Impact of Biosimilar Insulins on Clinical Practice

Abstract

The availability of biosimilar insulins can potentially lead to lower insulin costs and increased access for patients with diabetes, worldwide. However, clinicians and regulatory agencies have raised several concerns regarding the safety and efficacy of these new medications. The European regulatory agencies have established guidelines for market approval of biosimilar insulins; however, many issues remain unresolved. Moreover, although the FDA has developed preliminary pathways for biosimilar protein development and is prepared to review each application on a case-by-case basis, insulins do not fall under this pathway at this time. The development of effective postmarketing surveillance protocols, determination of product interchangeability, and product identification/labeling remain key concerns. Numerous issues surround the development and commercialization of biosimilar insulins; thus, it is important that all stakeholders fully understand the complexity of these issues and how they can potentially affect patient care. Bridging the educational gap among clinicians and regulatory agencies will be challenging but necessary for ensuring patient safety.

An expert panel of diabetes specialists met in Dallas, Texas, March 21-22, 2013, to discuss key issues regarding the current status of biosimilar insulin development and the potential impact of these medications on clinical practice. The panel comprised 10 US and European thought leaders who provided an array of different perspectives, including endocrinology, biotechnology, psychology, and research/patient advocacy.

The purpose of the meeting was to discuss the relevant issues and complexities associated with developing safe and effective biosimilar proteins. Participants heard presentations on the differences between generics and biosimilar proteins, how insulins are currently used/prescribed worldwide, regulatory requirements and scientific standards, and patient safety. This report summarizes the information presented and discussed at the meeting. Among the issues discussed were the following:

• Key differences between generic medications and biosimilar products

• Difficulties in development and manufacturing biopharmaceutical medications such as insulin

• How differences (due to formulation and manufacturing processes) in biosimilar products from their original reference products can impact efficacy and safety

• The need for effective clinical studies prior to regulatory approval and well-defined strategies for implementing extended postmarketing surveillance (pharmacovigilance) to monitor potential immunogenicity

• Importance of establishing effective tracking/tracing system, labeling biosimilar products with unique names and lot numbers, to quickly identify sources of any potential adverse effects

• Challenges of current and proposed regulatory pathways for the development of biosimilar products as they relate to the comprehensiveness of clinical evaluations required for product approval, whether unique names should be used to identify biosimilars, and the issue of drug interchangeability/substitution

• The need to educate clinicians, people with diabetes, and pharmacists about biosimilar medications

Overview of Biosimilar Insulins: What Do We Need to Consider?

Philip Home, MA, DPhil, DM, FRCP

Patents on 3 leading insulin analogs—lispro, aspart, and glargine—will expire within the next 2 years. Expiration of these patents has prompted several pharmaceutical manufacturers to develop alternative versions of these insulins, referred to as “biosimilars,” to take advantage of the new commercial opportunities. Although it is anticipated that these new medications will provide the same clinical benefits of the current insulin analogs but at a significantly lower costs, there are several issues that must be resolved.

A biosimilar medication is intended to mimic the metabolic action and efficacy of its original reference biologic medication, which is derived from cell culture/fermentation processes that produce the target therapeutic protein. An early example of a biopharmaceutical medication is recombinant human insulin, which was developed by Eli Lilly and Company in 1980. Other examples include cytokines and monoclonal antibodies.

Unlike generic medications, in which the chemical structures can be well defined and identically reproduced, the proteins used in biosimilar medications are more complex, 3-dimensional structures and are unlikely to be structurally identical to their reference products. Figure 1 presents a summary of the differences between chemical and biopharmaceutical medications.

Figure 1.

Differences between chemical and biopharmaceutical medications in the manufacture of copies.

Because the original manufacturer’s insulin formulation and production information remain proprietary and, thus, outside the public domain, biosimilar manufacturers will be challenged to first develop a new cell line and then design an entirely new manufacturing process. This can potentially result in significant differences in biologic activity, absorption properties and purity from the original insulin product.

Given the potential clinical impact of these factors, comprehensive research protocols are needed to exclude clinically meaningful differences in efficacy, safety and immunogenicity. This suggests that several different types of studies be conducted, including pharmacokinetic studies to assess differences in subcutaneous absorption, pharmacodynamic studies to ensure similar acute efficacy, clinical efficacy studies in various populations over time, immunogenicity studies, and clinical safety studies.

It was proposed that the immunogenicity and safety studies be greater than 6 months duration and focus on the most sensitive clinical population, specifically individuals with type 1 diabetes. Primary measurements should include preinjection glucose for basal biosimilar insulins, postprandial glucose for prandial (rapid-acting) biosimilar insulins, incidence/severity of nocturnal hypoglycemia, change in HbA1c for up to 12 months, and formation of antibodies to the biosimilar insulin.

The regulatory requirements and protocols for assessing the safety and efficacy of biosimilar insulins have not yet been developed in the United States and only recently defined in Europe; however, some copies of current insulins have already been approved for commercialization in China, India, Pakistan, Thailand, Peru, and Mexico, where regulatory requirements are less stringent. Although the emergence of biosimilar insulins has been widely discussed by researchers and regulatory bodies during the past several years, there remains a lack of awareness and understanding of the clinical concerns surrounding these medications within the medical community.

Practicing clinicians will need to know whether any differences in these formulations are clinically meaningful, and whether these products are interchangeable with the original branded formulation and/or other biosimilar insulins. Health care payers will need to understand the difference between generic and biosimilar medications, as well as the clinical costs of medication substitution.

Establishing Efficacy and Safety in Biosimilar Insulin: A European Perspective and Case Study

Lutz Heinemann, PhD

Europe has been one of the forerunners in the development of biosimilar guidelines in comparison to many other countries. European biosimilar quality guidelines were developed and approved in 2004 and 2005, respectively. However, because specific guidance for the development of biosimilar insulins was not included in these documents, separate guidelines were drafted in 2006 to address these insulin products.

In December 2012, a formal draft guideline was introduced, describing the nonclinical and clinical requirements for biosimilar human insulin and insulin analog products. The clinical studies required for insulin biosimilars include a pharmacokinetic (PK) study and a pharmacodynamic (PD) study to demonstrate comparability with respect to the time-effect profile of hypoglycemic effect. According to the guidelines, there is no anticipated need for specific efficacy studies since endpoints used in such studies (usually HbA1c) are not considered sensitive enough for the purpose of showing biosimilarity of 2 insulins. The guideline states that the study population should be homogenous and insulin-sensitive to best detect potential product related differences and may consist of normal-weight healthy volunteers or patients with type 1 diabetes.

For the purpose of comparing the PK and PD profiles of a biosimilar and its reference insulin, glucose clamp experiments should be conducted by experienced investigators under highly standardized conditions. Although similar considerations and scientific principles may apply to biosimilar insulin analogues and long-acting human insulin preparations as to soluble insulins, some additional factors must be considered. Specifically, it is important to consider the sensitivity of the clamp study for detection of potential differences in the duration of action or other summary measures between long-acting insulin formulations due to the flat PK profile of these insulins and the high variability often seen in the tail part of clamp studies.

A key concern is ensuring the long-term safety of biosimilar insulins after they have been approved. Although pharmacovigilance legislation and practice, including risk management plans (RMPs), are currently undergoing considerable change and development in the EU, it is uncertain whether diabetologists have a good understanding of how such procedures should be performed, and how to implement these guidelines in clinical practice. One obstacle to effective pharmacovigilance is that European physicians currently have no incentive to consistently report adverse effects of the medications they prescribe. Moreover, how biosimilars are identified can impact the traceability of biosimilar insulins, which is important if safety issues related to immunogenicity emerge.

Several biosimilar medications are already in the market in Europe, and applications for biosimilar insulin products have been submitted for the approval. However, there have been several problems with past drug applications for biosimilar insulins, especially in conducting and reporting findings on the PK/PD characteristics of these products.

One example is Marvel Pharmaceuticals, which has already failed at 2 attempts to gain approvals for its biosimilar insulin products. In both applications, several weaknesses were identified in the study reports, including statistical errors, unclear calculations (statistical analysis plan was not provided) and inconsistent or missing information. In the second application, reviewers criticized the glucose duration of the clamp procedure used, which was considered to be too short (5 hours) to fully reflect the PD profile of these short-acting insulins. In addition, reviewers determined that the glucose infusion rate (GIR) reported in the studies showed a constant plateau over the course of the clamp test, which is unexpected for short-acting insulins and not consistent with the PK profiles of these insulins.

European regulatory agencies have established relatively clear guidelines for market approval of biosimilar insulins, emphasizing their concerns regarding quality, safety, and efficacy, and recognizing that adequate clinical data and postmarketing surveillance are required. However, issues regarding product interchangeability remain and may require additional discussion and possible revision once biosimilar insulins are on the market.

Immunogenicity Considerations

Huub Schellekens, MD, PhD

Biopharmaceutical medications such as insulin are derived from a living organism through recombinant DNA or controlled gene expression methods. Unlike conventional, small-molecule drugs, the active substance of a biopharmaceutical is a large, high-molecular-weight, 3-dimensional structure that, in general, also contains many modified forms of the basic structure. Because of the complexity of these substances, along with intricate processes involved in their production, it is difficult to avoid batch-to-batch heterogeneity within a single manufacturing process and between proteins from different manufacturers.

The emergence of biosimilar insulins creates a new set of challenges. It is important to note that a biosimilar insulin is similar but not identical to the original insulin product. Although the original insulins have undergone extensive preclinical evaluation, followed by large, long-term clinical trials and ongoing postmarketing surveillance, safety and efficacy cannot be derived from physical chemical characterization, alone. A significant difference between biopharmaceuticals and classical chemical medications with regard to safety is the significant potential to induce an immune response.

Regardless of purity and origin, all therapeutic insulins have been shown to be immunogenic in most humans; approximately 90% of patients treated with insulin have antibodies. Several factors can influence insulin immunogenicity, including the structural properties of the molecule, glycosylation, contaminants and impurities from initial production or downstream processing, formulation, dosage, length of treatment, and route of application. Although there is little evidence to suggest that the development of insulin antibodies to exogenous insulin therapy affects glucose control, insulin dose requirements or incidence of hypoglycemia in nearly all insulin users, certain structures could enhance the probability of neutralizing antibodies that interfere with insulin activity. Because current analytical methods cannot characterize these complex insulin proteins sufficiently to confirm structural equivalence with their reference molecules, excluding the possibility of a clinically significant immunogenic response is not possible at this time. Thus, long-term clinical trials and well-defined strategies for implementing extended postmarketing surveillance (pharmacovigilance) to monitor potential immunogenicity must be required for regulatory approval. The European Medicines Agency (EMA) currently requires that manufacturers include a pharmacovigilance plan to address immunogenicity and potential rare adverse events in the data package submitted for the product approval.

Numerous documents recently published by the EMA outlining requirements for the market approval of biosimilar medications provide much-needed guidance to manufacturers. However, a number of other issues remain unresolved, such as the interchangeability of biosimilars and innovator products, the possible need for unique naming to differentiate the various biopharmaceutical products, and the comprehensiveness of labeling for biosimilars. All of these issues must be addressed to help ensure treatment efficacy and patient safety.

FDA Guidance on Biosimilars: Current and Future Implications for Insulins

Shefali Goyal, MS, MSc

Under the recent Patient Protection and Affordable Care Act (PPACA), which was passed in 2010, Title VII, Subtitle A, “Biologics Price Competition and Innovation,” allows for the creation of a regulatory approval pathway for biosimilars and a litigation procedure for patent infringement lawsuits against biosimilar applicants. Within this legislation, a biologic product is defined as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide) or analogous product, or arsphenamine or its derivatives (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” A biosimilar is defined as “a product that is highly similar to the reference product, not withstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and reference product in terms of safety, purity and potency.”

Although insulins are currently regulated by the US Food and Drug Administration (FDA) under Section 505 of the Food, Drug and Cosmetic Act (FDCA) as drugs (not biological medications), the new legislation amends Section 351 of the Public Health Service Act (PHSA) to create an abbreviated biological product application for highly similar biological products. This permits a proposed biosimilar product to be evaluated against only 1 reference listed product.

Ten years after enactment of the PPACA, certain biological products such as insulins will be deemed “biologics” and licensed under PHSA Section 351. Therefore, insulins and related products could qualify for the PHSA Section 351(k) or “biosimilar” pathway in the year 2020. Until then, these products may only be approved for the US market under the FDCA Section 505(b)(1), 505(b)(2) or 505(j) pathways.

A stepwise approach for the biosimilar development plan and FDA review will be used to complete these pathways, however, not all steps are expected to be required for all products. The stepwise approach begins with extensive structural and functional characterization of both the proposed product and the reference product, followed by animal toxicity studies, comparative PK and PD studies, comparison of clinical immunogenicity and comparative clinical and efficacy data (Table 1). The objective of this approach is comparison (not independent analysis) of the safety and effectiveness of the biosimilar. Manufacturers are encouraged to address residual concerns at each step to determine the need for additional analytical analysis and/or clinical studies. They are also encouraged to consult extensively with the FDA after completion of comparative structural and functional analysis before finalizing the clinical program.

Table 1.

Stepwise Approach for Biosimilar Development Plan and FDA Review.

Step 1	Structural and functional studies
Step 2	Animal toxicity studies
Step 3	Comparative human PK and PD studies (if there is an appropriate PD measure)
Step 4	Comparison of clinical immunogenicity
Step 5	Comparative clinical safety and effectiveness data

Not all steps are needed for every product. FDA, US Food and Drug Administration; PD, pharmacodynamic; PK, pharmacokinetic.

FDA will generally require structural and functional analysis data (eg, manufacturing process, assessment of physiochemical properties, stability) as well as other assessments, including: animal toxicity studies, immunogenicity comparisons, PK/PD studies and human clinical studies. Although some of these studies could be waived or narrowed based on analytical data, clinical human data will be required in all cases. The FDA will advise on the specific clinical study requirements after a complete review of structural/functional analysis data. FDA determination of the type and amount of animal and human clinical testing will be based on: resolution of the analytical characterization of the reference product and biosimilar; the degree of similarity; and the manufacturer’s ability to provide a satisfactory science-based explanation of why any small differences between the 2 products are not clinically meaningful.

Regarding detection of potential immunogenicity, the FDA recommends using a comparative parallel study design to assess potential differences, showing that the biosimilar insulin is no more immunogenic than the reference insulin. If the immune response to the reference protein is rare, 2 separate studies may be sufficient to evaluate immunogenicity. These would involve a premarket study powered to detect major differences and a postmarket study designed to detect more subtle differences.

Under the PPACA, the Secretary of Health and Human Services (HHS) will determine that a biosimilar product is interchangeable with the reference product if the information submitted in the application (or supplement) is deemed sufficient to show that the product is biosimilar to the reference product, and that it can be expected to produce the same clinical result as the reference product in any given patient and at the same risk of safety. It must also be shown that the risk (safety and/or diminished efficacy) of alternating or switching between the 2 products is not greater than the risk of using the reference product without such alternating or switching

In summary, the FDA will review each biosimilar application on a case-by-case basis, applying a stepwise approach. If initial steps indicate strong similarity, data required from later steps may be greatly reduced. The FDA proposes frequent interactions with the manufacturer during development before providing more in-depth advice regarding the clinical program.

Clinicians’ Perspectives on Biosimilars

Richard O. Dolinar, MD

Nomenclature is very important because biosimilar medicines are very different from generic medicines. Biosimilars are not generics. Generics have the same identical active ingredient as the originator drug. Biosimilars do not. They are similar to but not identical to the originator biologic drug. Thus, new standards for clinical assessment and regulatory approval are required. For physicians to feel confident in the safety and efficacy of these new medications, rigorous clinical testing of biosimilars is needed prior to approval and robust tracking and tracing after approval.

Biologics differ from chemical medicines. Unlike drugs that are chemically synthesized and have known structures biologics are complex compounds made from living cells and have highly intricate structures that are not easily understood, characterized, or replicated. Small differences between the structure of the innovator drug and the “biosimilar” copy can affect safety, efficacy, and immunogenicity. Biologics present a greater risk of triggering an immune response than traditional drugs due to their molecular size and complexity. Even a small change in the manufacturing process or downstream distribution and storage can alter the structure of the medicine and potentially mount an immune response.

Determining the source of the adverse reaction is of primary importance to the patient being treated; however, it is also important for the safety of other patients who are or may be treated with the same medicine. In some cases, a biologic may have been altered due to a change in formulation or manufacturing process, resulting in an increased likelihood of triggering an unexpected immune response. Accurately and promptly identifying the source of the problem for the immediate patient can help prevent other patients from being exposed to the medicine until the problem is identified and resolved. Because an immune response to a biologic can occur up to 9 to 12 months after a patient was first treated, it can be difficult for the clinician to know whether the response is to a medicine or if it is simply a progression of the disease. Moreover, if a patient has been exposed to more than 1 version of a biologic medicine, it may be difficult to know which product caused the reaction.

In its recommendations and subsequent testimony to the FDA in May 2012, the Alliance for Safe Biologic Medicines (ASBM) urged that patient safety should guide all agency decisions regarding implementation of the regulatory pathway for biosimilar development and approval. The main concerns raised by the ASBM focused on the comprehensiveness of clinical evaluations required for product approval, whether unique names should be used to identify biosimilars and the issue of drug interchangeability/substitution.

In addition to rigorous clinical trails, ASBM recommended that the biosimilar development and approval pathway require a robust pharmacovigilance protocol that includes the ability to track and trace products and to connect an adverse event with a specific product, manufacturer, and lot number to reduce systemic risks.

All biologics are expected to be structurally distinct and these distinctions may have implications for patients; therefore it was also recommended by ASBM that biosimilar medications be given names that are distinguishable from their reference biologic. This would provide physicians with more information, increase the ability to accurately attribute adverse events to the correct product, and hold manufacturers more accountable for their products. The ASBM suggested that this can be achieved by assigning a unique United States adopted name (USAN), also known as a nonproprietary name to every biologic.

Timely and accurate communication between health care providers is key when using biologic medicines. In a survey of 376 physicians who currently prescribe biologic medications, 85.9% indicated that they want to be notified before the patient receives a biosimilar medication instead of the original product prescribed, followed by 6.4% who indicated a preference for notification within 24 hours of the patient receiving the mediation. It is important that physicians and pharmacists work collaboratively to ensure that the treating physician is aware of the exact biologic (by name and manufacturer) given to a patient to facilitate patient care and accurate attribution of any adverse events that may occur. In addition, physicians must retain the authority to specify “do not substitute” for biological medications, and this should override any policy (state law or payer) that stipulates substitution as the standard or default practice.

In sum, it is critical that regulatory pathways for all biosimilar medications include appropriate safeguards. Approval of biosimilars should be based on appropriate data, including clinical data that demonstrates the product is indeed safe and effective. Interchangeability is a complex issue for biologics and warrants substantial caution on the part of the FDA before designating any product “interchangeable.” States have an important role to play in ensuring that pharmacy practices appropriately distinguish biosimilars and interchangeable biologics from generic drugs, particularly for the purpose of automatic substitution in the retail setting. It is inappropriate and contrary to sound science for any product lacking a designation of “interchangeable” to be substituted without the involvement of the prescribing physician.

Biosimilar Survey Results

William H. Polonsky, PhD, CDE

A survey was conducted in the United States to establish a baseline of current knowledge of and attitudes toward biosimilar medications, in general, and reaction to biosimilar insulins among prescribers, pharmacists, payers, and patients receiving basal insulin therapy. The goal of the survey was to identify specific areas where education would be important to develop effective educational curriculum.

A total of 629 individuals participated in the survey (Table 2). Among the people with diabetes surveyed, 9% of type 2 diabetes respondents and 27% of type 1 respondents reported being familiar with the term “biosimilar.” Approximately half of respondents who reported familiarity with biosimilars also reported having been prescribed a biosimilar medication in the past; however, some of these were erroneously identified as diabetes medications.

Table 2.

Survey Participants.

	n
Total participants	629
Prescribers	339
Primary care physicians	150
Endocrinologists	75
Nurse practitioners/physician assistants	100
Thought leaders	14
Pharmacists	50
Payers	40
Medical directors	20
Pharmacy directors	20
Plan size
National	18
Large regional	13
Small/medium regional	9
People with diabetes	200
Type 1 diabetes	60
Type 2 diabetes	140

Up to 30% of prescribers reported prescribing a biosimilar medication. Insulins were mentioned in 22% to 32% of prescribers as the biosimilar medication most often prescribed, suggesting confusion among this group of respondents because no biosimilar insulins are currently available in the United States. In addition, among the 12% of pharmacists who reported dispensing biosimilar medications, all identified either an insulin or a glucagon like protein-1 receptor agonist as the biosimilar medication most often dispensed, which, again, suggests confusion. Payers, however, demonstrated the greatest awareness of biosimilar medications; 37% reported having a biosimilar product (growth hormone) on their formulary. None of the payers erroneously identified insulin as a biosimilar product.

In the survey, a number of questions were submitted to participants to assess their understanding of the regulatory requirements associated with biosimilar approval and interchangeability. When asked if biosimilars require only bioequivalence studies to gain regulatory approval, only a small percentage of respondents in each subgroups correctly answered “no”: 7% of patients, 13% of prescribers, 22% of pharmacists, and 30% of payers. When asked if biosimilars can ever be substituted for the original brand by a pharmacy without the physician’s consent,” a slightly higher percentage of respondents correctly answered correctly “yes”: 29% of patients, 16% of prescribers, 18% of pharmacists, and 33% of payers.

Regarding respondents’ attitudes toward biosimilar, most prescribers welcome the availability of biosimilar medications because they felt that generics already reduce the cost of medications to the US health care system: 59% of primary care physicians (PCPs), 48% of endocrinologists, and 58% of nurse practitioners/physician assistants. When asked to assume that the FDA had already approved a biosimilar basal insulin (such as biosimilar glargine) but it was not designated by the FDA as interchangeable with Lantus (Sanofi US, Bridgewater, NJ, USA), a smaller percentage of prescribers were somewhat or very likely to prescribe the biosimilar for their patients.

Overall, the survey showed significant enthusiasm for biosimilars (including biosimilar insulins), especially among PCPs. However, there remains a general lack of knowledge and misunderstandings about biosimilars within the health care community.