This presentation provides an overview of the guiding principles for a science-based regulatory pathway for biosimilar products.
Specific topics to be covered include the following: an introduction to biologic and biosimilar products, and explanation of how they differ from small molecule drugs an overview of the Biologics Price Competition and Innovation Act of 2009, that, when approved as part of the Patient Protection and Affordable Care Act of 2010, created an abbreviated regulatory pathway for approval of biological products that are highly similar to FDA-licensed biological reference products a summary of three draft guidance documents that the US Food and Drug Administration (FDA) issued to assist industry in developing biosimilar products Comments from the Pharmaceutical Research and Manufacturers of America (PhRMA) on the three draft guidances, including specific recommendations for FDA to consider prior to finalizing these documents, and a summary of the principles PhRMA endorses for a science-based regulatory pathway for biosimilar products
It is important to understand that biosimilars are not equivalent to generic drugs. In the case of generic drugs, the active ingredient is chemically identical to its branded counterpart. Because the active ingredient is chemically identical, the generic versions share the same non-proprietary name as the original version. And, as previously discussed, the active ingredient of a generic drug can be duplicated and manufactured via clearly defined chemical reactions. By comparison, the active ingredient in a biosimilar product may be highly similar to the reference product, but will not be identical. Because reference products cannot be duplicated by another manufacturer, biosimilars and reference products should have distinguishable names. One commonality between generics and biosimilars is that they have the same dosage form, strength, and route of administration as their respective parent products for each approved condition of use.
The Biologics Price Competition and Innovation Act of 2009 (BPCIA) was passed by Congress and signed into law in March 2010 as part of the Patient Protections and Affordable Care Act. This legislation created an abbreviated regulatory pathway for biological products that are shown to be biosimilar to or interchangeable with an FDA-licensed reference product. To be eligible for the abbreviated licensure pathway, a sponsor must demonstrate that the proposed product is highly similar to an FDA-licensed reference product, that it has the same mechanism of action (to the extent known) for the proposed conditions of use previously approved for the reference product, and that it has the same route of administration, dosage form, and strength as the reference product. The Public Health Service Act defines “biosimilarity” to mean that “the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”
The BPCIA established a regulatory approval pathway for two types of products: those that are biosimilar to and those that are interchangeable with an FDA-licensed reference product. While both biosimilar and interchangeable biological products must be demonstrated to be highly similar to the innovative reference product, there is a higher standard for interchangeable biological products. In addition to demonstrating biosimilarity to and lack of clinically meaningful differences from the reference product, for a product to be interchangeable, it must be shown that there is no increased risk in terms of safety or diminished efficacy of alternating or switching between the interchangeable product and the reference product when the product is administered more than once to an individual patient, compared with using only the reference product without such alternation or switch. Interchangeable biologics must be demonstrated to produce the same clinical result as the reference product in any given patient.
To assist the biopharmaceutical industry in developing biosimilar products, the FDA issued in February 2012 drafts of three initial guidance documents. The three documents were titled: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, and Biosimilars: Questions and Answers Regarding Implementation of the BPCIA. At the time FDA issued the draft guidances, the Agency indicated its intention to seek public comment on the documents, and to consider the information received from the public prior to finalizing the drafts. When finalized, these guidance documents will provide product sponsors with the FDA’s current thinking on important scientific and regulatory factors involved in submitting applications for biosimilar products to the Agency.
The draft of the Quality Considerations document provides guidance on the analytical factors to consider as part of the demonstration of biosimilarity. Together with animal and clinical studies, comparative analytical studies are used to evaluate the safety, purity and potency of a proposed product compared with a reference product. The document discusses the importance of establishing analytical similarities (such as molecular weight and functional properties), conducting extensive physicochemical and biological characterization (including biological assays and binding studies), and demonstrating comparative stability in multiple stress conditions to establish that a proposed biosimilar product is highly similar to the reference product. The draft guidance also describes considerations for additional chemistry, manufacturing, and controls information that may be relevant to the assessment of biosimilarity. In addition to comparative analytical studies, an assessment of biosimilarity will generally include animal studies and clinical trials.
The Scientific Considerations draft guidance provides an overview of the FDA’s current thinking on determining biosimilarity. The draft guidance discusses important scientific considerations, such as the stepwise approach the FDA recommends in the development of biosimilar products, and the risk-based, “totality-of-the-evidence” approach the Agency intends to use to evaluate data and information submitted in support of a proposed biosimilar product. The document also describes FDA’s views on general scientific principles in conducting assays, preclinical testing, and clinical studies, as well as considerations related to the complexities of therapeutic protein products, extrapolation of clinical data across indications, and the importance of post-marketing safety monitoring. Considerations for immunogenicity studies, both preclinical and clinical, are also addressed.
The Questions and Answers draft guidance provides answers to common questions from sponsors interested in developing biosimilar products. The questions are grouped into three general categories, and address topics such as who to contact and how to request meetings with the FDA to discuss a proposed development program, differences in formulation between a proposed biosimilar and a reference product, and how to request exclusivity for innovative biological products. FDA stated that the question and answer format is intended to promote transparency and facilitate development programs by addressing questions that may arise in the early stages of product development. FDA has indicated its intention to add to the question and answer document as new questions emerge.
The Scientific Considerations draft guidance describes a stepwise approach the FDA recommends in the development of biosimilar products, beginning with analytical studies to demonstrate that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components. The second step involves studies with animals, including assessments of toxicity, pharmacokinetics and pharmacodynamics, and immunogenicity. Finally, clinical studies are to be conducted, to demonstrate safety, purity, and potency in the condition(s) of use for which the reference product has been approved, as well as to assess immunogenicity and comparative pharmacokinetics and pharmacodynamics in patients. FDA has proposed using a risk-based, “totality-of-the-evidence” approach to evaluate data and information submitted in support of a proposed biosimilar product. The Agency has the discretion to determine whether any of the steps are not necessary for approval.
In contrast to FDA’s position that some steps may be unnecessary to support approval, it is PhRMA’s view that evaluation of biosimilars to demonstrate the absence of clinically meaningful differences should include comparative molecular evaluations and preclinical studies and clinical testing. Given the size and complexity of biologic products and the use of living systems for their production, even seemingly small differences in a product’s structure or means of production may have unintended clinical consequences. Such consequences may be difficult to predict, particularly for applicants lacking extensive manufacturing experience with the proposed biosimilar product. Thus, a clear, science-based process for comprehensive evaluation of potential differences between proposed biosimilars and their reference products is essential, and should include at least one comparative clinical trial of adequate size and design to establish that the proposed biosimilar does not possess clinically meaningful differences in safety or efficacy from its reference product.
FDA should provide guidance that sponsors of proposed biosimilar products minimize the potential for unintended or unanticipated differences between biosimilars and reference products. PhRMA believes it would be prudent for biosimilar applicants to minimize, to the extent possible, controllable differences in process and design, and provide scientific justification for any changes to controllable elements that are intentionally introduced during biosimilar development. Since intentionally introducing changes may lead to unintended or unanticipated differences between a biosimilar and its reference product, additional analytical, preclinical and clinical studies will be necessary to demonstrate that a proposed biosimilar product is highly similar to its reference product. Thus, intentional changes may decrease the feasibility of using an abbreviated development pathway for a proposed biosimilar product.
PhRMA supports a scientifically rigorous approach to development of biosimilars, which should include comparative molecular evaluations of physical, chemical and functional properties to demonstrate the absence of clinically meaningful differences between biosimilars and their reference products. Multiple analytical procedures that are sufficiently sensitive should be performed to detect differences between a proposed biosimilar and a reference product, since seemingly minor structural differences may significantly affect safety, purity or potency. It must be recognized, however, that even state-of-the-art technology may not identify all differences between a proposed biosimilar and the reference product. Understanding the limitations of the analytical program will be essential to the appropriate design of preclinical and clinical studies to evaluate remaining uncertainties.
In vitro functional assays are important to the evaluation of biologic activity and the demonstration of biosimilarity, but in vitro studies alone are insufficient to establish that a proposed biosimilar does not possess clinically meaningful differences compared to the reference product. While there may be challenges associated with the relevance of animal studies in predicting immunogenic responses in humans, preclinical testing based on sound science, and aligned with the ICH guidelines plays an important role in biosimilarity assessment.
Clinical testing is essential to address the statutory requirement that there be no clinically meaningful differences between a proposed biosimilar product and its reference product. It is PhRMA’s view that the primary concern should be for patient wellbeing, and therefore recommends that clinical immunogenicity testing, as well as at least one comparative clinical trial of adequate size and with appropriate endpoints to detect small differences in safety or efficacy be included in all biosimilar development programs.
PhRMA believes that each indication for which a biosimilar applicant is seeking approval will need to be supported with appropriate clinical data, unless strong scientific justification for extrapolation is provided. For example, FDA should recommend that applicants seeking to extrapolate data across populations within an indication study the patient population most sensitive to differences in efficacy, safety, and immune response, recognizing that the most sensitive patient population may not be the same when evaluating differences in efficacy, safety, or immunogenicity. Biosimilar applicants should also demonstrate that there are no significant differences in the pharmacokinetics and bio-distribution of the product across indications and patient populations for which the reference product is approved and for which they are seeking approval. Scientific justification for extrapolation should include consideration of whether the indications share the same mechanism of action.
The potential to provoke an immune response is associated with all biologic products. Even seemingly small changes may significantly alter the immunogenicity of a biosimilar compared to its reference biologic. PhRMA, therefore, believes that pre- and postmarket immunogenicity testing should be conducted, including during preclinical and clinical testing, as well as postmarketing pharmacovigilance. Testing of biosimilars and their reference products should compare cross-reactivity and target epitopes of immune responses, in addition to both binding and neutralizing antibodies. Immunogenicity testing of products that are chronically administered should be carefully considered due to the time-dependent nature of immune responses associated with chronic use. The purpose of testing is to assess whether a biosimilar has increased or decreased immunogenicity compared to the reference product, as either may affect the severity of any clinical consequences. To safeguard patients, any extrapolation of data to support another indication should include immunogenicity assessments in the patient population most sensitive to immune responses.
“ Labeling” refers to all of the printed information that accompanies a biological product, it provides instruction to health care practitioners on the proper use of the product. Since biosimilar products are highly similar to, but not exactly the same as, their reference products, it will be important for labeling to make clear whether a given product is biosimilar to and/or interchangeable with its reference product. PhRMA believes that the final guidance should recommend that product labeling disclose which of the biosimilar’s indications were supported by clinical data and which were based on extrapolation, as well as how much (and what type of) clinical data supported the product’s approval. And due to the risk of unsafe and inappropriate substitution of a non-interchangeable biosimilar with the reference product, the labeling should state prominently that a non-interchangeable biosimilar should not be substituted for the prescribed product without the express consent of the treating physician.
Pharmacovigilance is the process of monitoring, collecting, and evaluating information on the adverse effects of biological products, for the purpose of identifying new information about potential safety risks associated with these products and preventing harm to patients. Pharmacovigilance begins during the premarketing phase, and continues throughout the product’s life cycle. PhRMA believes that a pharmacovigilance plan for each approved biosimilar should be tailored to the known benefit-risk profile of the biosimilar and its reference product. FDA is encouraged to identify the extent to which immunogenicity concerns associated with a biosimilar have been addressed during premarket testing, and to determine the need for postmarketing studies and risk evaluation and mitigation strategies (REMS) to assess rare safety risks. In general, a biosimilar product should have a REMS at least as rigorous as its reference product. However, if previously undetected differences between a biosimilar and its reference product emerge during the postmarketing period, a more extensive REMS may be necessary.
Unique non-proprietary names are an essential feature of a robust pharmacovigilance system for biologics that permits accurate attribution of adverse events to a particular biologic or biosimilar product. It will be advisable for biosimilars and their reference products to have unique names regardless of the possibility that a biosimilar applicant may later seek approval as an interchangeable biologic. Having unique names would prevent inappropriate substitution of a non-interchangeable product if there are both biosimilar and interchangeable products available for the same reference product.
To summarize, a biosimilar product is highly similar to, but not the same as, an FDA-licensed reference biologic product. The BPCIA created an abbreviated regulatory pathway for the approval of biosimilar products, and recently the FDA issued three draft guidance documents to assist industry in development of these products. PhRMA supports the ongoing implementation of the BPCIA, and has offered specific recommendations on the draft guidances for FDA to consider prior to finalization. Overall, PhRMA believes that a rigorous, science-based process for evaluating proposed biosimilars and their reference products must include analytical, preclinical, and clinical testing, all of which are essential to ensuring the quality, safety, and efficacy of biosimilars. Additionally, the use of unique non-proprietary names for biosimilar and interchangeable products is an essential component of a robust pharmacovigilance system that adequately protects patient safety. Any decision to take a biological medicine should be made with the oversight and guidance of a physician, as the well-being of patients must remain the paramount concern. Incentive for continued innovation of biologics is critical to ensure patient access to new medicines.
13. Dr. Kristin Van Goor - PhRMA
Principles of a Science-BasedPrinciples of a Science-BasedRegulatory Pathway for BiosimilarRegulatory Pathway for BiosimilarProductsProductsKristin Van Goor
Overview• Biosimilars• Biologics Price Competition and InnovationAct of 2009 (BPCIA)• FDA Draft Guidances Relating to Implementationof BPCIA• PhRMA’s Comments on the FDA’s Draft Guidances• Summary2
• However, both generics and biosimilars have the same dosage form,strength, and route of administration as their respective parentproducts for approved conditions of useBiosimilars Are Not Generics3= ≠ ≠
Biologics Price Competition andInnovation Act of 2009 (BPCIA)• Created an abbreviated licensure pathway for biological productsshown to be biosimilar to or interchangeable with an FDA-licensedreference product• Sponsor must show that the proposed product• Is highly similar to a single, FDA-licensed biological referenceproduct• Utilizes the same mechanism(s) of action (to the extent known forthe reference product) for the proposed condition(s) of use of thebiosimilar that have been previously approved for the referenceproduct• Has the same route of administration, dosage form, and strengthas the reference product4
5BPCIA Established a Regulatory Pathway forTwo Types of Biosimilar Products• BPCIA created an approval pathway for biosimilar products andinterchangeable biological products• Both biosimilar and interchangeable biological products must bedemonstrated to be highly similar to an innovative biological product• BPCIA establishes a higher standard for interchangeable products1. Biosimilar to the reference product2. Expected to produce the same clinical result asthe reference product in any given patient3. No increased risk associated with alternating orswitching between the interchangeable product andthe reference product compared with using only thereference productMust Meet3 CriteriaMust Meet3 Criteria
FDA Draft Guidance to IndustryRelating to Implementation of BPCIA• In February 2012, FDA issued three draft guidance documentson biosimilar product development to assist industry in developingthese products• When finalized, these guidances will represent the FDA’s currentthinking on these topics6
FDA Draft Guidance: Quality Considerationsin Demonstrating Biosimilarity• Provides FDA’s views on comparative analytical studies that make up onecomponent of the demonstration of biosimilarity to a reference product• Analytical similarities – amino acid sequence, molecularweight, complexity, degree of heterogeneity, functional properties,impurity profiles, etc• Extensive, robust comparative physiochemical andfunctional studies – biological assays, binding assays,enzyme kinetics, etc• Comparative stability studies – multiple stress conditions,eg, high temperature, freeze/thaw, light exposure, etc• Describes considerations for additional chemistry,manufacturing, and controls (CMC) information thatmay be relevant to the assessment of biosimilarity• In addition to comparative analytical studies, an assessment of biosimilaritywill generally include animal studies and clinical trials7
FDA Draft Guidance: Scientific Considerationsin Demonstrating Biosimilarity• Overview of FDA’s current thinking on demonstrating biosimilarity by using atotality-of-the-evidence approach to evaluation of scientific data• Discusses FDA’s view on important scientific considerations including• Stepwise approach to demonstrating biosimilarity• Considerations of the complexities of therapeuticprotein products• General scientific principles in conducting structuraland functional analyses and assays• Animals studies, including toxicity, PK/PD, andimmunogenicity studies• Clinical studies, including pharmacology andimmunogenicity studies, and general considerationsfor clinical safety and efficacy data• Extrapolation of clinical data across indications• Postmarketing safety monitoring considerations8
Draft Guidance: Biosimilars: Q&AsRegarding Implementation of the BPCIA• Provides answers to three categories of common questionsfrom sponsors interested in developing biosimilar products• Biosimilarity or interchangeability• Provisions related to a requirement tosubmit a Biologic License Application (BLA)for a “biological product”• Reference product exclusivity• Intended to promote transparency and facilitate developmentprograms for proposed biosimilar products by addressingquestions that may arise in the early stages of developmentQQAA9
FDA’s Stepwise Approach toDemonstrate Biosimilarity• FDA proposes to use risk-based, totality-of-the-evidence approach toevaluate all available data and information• However, FDA has the discretion to determine that an element above isunnecessary for approval10
PhRMA’s Comments on FDA’sProposed “Stepwise” Approach• Evaluation of biosimilars to demonstrate the absence of clinicallymeaningful differences should include comparative molecularevaluations, preclinical studies and clinical testing• Seemingly small changes to a product’s structure or means ofproduction may have unintended clinical consequences• Such consequences may be very difficult to predict, particularly forproducts for which the sponsor lacks extensive manufacturingexperience• A science-based approach should include at least one comparativeclinical trial of adequate size and design to establish that theproposed biosimilar product does not possess clinically meaningfuldifferences in safety and efficacy from its reference product11
• Applicants should minimize controllable process anddesign differences and provide scientific justification forchanges to controllable elements of the proposedbiosimilar product• Intentionally introduced changes may lead to unintendedor unanticipated differences between a biosimilar and itsreference product, and diminish the feasibility of anabbreviated development program• Additional analytical, preclinical, and clinical studies maybe necessary to demonstrate that a proposed biosimilarproduct is highly similar to its reference productPhRMA’s Comments on MinimizingControllable Differences12
PhRMA’s Comments onAnalytical Testing• Multiple analytical procedures thatare sufficiently sensitive should beperformed to detect differencesbetween a proposed biosimilar andreference product• Even state-of-the-art technologymay not identify all differences• Understanding the limitations of theanalytical program will be essentialto design appropriate preclinical andclinical testing to evaluate remaininguncertainties 13
PhRMA’s Comments onPreclinical Testing• In vitro functional assays are important tothe evaluation of biologic activity and thedemonstration of biosimilarity• In vitro studies alone are insufficient toestablish that a proposed biosimilar doesnot possess clinically meaningful differencescompared to a reference product• Preclinical animal testing, based on soundscience and performed according to ICHguidelines, also plays an important role inbiosimilarity assessment14
PhRMA’s Comments onClinical TestingFDA guidance should recognize that:•Clinical testing is essential to determinethat there are no clinically meaningfuldifferences between a proposedbiosimilar product and its referenceproduct•Patient wellbeing should be ensured withimmunogenicity testing and at least onecomparative clinical trial to detect safetyor efficacy differences15
• Each indication for which a biosimilar applicant is seeking approval will needto be supported with clinical data, unless strong scientific justification forextrapolation is provided• Should be sufficiently rigorous to ensure that safety andefficacy can be predicted in an unstudied indication• Applicants seeking to extrapolate data acrosspopulations within an indication should study thepopulation(s) most sensitive to differences in safety,efficacy, and immune response• Important to demonstrate that there are no significantdifferences in PK and bio-distribution• Restricting extrapolation to indications that share the same, well-definedmechanism of action will help to ensure that the disease states are similarand well understoodPhRMA’s Comments onExtrapolation of Clinical DataApproval AApproval A Approval BApproval BIndication AIndication A Indication BIndication BClinical DataClinical Data16
PhRMA’s Comments onImmunogenicity Testing• Biologics have the potential to evoke an immuneresponse; even seemingly small changes to a referencebiologic may significantly alter immunogenicity• FDA should require that pre- and postmarket testing beperformed, including preclinical, clinical, andpostmarketing pharmacovigilance• Increased or decreased immunogenicity relative to areference product may have potentially severe clinicalconsequences• Extrapolation of data to support another indication shouldinclude immunogenicity assessments in the patientpopulation most sensitive to immune responses17
PhRMA’s Comments onProduct Labeling• Product labeling should include a clear statement to indicate whetherthe product is a biosimilar or if it is an interchangeable product• The labels of biosimilars that are not interchangeable should clearlyindicate that the products are not interchangeable with the referenceproduct• However, PhRMA believes that additional labelingis necessary for health professionals to makeinformed prescribing decisions, including:• A description of clinical data (type and quantity) thatsupports the biosimilars indications18
PhRMA’s Comments onPharmacovigilance• The pharmacovigilance plan for each approvedbiosimilar should be tailored to the benefit-risk profileof the biosimilar and the reference product• Postmarket studies and risk evaluation andmitigation strategy (REMS) programs may berequired as part of broader postmarket safetymonitoring• Undetected differences may emerge in thepostmarket period due to the abbreviated premarketprogram, data extrapolation, or product drift19
Naming of Biosimilar Products• Unique non-proprietary names are an essential feature of a robustsystem for adequately tracking adverse events• Biosimilars and their reference products should have unique namesregardless of possible later approval as an “interchangeable” product• Necessary to prevent inappropriate substitution of a non-interchangeableproduct if there are both biosimilar and interchangeable productsavailable for the same reference product20
Summary• A biosimilar is highly similar to, but not the same as, anFDA-licensed reference biologic product• A rigorous, science-based process for evaluating proposedbiosimilars and their reference products – which includes analytical,preclinical, and clinical testing – is essential to ensure the quality,safety, and efficacy of biosimilars• Unique non-proprietary names for biosimilar and interchangeablebiological products are essential to a robust pharmacovigilancesystem that adequately protects patient safety• The decision to take a particular biological medicine should be madewith the oversight and guidance of a physician• Patient well-being is the paramount concern• Incentive for continued innovation of biologics is critical to ensurepatient access to new medicines21