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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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Supported by an independent medical education grant from Sandoz Inc., a Novartis Division.
Community Practice Connections™: Evaluating the Emerging Role of Biosimilar Agents for the Treatment of Hematologic Malignancies
Release Date: March 8, 2018
Expiration Date: March 8, 2019
Media: Internet - based
Many biologic therapies serve as key components of standard-of-care management approaches for patients with hematologic malignancies, including active treatment and supportive care. However, many such biologic options are quite costly, potentially limiting the access of treatments which may improve outcomes for patients. Biosimilars are biologics that are highly similar to the reference biologic products, and they may offer the potential to bridge the treatment gap. Many health care providers lack familiarity with the complex regulatory approval process pathway for biosimilars, as well as safety and efficacy data for biosimilars that are emerging or have already been approved. This activity will provide clinicians with updates on the latest clinical advancements in biosimilar treatments for hematologic malignancies.
This activity features video interviews with leading clinical experts who will review and discuss aspects of biosimilars important to cancer care providers, including basic scientific principles of biosimilars and their production, FDA regulatory pathways and requirements, the intricacies of clinical study design and data interpretation, biosimilar agents in different stages of development for the management of patients with hematologic malignancies, and practical issues related to potential clinical integration.
Acknowledgement of Commercial Support
This activity is supported by an independent medical education grant from Sandoz, Inc., a Novartis Division.
CME Activity Table of Contents
Section I: Summary of Biosimilar Development: Differences Between Biosimilars and Generics
Video commentary by Edward Li, PharmD, MPH, BCOP
Section II: Determining the Efficacy and Safety of Biosimilars
Video commentary by Edward Li, PharmD, MPH, BCOP, and Bertrand Coiffier, MD, PhD
Section III: Health Agencies and Biosimilars: Regulatory Approval Process
Video commentary by Edward Li, PharmD, MPH, BCOP, and Bertrand Coiffier, MD, PhD
Section IV: Integrating Biosimilars Into the Treatment of Hematologic Malignancies
Video commentary by Pamela S. Becker, MD, PhD, and Andrew Zelenetz, MD, PhD
Section V: Biosimilars in Clinical Practice: Patient Education and Safety Monitoring
Video commentary by Pamela S. Becker, MD, PhD, and Andrew Zelenetz, MD, PhD
Instructions for This Activity and Receiving Credit
This educational activity is intended for hematologists, medical oncologists, and other health care professionals interested in the latest advances in the treatment of patients with hematologic malignancies. Fellows, researchers, nurses, nurse practitioners, physician assistants, and other health care professionals interested in the treatment of patients with hematologic malignancies are also invited to participate.
At the conclusion of this activity, you should be better prepared to:
- Describe the developmental process of biosimilar agents, including manufacturing complexities
- Explain the regulatory process associated with the approval of biosimilar agents by the FDA, along with the required efficacy and safety data to support a claim that a biosimilar is as safe and effective as the reference product
- Summarize current and emerging efficacy and safety data for biosimilar agents for the treatment of hematologic malignancies
- Effectively counsel and communicate the impact that biosimilar agents may have on a patient’s treatment plan, while being able to integrate biosimilars into clinical practice
Faculty, Staff, and Planners' Disclosures
Edward Li, PharmD, MPH, BCOP
Professor, Department of Pharmacy Practice
University of New England College of Pharmacy
Disclosure:Pfizer, Eli Lilly, Heron Therapeutics, Mylan; Speakers Bureau: Pfizer
Pamela S. Becker, MD, PhD
Professor of Medicine, Division of Hematology
University of Washington School of Medicine
Disclosure:Grant/Research Support: AbbVie, Amgen, Bristol-Myers Squibb, GlycoMimetics, JW Pharmaceutical; Consultant: Member of a Scientific Steering Committee, Pfizer; Medical Advisor, Caremark/Accordant
Bertrand Coiffier, MD, PhD
Professor of Hematology, Department of Hematology
Hospices Civils de Lyon
Université Claude Bernard
Disclosure: Grant/Research Support: Roche, Celgene; Consultant: Celltrion, Pfizer, Apobiologix, Novartis
Andrew D. Zelenetz, MD, PhD
Medical Director, Quality Informatics
Attending Physician, Lymphoma Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY
Disclosure: Grant/Research Support: GlaxoSmithKline, Janssen, Roche, Gilead Sciences, Bristol-Myers Squibb; Consultant: Genentech/Roche, GlaxoSmithKline, Gilead Sciences, Celgene, Pharmacyclics/Janssen, Amgen, Takeda, NanoString Technologies, Adaptive Biotechnologies
The staff of PER® have no relevant financial relationships with commercial interests to disclose.
Disclosure Policy and Resolution of Conflicts of Interest (COI)
As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.
Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.
Off-Label Disclosure and Disclaimer
This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.
PER Pulse Recap™PER Pulse Recap (1 of 3)
How are biosimilars unique with respect to other treatments for patients with hematologic malignancies?
While biosimilars and generic drugs are both versions of brand name medications that may offer cost savings to patients, there are key distinctions between these treatment options. Given the potential of biosimilar medications to influence clinical practice and shape outcomes for patients with hematologic malignancies, it is imperative for clinicians to be able to distinguish between biosimilars and generic medications with respect to features such as structure, complexity, immunogenicity, and manufacturing and approval considerations.1
Biosimilars are biological medicines that are highly similar to a previously approved biologic reference product, with respect to biological safety, efficacy, and immunogenicity. Generic medications, which are often chemically synthesized, are generally smaller molecules that have a simple structure and are less likely to create immunogenic responses than biologics.1
Because biologics are created in living cells and refined through multistep processes, they are more susceptible to variations in manufacturing conditions than are small molecules which are chemically synthesized. Even small changes in components of these systems can lead to product “drift,” which can influence quality, safety, and efficacy of biologics.1
With biosimilars becoming progressively incorporated into clinical practice, different systems will be used to produce similar biologics, and drift could lead to clinical variation not only among biologic originators, but also between originators and biosimilar products. Pharmacovigilance and rigorous standards for interchangeability may help minimize the influence of drift.2
- Nonbiologic generics have a relatively simple structure compared with biologics and biosimilars
- Biosimilars are sensitive to handling and storage
- Nonbiologic generics have a more predictable manufacturing process and are bioequivalent to the brand name drug
- It is easier to characterize nonbiologic generics than it is to characterize biosimilars
- Approval requirements for biosimilars and nonbiologic generics are quite different
1. Li E, Ramanan S, Green L. Pharmacist substitution of biological products: issues and considerations. J Manag Care Spec Pharm. 2015;21(7):532-539.
2. Ramanan S, Grampp G. Drift, evolution, and divergence in biologics and biosimilars manufacturing. BioDrugs. 2014;28(4):363-372. doi: 10.1007/s40259-014-0088.
PER Pulse Recap (2 of 3)
How are biosimilars developed, established as “biosimilar” to biologic therapies, and approved?
It is not a goal of biosimilar product development programs to independently establish safety and efficacy of the proposed biosimilar product. In lieu of “identicality,” biosimilars must demonstrate that they are “highly similar” to reference products. Biosimilars are reverse-engineered, using a risk-based approach, and they are extensively tested against the reference. The FDA’s stepwise approach generates data in support of biosimilarity with assessment of any residual uncertainty at each step. This “totality of the evidence” approach does not rely upon a single key study to establish biosimilarity. In this approach, it is essential for extensive structural and functional characterization to take place, identifying critical quality attributes and active components. Analytical similarity data serve as the foundation for biosimilar development.1,2 Possessing a comprehension of the relationship between these quality attributes and the clinical safety and efficacy profile can help to determine any residual uncertainty and predict clinical similarity. Animal toxicity data may help to address uncertainties about the safety of the proposed biosimilar before any clinical studies begin.1,2
Adequate clinical pharamacokinetic and pharmacodynamic comparisons between biosimilars and their reference products are components of biosimilar development programs.2 Comparative pharmacokinetic and pharmacodynamic data may support biosimilarity, assuming that similar exposure (and pharmacodynamics response) provides similar efficacy and safety. In addition, a comparison of the immunogenicity of the biosimilar and its reference product are usually included as well.2 Comparative clinical studies take place if there are any residual uncertainties after the earlier steps are completed.
Biosimilars currently have an abbreviated pathway for approval under the Biologics Price Competition and Innovation Act (part of the Affordable Care Act). This approval process relies in part on the prior approval of the reference product. Licensure may be based upon information regarding the FDA’s previous assessment that the reference biologic is safe, potent, and pure. The application process for biosimilars is simpler than the process for the reference biologic, but it is more complicated than the process for generics. Applications generally include demonstration of biosimilarity based upon analytical studies, animal studies, and clinical studies.2
If a product is to be reviewed as “interchangeable,” manufacturers must demonstrate biosimilarity and show that the biosimilar is expected to produce the same clinical results as the reference medication in any given patient.2 For products administered more than once, it has to be demonstrated that safety risk or diminished efficacy due to alternating or switching between reference and biosimilar is not greater than the risk of using the reference product without alternating or switching.2 Sponsors are expected to include data from switching studies for biosimilars administered 2 or more times in order to demonstrate interchangeability in 1 or more appropriate conditions of use.3 The switching arm is expected to incorporate at least 2 separate exposure periods to each of the 2 products.3
- In lieu of “identicality,” biosimilars must demonstrate that they are “highly similar” to reference products.
- “Highly similar” has been an industry standard that reference products must meet after manufacturing changes occur.
- Biosimilars are reverse-engineered, using a risk-based approach, and are extensively tested against the reference.
For further exploration of biosimilars in hematologic malignancies and expert clinical faculty commentary, please go to gotoper.com.
1. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. FDA website. www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Published April 2015. Accessed January 26, 2018.
2. Christl L. FDA’s overview of the regulatory guidance for the development and approval of biosimilar products in the US. FDA website. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM428732.pdf. Accessed January 26, 2018.
3. Considerations in demonstrating interchangeability with a reference product: guidance for industry—draft guidance. FDA website. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm537135.pdf. Published January 2017. Accessed January 25, 2018.
PER Pulse Recap (3 of 3)
How are biosimilars being integrated into the management of patients with hematologic malignancies?
In the management of patients with different malignancies, biologic therapies are widely used in active treatment (eg, monoclonal antibodies) and supportive care (myeloid growth factors, erythropoietin-stimulating agents, etc), but these therapies are often extremely costly.
Several recombinant growth factors and growth factor mimetics have been approved by the FDA. Tbo-filgrastim, a nonglycosylated recombinant methionyl human granulocyte colony-stimulating factor, received US FDA approval in 2012, but as a biologic, rather than a biosimilar.1 As a result, it has a narrower indication than does biosimilar therapy. Filgrastim-sndz was, in 2015, the first drug approved as a biosimilar in the United States; it is approved for all the same indications as filgrastim. The pivotal phase III PIONEER study assessed the safety and efficacy of filgrastim-sndz in 218 patients with breast cancer who were receiving myelosuppressive chemotherapy compared with reference filgrastim.3 The primary end point of this study was the duration of severe neutropenia during cycle 1. The biosimilar was shown to be noninferior to the reference product with respect to the primary endpoint, with no meaningful differences reported regarding time and depth of absolute neutrophil count (ANC) nadir, time to ANC recovery, incidence of febrile neutropenia, hospitalization due to febrile neutropenia, and infections.3
Rituximab has been extensively integrated into treatment protocols for patients with B-cell lymphoma, and several rituximab biosimilar candidates are currently in varying stages of development. Two rituximab biosimilar agents, CT-P10 and GP2013, have been approved by the European Medicines Agency for a variety of conditions, such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis. Both of these agents are currently undergoing FDA review. Other rituximab biosimilar agents being investigated include ABP 798 and RTXM83 for non-Hodgkin lymphoma, PF-05280586 for CD20+ follicular lymphoma, and HLX01 for CD20+ B-cell lymphomas.5-8 Clinical evaluation of biosimilar candidates such as these needs at minimum to demonstrate no differences in pharmacokinetics, pharmacodynamics, and immunogenicity (including postmarketing assessment). The safety and efficacy of rituximab were established in pivotal studies of the original molecule, with subsequent clinical trials addressing residual uncertainty regarding biosimilarity. Extrapolation to other indications may be appropriate if the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity are the same across indications.
- Several biosimilars are in advanced stages of development for patients with hematologic malignancies, both as active treatment and as supportive care
- Studies to date have shown that there are no additional safety risks with biosimilars in clinical practice compared with the reference
- Pharmacovigilance for biosimilars will be no different than for other types of products
- Pharmacists will be able to substitute biosimilars only if they are deemed to be interchangeable by the FDA
1. Center for Drug Education and Research: application number: 125294Orig1s000. proprietary name review(s). FDA website. accessdata.fda.gov/drugsatfda_docs/nda/2012/125294Orig1s000NameR.pdf. Published August 2, 2012. Accessed January 26, 2018.
2. Tbo-flgrastim [prescribing information]. North Wales, PA: Cephalon, Inc; 2017. granixhcp.com/pdf/grx-41132-pi.pdf.
3. Blackwell K, Semiglazov V, Krashnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol. 2015;26(9):1948-1953. doi: 10.1093/annoncmdv281.
4. Blackwell K, Gascon P, Krendyukov A, et al. Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim: a phase III, randomised, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol. 2018;29(1):244-249. doi: 10.1093/annonc/mdx638.
5. Study to assess if ABP798 is safe & effective in treating non-Hodgkin lymphoma compared to rituximab (JASMINE). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02747043. Updated December 15, 2017. Accessed January 29, 2018.
6. Study of RTXM83 plus CHOP chemotherapy versus a rituximab plus CHOP therapy in patients with non-Hodgkin’s lymphoma. ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02268045. Updated September 21, 2017. Accessed January 29, 2018.
7. A study of PF-05280586 (rituximab-Pfizer) or MabThera® (rituximab-EU) for the first-line treatment of patients with CD20-positive, low tumor burden, follicular lymphoma (REFLECTIONS B328-06). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02213263. Accessed February 8, 2018.
8. A study to evaluate safety, tolerability, PK and PD of HLX01 in patients with CD20-positive B-cell lymphomas. ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT03218072. Updated July 19, 2017. Accessed January 29, 2018.
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