the therapeutic modalities they want to employ for the patient by lowering the drug costs.”

Further investigation of biosimilars could potentially lead to treatment expansion across the board. Front-line oncologists could be more likely to present a patient with a treatment plan that would have been otherwise inaccessible due to cost, Blackwell said.

“There are many, many good drugs that are not employed because of cost or coverage,” Blackwell said. “That seems unfortunate. We don’t see that in many other aspects of medicine.”

Despite this excitement, the availability and free flow of biosimilar supply remain to be seen. As the products are untested in the U.S. market — and their potential popularity unknown — it falls to manufacturers to ensure that they are able to meet the market demands that would follow a biosimilar rollout.

“The infrastructure to develop and continuously supply complex biological products are among the most challenging aspects of developing biosimilars,” Camacho said. “Manufacturers embarking on this new field of medicine must ensure appropriate expertise, infrastructure and stable capital.” – by Cameron Kelsall

References:

Aapro M. GaBl Journal. 2013;doi:10.5639/gablj.2013.0202.023.

Blackwell K, et al. Blood. 2014;124:5133.

Camacho LH, et al. Cancer Med. 2014;doi:10.1002/cam4.258.

Congressional Budget Office. Biologics Price and Competition and Innovation Act. Available at: www.cbo.gov/sites/default/files/s1695.pdf. Accessed May 13, 2015.

Fernandez-Lopez S, et al. J Manag Care Spec Pharm. 2015;21:188-195.

Olson K, et al. Alliance for safe biologic medicines prescriber survey. Alliance for Safe Biologic Medicines. Available at: safebiologics.org/resources/wp-content/uploads/2012/09/ASBM-Survey-2.pdf. Accessed May 13, 2015.

Mulcahy AW, et al. RAND Corporation. The cost savings potential of biosimilar drugs in the United States. Available at: www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed May 13, 2015.

Rader RA. BIOPHARMA: Biosimilars/Biobetters Pipeline Database. Available at: www.biosimilarspipeline.com. Accessed May 13, 2015.

For more information:

Kimberly L. Blackwell, MD, can be reached at Duke University Medical Center, 200 Trent Drive, Durham, NC 27710; email: kimberly.blackwell@duke.edu.

Luis H. Camacho, MD, can be reached at Center for Oncology and Blood Disorders, 6560 Fannin St. #1244, Houston, TX 77030; email: lcamacho@stlukeshealth.org.

Maurie Markman, MD, can be reached at Cancer Treatment Centers of America at Eastern Regional Medical Center, 1331 E. Wyoming Ave., Philadelphia, PA 19124; email: maurie.markman@ctca-hope.com.

Scott Soefje, PharmD, MBA, BCOP, can be reached at Department of Pharmacy, University Medical Center Brackenridge, 601 E. 15th St., Austin, TX 78701; email: sasoefje@seton.org.

Louis M. Weiner, MD, can be reached at Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC 20007; email: weinerl@georgetown.edu.

Disclosure: Blackwell reports a consultant role with Sandoz Pharmaceuticals. Camacho reports speakers bureau roles with Amgen, Bristol-Myers Squibb and Merck, as well as an advisory role with Merck. Soefje reports a consultant role with Amgen. Weiner reports a consultant role with Sandoz Pharmaceuticals. Markman reports no relevant financial disclosures.

 

POINTCOUNTER 

Do biosimilar medications present a greater risk for adverse events than their originator products?

POINT

Biosimilars are not exact copies of their originator product. Therefore, physicians need to vigilantly monitor their safety and efficacy.

John Glaspy, MD, MPH

John Glaspy

We were taught in medical school that we should accept generics as being no different than their branded drug. However, that is not the model that we are going to take forward with biosimilars. That places a tremendous responsibility on practitioners to be alert and aware, and to participate in monitoring programs for potential safety issues.

There are two primary concerns to keep in mind as we take Sandoz’s biosimilar version of granulocyte colony–stimulating factor into practice. First, we have been disappointed in the past when we thought that a cloned protein was identical to its innovator molecule and that it was immunogenic. I am referring to the pure red blood cell aplasia experience with recombinant erythropoietin that occurred in Canada and Europe. It was impossible to detect any difference in the two molecules; however, the immune system could. Because pure red blood cell aplasia occurred in only one out of every several thousand patients treated, it was something we could not see until the drug was tested, released and available on the market.

Most of us think the G-CSF biosimilar is less likely to be immunogenic than the erythropoietin, but it is still very important that we participate in post-release safety programs and keep track of which drug is given to each patient in case there is a problem down the line. To track not only which drug a patient receives, but also which preparation of a drug a patient received, is a responsibility that all practitioners and prescribers bear.

The other issue for G-CSF is that, in most of its application in hematology and oncology practice, it is used to prevent infections in patients who are receiving chemotherapy. It does not prevent neutropenia; rather, it has the ability to shorten the duration of neutropenia so the risk for infection is significantly reduced. That means we have to be vigilant about whether we are seeing infections at a rate we would not have otherwise expected when using the new molecule. We know this molecule works, but what if it has some stability issue that only emerges when patients are storing it themselves and may not be as careful as we have been in the clinical trials?

As these new biosimilar medicines begin to roll out, we need to take responsibility for keeping data and reporting any significant issues. This is different than the generic model that many of us have been using since we began to practice, when we were taught that the difference between a generic and an originator was only something with which the drug companies were concerned. One of the reasons we call these drugs biosimilars — as opposed to generics — is that this is a new game, and it will be more complex. Now that these drugs are available in more than one form, we need to make sure they are doing what they should be without causing any problems. That is our responsibility.

John Glaspy, MD, MPH, is professor of medicine in the division of hematology/oncology at UCLA Jonsson Comprehensive Cancer Center. He can be reached at jglaspy@mednet.ucla.edu. Disclosure: Glaspy reports research funding from Amgen and Sandoz Pharmaceuticals, and an advisory role with Amgen.

COUNTER

Toxicity risks for biosimilars likely will be less or comparable to those of any new biological agent.

Edward A. Sausville, MD, PhD

Edward A. Sausville

Biosimilars are analogous to generic drugs in that they are another “version” of an already approved drug. In other respects, biosimilars are quite different.

Biosimilars will be, for the most part, macromolecules (eg, cytokines or antibodies produced from a biological entity, usually in bacteria or cultured mammalian cells). As biosimilars are produced and purified by these organisms, there could be the introduction of important differences in detail from an originator or “reference” biological for whose indication the biosimilar is being targeted. An extensive regulatory framework has evolved defining a rigorous testing path to ensure the comparability of the new product to the reference biological (Bennett CL, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70365-1).

The availability of biosimilars hopefully will reduce costs by stimulating competition among manufacturers and enhancing availability of these agents. There would be an impetus to promote exploration of value of these agents in clinical research in indications in which the reference biological might not have been explored. Another very valuable potential outcome is a lower likelihood of drug shortages caused by the unavailability of a reference biological.

What are the potential “downsides” of biosimilar use? The variations in process in their purifications, and the use of different excipients in the formulation, compared with the reference biological might conceivably alter the immunogenicity or pharmacology of the product. In a well-described case of such an issue, a new erythropoietin formulation led to cases of immune-related pure red cell aplasia. This type of concern might not be relevant to a therapeutic oncology product that has no actual analog produced in the body. Altered glycosylation patterns might result in differing pharmacology or engagement of effector mechanisms. Despite these concerns, evidence of useful and comparable clinical activity has been obtained with biosimilars for trastuzumab (Herceptin, Genentech) and rituximab (Rituxan; Genentech, Biogen Idec).

Conscientious adherence to FDA guidances for biosimilar development and approval will address as much as can be reasonably expected toxicity risks for a biosimilar, which would actually likely be less or comparable to the launch of any new biological agent: not zero, but something that should and could be tracked through pharmacovigilance procedures already available to the oncology community. Also, the reference biological is not subject to potential competition from biosimilars for 12 years of exclusivity for the reference biological. Although this period will considerably assuage concerns that biosimilars will limit incentives to develop new biologicals, this clinical experience will provide a strong basis for judging the behavior of newly introduced biosimilars. It also will be a way of bringing biologicals into comparability with the patent limitations familiar with small molecules: within a generation or sooner of entry to the market, loss of exclusivity for functionally (biosimilar) as well as molecularly (small molecules) identical agents will be possible.

Clinical oncologists should embrace the opportunities provided by a vigorous biosimilars development community and fold the products as available into routine clinical and research applications.

Edward A. Sausville, MD, PhD, is professor of medicine and adjunct professor of pharmacology at University of Maryland School of Medicine, as well as deputy director and associate director for clinical research at University of Maryland Marlene and Stewart Greenebaum Cancer Center. He can be reached at esausville@umm.edu. Disclosure: Sausville reports no relevant financial disclosures.

When the Affordable Care Act established an abbreviated licensure pathway for biosimilars in the United States, development of the agents accelerated at a staggering pace.

A Biotechnology Information Institute report released last year identified more than 650 biosimilars in the pipeline in the U.S. and Europe, 380 of which were under investigation for cancer-related indications. Nearly two dozen biosimilar products had advanced to clinical trials in the United States by mid-2014, and more than 40 others were the subjects of development-phase meetings.

However, only one biosimilar has received FDA approval. That agent, filgrastim-sndz (Zarxio, Sandoz Biopharmaceuticals), primarily will be used to reduce incidence of infection — manifested by febrile neutropenia — in patients with nonmyeloid malignancies who receive myelosuppressive anticancer drugs.

The FDA’s decision in March to approve filgrastim-sndz sparked a contentious debate about the potential role for biosimilars — copies of originator, or “reference,” biologic medical products manufactured by different companies — in the treatment of patients with cancer.

Biosimilars and their reference biologic products both are made from living cells, tissue or blood. Because biosimilars often are considerably cheaper, proponents tout them as a cost-effective alternative that may dramatically expand patients’ access to treatment.

However, unlike generic medications, biosimilars are not precise copies of branded biologics because living organisms cannot be copied exactly. Given the potential that biosimilars may differ from their reference products, questions have emerged about their safety and efficacy profiles. The lack of consensus about what biosimilars should be called — and the potential for confusion between them and their reference products — has contributed to the controversy.

“As traditional biologics rapidly approach the end of their commercial patents, the development of biosimilar products will likely become a more common occurrence,” Luis H. Camacho, MD, MPH, medical director of the Center for Oncology and Blood Disorders in Houston, told HemOnc Today. “As with any other new products in the market, the approved biosimilars will have to gain the trust of their consumers in the community and satisfy the financial needs of large medical practices.”

HemOnc Today spoke with several experts about the implications of the FDA’s decision to approve the first biosimilar for use in the United States, whether safety and supply concerns might make clinicians hesitant to prescribe biosimilars, and the need for specific naming guidelines.

‘Functionally identical’

Unlike chemical drugs, biologics long enjoyed regulatory protection in the United States because they were not included in the Hatch-Waxman Act, a federal law passed in 1984 that established a pathway for low-cost generic versions of small molecule drugs.

That changed in 2010 with the adoption of the Affordable Care Act, which established an approval pathway for biologic products determined to be biosimilar — or interchangeable — with previously approved biologics. Biosimilars contain a version of the active substance in their reference product, and they must demonstrate comparable efficacy and safety to receive FDA approval.

In summer 2014, Sandoz Biopharmaceuticals — a Novartis subsidiary — became the first company to seek approval for a biosimilar in the United States. The company contended filgrastim-sndz was biosimilar to filgrastim (Neupogen, Amgen), a biologic response modifier that was licensed in 1991 and came off patent in 2013.

In January, the FDA’s Oncologic Drugs Advisory Committee (ODAC) unanimously recommended approval of filgrastim-sndz, and the agent received full FDA approval in March. However, a U.S. appeals court in May granted Amgen’s motion for an injunction that temporarily blocked the sale of filgrastim-sndz pending resolution of the company’s legal dispute with Sandoz. The matter had not been resolved by press time.

To receive regulatory approval, biosimilars must be shown to be highly similar to an already-approved biologic product. The biosimilar must demonstrate it has no clinically meaningful differences in terms of safety and effectiveness from the reference product, and only minor differences in clinically inactive components are allowed.

PAGE BREAK

Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology in the department of medicine at Duke University, and colleagues evaluated filgrastim-sndz in the PIONEER study.

The randomized, double blind, multicenter phase 3 study included 218 patients with breast cancer who underwent treatment with myelosuppressive chemotherapy. Researchers divided patients into four groups. One group received reference filgrastim only. A second group received the biosimilar only. Patients in the other two groups received both agents in alternating sequences.

Results — published in 2014 in Blood — showed incidence of febrile neutropenia during six cycles of chemotherapy was low in all cohorts, including among women who received filgrastim-sndz alone (5%) and those who received reference filgrastim alone (0%). Severe adverse events occurred in five women (9.4%) who received the biosimilar alone and two women (3.8%) who received the reference product alone; however, none of these adverse events were considered related to the study drug.

Based in part on these data, the FDA approved filgrastim-sndz for the same indications as its reference product. They include patients with cancer who receive myelosuppressive chemotherapy or undergo bone marrow transplantation; those with acute myeloid leukemia who receive induction or consolidation chemotherapy; patients with severe chronic neutropenia; and those who undergo autologous peripheral blood progenitor cell collection and therapy.

“A biosimilar, by definition, has a molecular biological profile that is functionally identical to the originator compound,” Louis M. Weiner, MD, director of Lombardi Comprehensive Cancer Center at Georgetown University, said in an interview. “The big difference between biosimilars and originator compounds is that when the originator compounds are developed, a disproportionate amount of the cost and time spent in drug development is devoted to the clinical evaluation to demonstrate that there is, in fact, a value related to its use in a particular disease setting. The primary evaluation of the biosimilar compound is to determine whether the biosimilar is structurally similar and functionally similar to the originator compound.”

‘An educational curve’

Although ODAC unanimously supported the approval of filgrastim-sndz, it may take time to build consensus in the clinical community that biosimilar medicines offer a safe, effective alternative to their reference products.

The Alliance for Safe Biologic Medications conducted an Internet-based survey of 376 U.S. oncologists and other prescribers. Results showed 85% of respondents would prefer to have the authority to specify that a biologic should not be substituted for a biosimilar without physician approval.

Luis H. Camacho, MD, MPH

Luis H. Camacho

“This [finding] will indeed be important for policymakers at a state level,” Camacho said. “Nonetheless, I can see these numbers changing as providers become more familiar and comfortable with the new products.”

An unscientific poll conducted in March on Healio.com/HemOnc asked clinicians whether they would feel comfortable prescribing an FDA-approved biosimilar to their patients. More than one-third (35.5%) of respondents indicated they would not.

Their reluctance may be due to the recency of their approval in the United States, despite the fact biosimilars have been marketed in Europe since 2006.

“Unlike generic drugs, biosimilars are more complex, larger and [more] sensitive agents to manufacture, store and handle,” Camacho said. “Moreover, there could be immunogenic factors affecting their biological behavior. Nonetheless, I believe these [survey] numbers reflect an initial reaction to novelty, and time will allow these compounds to find their place in our cancer armamentarium.”

The novelty may be particularly important for oncologists.

Maurie Markman, MD

Maurie Markman

“There are a lot of physicians who are not sure what everything means when it comes to biosimilars,” Maurie Markman, MD, president of medicine and science at Cancer Treatment Centers of America’s Eastern Regional Medical Center and a HemOnc Today Editorial Board member, said in an interview. “Concern has been raised in the oncology community by the companies that produced the branded drugs informing clinicians that these drugs are not the same. This is something more complicated than what we’ve seen.”

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Greater understanding of the scientific development of biosimilar medicines compared with brand-name drugs and generics also may lead to a greater acceptance of their efficacy among physicians, Blackwell said.

“There’s going to be an educational curve,” Blackwell told HemOnc Today. “As someone who just recently entered the world of biosimilars, I can say that the biology and the chemistry behind this are really tremendous. Most practicing clinicians may not necessarily understand the rigor that goes into making therapeutic proteins, whether they be antibodies or granulocyte colony–stimulating factor. It’s probably worth taking 5 minutes to understand the policies or the guidance on biosimilars.”

This understanding may play a role in how often biosimilars are prescribed.

“Without firm knowledge of the composition of biosimilars, one would naturally be concerned,” Markman said. “But that doesn’t necessarily mean that one wouldn’t use a biosimilar — just that they want to understand the evidence that is going to be required.”

Scott Soefje, PharmD, MBA, BCOP

Scott Soefje

It is possible that a learning curve will lead to a stronger understanding of both the biology and practical uses of biosimilar medicines, Scott Soefje, PharmD, MBA, BCOP, director of pharmacy at University Medical Center Brackenridge in Austin, Texas, and president of the Hematology/Oncology Pharmacy Association’s board of directors, told HemOnc Today.

“It is important to remember that generics were not immediately accepted by all when they were first introduced,” Soefje said.

The price of treatment

The introduction of biosimilars to the U.S. market has the potential to drive down health care costs through competition.

A Congressional Budget Office analysis estimated the introduction of biosimilars would reduce health care spending by $25 billion over 10 years. This reduction would save the federal government approximately $6 billion.

A report from the RAND Corporation predicted even greater cost savings. In that report, Mulcahy and colleagues estimated the introduction of biosimilar medicines to the U.S. market could lead to a $44.2 billion reduction in spending on biologic drugs between 2014 and 2024, or the equivalent of 4% of the total spending on biologics.

The reduced cost of biosimilars may increase access to treatment, according to Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke University.

The reduced cost of biosimilars may increase access to treatment, according to Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke University. “What my hope would be is that the projected cost savings … will have direct implications and trickle down to benefitting our patients,” Blackwell said.

Source: Photo by Shawn Rocco/Duke Medicine

“Even if the savings were one-tenth of that, a lot of people would be pretty happy,” Blackwell said. “Biosimilars will have a societal benefit, and they will benefit the individual patients who are making tough decisions about cancer drug costs.”

The RAND Corporation estimate was based on several factors, such as the impact of biosimilar availability on European markets and the role the availability of generic medications has played since they were introduced.

“I would really love [for these cost-saving estimates to be] accurate, but we just don’t know yet,” Soefje said. “It’s an estimate based upon our belief that the biosimilars are going to be about 10% to 20% cheaper than the originator products, given the volume of the originator product.”

Generic drugs typically cost anywhere from 3% to 40% of the price of brand-name drugs, but the savings can be as great as 70%, Soefje said. Still, this cost reduction does not occur immediately with the availability of a generic.

“As we see different biosimilars entering the market, we do not know if it is going to stay at that 10% to 20% or go higher,” Soefje said. “However, considering everything, [a $50 billion reduction in biologics spending] is probably a good estimate.”

A major factor in the potential financial benefit is the reduced costs associated with biosimilar development compared with originator drugs. A lower manufacturing cost could lead to lower prices for patients.

Camacho and colleagues conducted a literature review — published in 2014 in Cancer Medicine — that showed the development of a biosimilar may cost an estimated $100 million to $200 million, whereas the development of reference biologics is estimated to cost $800 million.

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“Based on that experience, it is expected biosimilars would decrease the cost of therapy with a parental drug by perhaps 25% to 35%,” Camacho said.

Any reduction in cost may improve patient access to treatments.

“By lowering drug costs, it makes it easier to offer the drugs to more people,” Weiner said. “This leads to the possibility of greater and more appropriate utilization. Just by definition, these drugs are likely to cost less than their originators.”

Because high drug costs have been linked to patients skipping or rationing treatment, reduced costs with biosimilars may improve patient adherence and, thus, treatment outcomes.

“What my hope would be is that the projected cost savings, whatever those may look like, will have direct implications and trickle down to benefitting our patients,” Blackwell said. “Every day I face the task of helping my patients make the decision about whether it’s worth making another trip back to the cancer center to avoid a $100 co-pay. The payers who will see the direct cost savings in the biosimilars will hopefully extrapolate those cost savings in a way that will make it cheaper for the patients to receive biosimilars.”

The name dilemma

Because generic drugs have the same active ingredients as their reference products, there is little to no risk of one product producing different adverse events. Pharmacists filling prescriptions often substitute a generic for a brand-name drug — due to their reduced costs and proven efficacy — unless the prescribing physician specifies otherwise.

Biosimilars could potentially be used in a similar manner in cancer treatment.

If so, a lack of direction about what biosimilars should be called — specifically whether they should include the same name as their reference product — could be a source of confusion.

To date, the FDA has not formally issued a recommendation about whether biosimilars will be permitted to share international proprietary names with their originator drugs. However, the FDA in May added biosimilar naming guidance to its 2015 agenda.

The Hematology/Oncology Pharmacy Association has advocated for a specific naming policy for biosimilars.

“Because of the complexity of the preparation of the agents, we need some method to track the efficacy and the toxicity of the biosimilars,” Soefje said. “Our concern is that if we started to see trends toward a decrease in efficacy or increase in toxicity in the age of electronic databases, it would be difficult to tease out whether it was an effect of the biosimilar, the originator drug, or if those products just don’t work anymore if the drugs all had the same generic name. [A naming policy] will give us a solid way to track efficacy, toxicity and even patient cost, and a good way for people to understand the differences between biosimilars, generics and originator drugs.”

European regulators never developed specific guidelines for naming and tracking biosimilars in contrast to generics and brand names.

“This issue is particularly important when developing pharmacovigilance guidelines,” Camacho said. “I see the importance of having a specific nomenclature to better identify a compound as a biosimilar. This is just another issue that will be identified and implemented with time. It has not been the case with EU approvals, but a prefix such as bio-XXXX would be a possibility.”

A survey conducted by Fernandez-Lopez and colleagues — published in March in Journal of Managed Care & Specialty Pharmacy — showed 74.6% of pharmacists would be confident or very confident substituting a biosimilar for its reference product if both shared the same active ingredient or nonproprietary name. Further, 25.3% of pharmacists reported they would confidently substitute even when the nonproprietary name is not shared with the biologic, and 37.3% expressed confidence substituting when the biologic and biosimilar product did not share the same nonproprietary name due to a prefix or suffix.

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To provide safe and accurate care, any potential confusion regarding biosimilars vs. originator products based on naming should be diffused, Markman said.

“Naming is becoming very complicated, because there have been lots of drugs and lots of names,” Markman said. “Companies are trying to come up with names that are both distinctive and unique. It becomes very confusing to physicians. As the person who is going to be trying to figure out what I’m giving and I’m saying ‘What does that name mean?’ I would think there should be some kind of established convention.”

The next chapter

A market date for filgrastim-sndz had not been determined by press time due to the injunction granted by the U.S. Court of Appeals for the Federal Circuit. A court hearing had been scheduled for early June.

Sandoz currently markets two other biosimilars outside the United States and has five biosimilars in its R&D pipeline that either are undergoing or are about to undergo evaluation in phase 3 clinical trials. Many other pharmaceutical companies, including Amgen, have developed or are in the process of developing their own biosimilars.

The potential for future development is vast, Blackwell said.

“The next chapter in the story will really be what I consider the more important one: the therapeutic biosimilars, and in particular, antibody therapies whose prices continue to be astronomical,” Blackwell said. “In the therapeutic world, this development will broaden practicing oncologists’ ability to make good choices in the therapeutic modalities they want to employ for the patient by lowering the drug costs.”

Further investigation of biosimilars could potentially lead to treatment expansion across the board. Front-line oncologists could be more likely to present a patient with a treatment plan that would have been otherwise inaccessible due to cost, Blackwell said.

“There are many, many good drugs that are not employed because of cost or coverage,” Blackwell said. “That seems unfortunate. We don’t see that in many other aspects of medicine.”

Despite this excitement, the availability and free flow of biosimilar supply remain to be seen. As the products are untested in the U.S. market — and their potential popularity unknown — it falls to manufacturers to ensure that they are able to meet the market demands that would follow a biosimilar rollout.

“The infrastructure to develop and continuously supply complex biological products are among the most challenging aspects of developing biosimilars,” Camacho said. “Manufacturers embarking on this new field of medicine must ensure appropriate expertise, infrastructure and stable capital.” – by Cameron Kelsall

References:

Aapro M. GaBl Journal. 2013;doi:10.5639/gablj.2013.0202.023.

Blackwell K, et al. Blood. 2014;124:5133.

Camacho LH, et al. Cancer Med. 2014;doi:10.1002/cam4.258.

Congressional Budget Office. Biologics Price and Competition and Innovation Act. Available at: www.cbo.gov/sites/default/files/s1695.pdf. Accessed May 13, 2015.

Fernandez-Lopez S, et al. J Manag Care Spec Pharm. 2015;21:188-195.

Olson K, et al. Alliance for safe biologic medicines prescriber survey. Alliance for Safe Biologic Medicines. Available at: safebiologics.org/resources/wp-content/uploads/2012/09/ASBM-Survey-2.pdf. Accessed May 13, 2015.

Mulcahy AW, et al. RAND Corporation. The cost savings potential of biosimilar drugs in the United States. Available at: www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed May 13, 2015.

Rader RA. BIOPHARMA: Biosimilars/Biobetters Pipeline Database. Available at: www.biosimilarspipeline.com. Accessed May 13, 2015.

For more information:

Kimberly L. Blackwell, MD, can be reached at Duke University Medical Center, 200 Trent Drive, Durham, NC 27710; email: kimberly.blackwell@duke.edu.

Luis H. Camacho, MD, can be reached at Center for Oncology and Blood Disorders, 6560 Fannin St. #1244, Houston, TX 77030; email: lcamacho@stlukeshealth.org.

Maurie Markman, MD, can be reached at Cancer Treatment Centers of America at Eastern Regional Medical Center, 1331 E. Wyoming Ave., Philadelphia, PA 19124; email: maurie.markman@ctca-hope.com.

Scott Soefje, PharmD, MBA, BCOP, can be reached at Department of Pharmacy, University Medical Center Brackenridge, 601 E. 15th St., Austin, TX 78701; email: sasoefje@seton.org.

Louis M. Weiner, MD, can be reached at Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC 20007; email: weinerl@georgetown.edu.

Disclosure: Blackwell reports a consultant role with Sandoz Pharmaceuticals. Camacho reports speakers bureau roles with Amgen, Bristol-Myers Squibb and Merck, as well as an advisory role with Merck. Soefje reports a consultant role with Amgen. Weiner reports a consultant role with Sandoz Pharmaceuticals. Markman reports no relevant financial disclosures.

 

POINTCOUNTER 

Do biosimilar medications present a greater risk for adverse events than their originator products?

POINT

Biosimilars are not exact copies of their originator product. Therefore, physicians need to vigilantly monitor their safety and efficacy.

John Glaspy, MD, MPH

John Glaspy

We were taught in medical school that we should accept generics as being no different than their branded drug. However, that is not the model that we are going to take forward with biosimilars. That places a tremendous responsibility on practitioners to be alert and aware, and to participate in monitoring programs for potential safety issues.

There are two primary concerns to keep in mind as we take Sandoz’s biosimilar version of granulocyte colony–stimulating factor into practice. First, we have been disappointed in the past when we thought that a cloned protein was identical to its innovator molecule and that it was immunogenic. I am referring to the pure red blood cell aplasia experience with recombinant erythropoietin that occurred in Canada and Europe. It was impossible to detect any difference in the two molecules; however, the immune system could. Because pure red blood cell aplasia occurred in only one out of every several thousand patients treated, it was something we could not see until the drug was tested, released and available on the market.

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Most of us think the G-CSF biosimilar is less likely to be immunogenic than the erythropoietin, but it is still very important that we participate in post-release safety programs and keep track of which drug is given to each patient in case there is a problem down the line. To track not only which drug a patient receives, but also which preparation of a drug a patient received, is a responsibility that all practitioners and prescribers bear.

The other issue for G-CSF is that, in most of its application in hematology and oncology practice, it is used to prevent infections in patients who are receiving chemotherapy. It does not prevent neutropenia; rather, it has the ability to shorten the duration of neutropenia so the risk for infection is significantly reduced. That means we have to be vigilant about whether we are seeing infections at a rate we would not have otherwise expected when using the new molecule. We know this molecule works, but what if it has some stability issue that only emerges when patients are storing it themselves and may not be as careful as we have been in the clinical trials?

As these new biosimilar medicines begin to roll out, we need to take responsibility for keeping data and reporting any significant issues. This is different than the generic model that many of us have been using since we began to practice, when we were taught that the difference between a generic and an originator was only something with which the drug companies were concerned. One of the reasons we call these drugs biosimilars — as opposed to generics — is that this is a new game, and it will be more complex. Now that these drugs are available in more than one form, we need to make sure they are doing what they should be without causing any problems. That is our responsibility.

John Glaspy, MD, MPH, is professor of medicine in the division of hematology/oncology at UCLA Jonsson Comprehensive Cancer Center. He can be reached at jglaspy@mednet.ucla.edu. Disclosure: Glaspy reports research funding from Amgen and Sandoz Pharmaceuticals, and an advisory role with Amgen.

COUNTER

Toxicity risks for biosimilars likely will be less or comparable to those of any new biological agent.

Edward A. Sausville, MD, PhD

Edward A. Sausville

Biosimilars are analogous to generic drugs in that they are another “version” of an already approved drug. In other respects, biosimilars are quite different.

Biosimilars will be, for the most part, macromolecules (eg, cytokines or antibodies produced from a biological entity, usually in bacteria or cultured mammalian cells). As biosimilars are produced and purified by these organisms, there could be the introduction of important differences in detail from an originator or “reference” biological for whose indication the biosimilar is being targeted. An extensive regulatory framework has evolved defining a rigorous testing path to ensure the comparability of the new product to the reference biological (Bennett CL, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70365-1).

The availability of biosimilars hopefully will reduce costs by stimulating competition among manufacturers and enhancing availability of these agents. There would be an impetus to promote exploration of value of these agents in clinical research in indications in which the reference biological might not have been explored. Another very valuable potential outcome is a lower likelihood of drug shortages caused by the unavailability of a reference biological.

What are the potential “downsides” of biosimilar use? The variations in process in their purifications, and the use of different excipients in the formulation, compared with the reference biological might conceivably alter the immunogenicity or pharmacology of the product. In a well-described case of such an issue, a new erythropoietin formulation led to cases of immune-related pure red cell aplasia. This type of concern might not be relevant to a therapeutic oncology product that has no actual analog produced in the body. Altered glycosylation patterns might result in differing pharmacology or engagement of effector mechanisms. Despite these concerns, evidence of useful and comparable clinical activity has been obtained with biosimilars for trastuzumab (Herceptin, Genentech) and rituximab (Rituxan; Genentech, Biogen Idec).

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Conscientious adherence to FDA guidances for biosimilar development and approval will address as much as can be reasonably expected toxicity risks for a biosimilar, which would actually likely be less or comparable to the launch of any new biological agent: not zero, but something that should and could be tracked through pharmacovigilance procedures already available to the oncology community. Also, the reference biological is not subject to potential competition from biosimilars for 12 years of exclusivity for the reference biological. Although this period will considerably assuage concerns that biosimilars will limit incentives to develop new biologicals, this clinical experience will provide a strong basis for judging the behavior of newly introduced biosimilars. It also will be a way of bringing biologicals into comparability with the patent limitations familiar with small molecules: within a generation or sooner of entry to the market, loss of exclusivity for functionally (biosimilar) as well as molecularly (small molecules) identical agents will be possible.

Clinical oncologists should embrace the opportunities provided by a vigorous biosimilars development community and fold the products as available into routine clinical and research applications.

Edward A. Sausville, MD, PhD, is professor of medicine and adjunct professor of pharmacology at University of Maryland School of Medicine, as well as deputy director and associate director for clinical research at University of Maryland Marlene and Stewart Greenebaum Cancer Center. He can be reached at esausville@umm.edu. Disclosure: Sausville reports no relevant financial disclosures.