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U.S. Department of Health and Human Services

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Guidance for Industry on Biosimilars: Q & As Regarding Implementation of the BPCI Act of 2009: Questions and Answers Part I

 Table of Contents

PART I. BIOSIMILARITY OR INTERCHANGEABILITY

Q.I.1. 

Whom should a sponsor contact with questions about its biosimilar development program?

Q.I.2.When should a sponsor request an initial meeting with FDA and what data and information should a sponsor provide to FDA as background for a proposed biosimilar development program? 
Q.I.3.

Can a proposed biosimilar product have a different formulation than the reference product?

Q.I.4.

Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product? 

Q.I.5. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed?
Q.I.6. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?
Q.I.7. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?
Q.I.8.Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is biosimilar to the reference product?
Q.I.9.Is a clinical study to assess the potential of the biological product to delay cardiac repolarization (a QT/QTc study) or a drug-drug interaction study generally needed for licensure of a proposed biosimilar product?
Q.I.10.
Q.I.11.Can an applicant extrapolate clinical data intended to support a demonstration of biosimilarity in one condition of use to support licensure of the proposed biosimilar product in one or more additional conditions of use for which the reference product is licensed?
Q.I.12.How can an applicant demonstrate that its proposed injectable biosimilar product has the same “strength” as the reference product?
Q.I.13.What constitutes “publicly-available information” regarding FDA’s previous determination that the reference product is safe, pure, and potent to include in a 351(k) application?
Q.I.14.Can an applicant obtain a determination of interchangeability between its proposed product and the reference product in an original 351(k) application?
Q.I.15.Is a pediatric assessment under the Pediatric Research Equity Act (PREA) required for a proposed biosimilar product?
  
  
Q.I.1.Whom should a sponsor contact with questions about its biosimilar development program?
A.I.1. 

(Proposed Answer): If the reference product for a proposed biosimilar product is regulated by the Center for Drug Evaluation and Research (CDER), contact the Biosimilars Program Staff in CDER’s Office of New Drugs at 301-796-0700. 

If the reference product for a proposed biosimilar product is regulated by the Center for Biologics Evaluation and Research (CBER), contact the Office of Communication, Outreach and Development (OCOD) at 800-835-4709 or 301-827-1800 or by email to ocod@fda.hhs.gov.  

For general questions related to FDA’s implementation of the BPCI Act, contact Sandra Benton in CDER’s Office of Medical Policy at 301-796-2500.
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Q.I.2.     
When should a sponsor request an initial meeting with FDA and what data and information should a sponsor provide to FDA as background for a proposed biosimilar development program?
A.I.2.(Proposed Answer): FDA recommends that sponsors of proposed biosimilar products request an initial meeting with FDA at such time as the sponsor can provide a proposed plan for its biosimilar development program, manufacturing process information (including planned methodology and assay validation), and preliminary comparative analytical data with the reference product. 
 
Comparative analytical data provide the foundation for a biosimilar development program and can influence decisions about the type and amount of animal and clinical data needed. Such data should be available early in development and allow for a more detailed discussion with the Agency. FDA will best be able to provide meaningful input on the extent and scope of animal and clinical studies for a proposed biosimilar development program once the Agency has considered the comparative analytical data.
Q.I.3.Can a proposed biosimilar product have a different formulation than the reference product?
 
A.I.3.(Proposed Answer): Yes, differences between the formulation of a proposed product and the reference product may be acceptable.  A 351(k) application must contain information demonstrating that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. In addition, an applicant would need to demonstrate that there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency. It may be possible, for example, for a proposed product formulated without human serum albumin to demonstrate biosimilarity to a reference product formulated with human serum albumin. For more information about FDA’s current thinking on the interpretation of the statutory standard for biosimilarity, see FDA’s draft guidances for industry on Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product and Scientific Considerations in Demonstrating Biosimilarity to a Reference Product                                
Q.I.4.      Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product?
A.I.4. (Proposed Answer): Yes, some design differences in the delivery device or container closure system used with the proposed biosimilar product may be acceptable. It may be possible, for example, for an applicant to obtain licensure of a proposed biosimilar product in a pre-filled syringe or in an auto-injector device (which are considered the same “injectable” dosage form), even if the reference product is licensed in a vial presentation, provided that the proposed product meets the statutory standard for biosimilarity and adequate performance data for the delivery device or container closure system are provided. For a proposed biosimilar product in a different delivery device or container closure system, the presentation must be shown to be compatible for use with the final formulation of the biological product through appropriate studies, including, for example, extractable/leachable studies and stability studies. Also, for certain design differences in the delivery device or container closure system, performance testing and a human factors study may be needed. 
 
However, a prospective biosimilar applicant will not be able to obtain licensure under section 351(k) for its product when a design difference in the delivery device or container closure system results in:
  • a clinically meaningful difference between the proposed product and the reference product in terms of safety, purity, and potency;
  • a different route of administration or dosage form; or
  • a condition of use for which the reference product has not been previously approved;
or otherwise does not meet the standard for biosimilarity. 
 
Additional considerations apply for a proposed interchangeable product. For example, in reviewing an application for a proposed interchangeable product, FDA may consider whether the differences from the reference product significantly alter critical design attributes, product performance, or operating principles, or would require additional instruction to healthcare providers or patients, for patients to be safely alternated or switched between the reference product and one or more interchangeable products without the intervention of the prescribing healthcare provider. Additional performance data about the delivery device may also be necessary.
 
A proposed biosimilar product in a delivery device will be considered a combination product and may, in some instances, require a separate application for the device.
Q.I.5. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed?
A.I.5.
(Proposed Answer): Yes, an applicant may obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed. An applicant must demonstrate that there are no clinically meaningful differences between the proposed biosimilar product and the reference product in terms of safety, purity, and potency. This may include providing information from one or more studies using a route of administration for which licensure is not requested (e.g., a study using subcutaneous administration may provide a more sensitive comparative assessment of immunogenicity of the reference product and a proposed biosimilar product, even though licensure of the proposed biosimilar product is requested only for the intravenous route of administration). 
Q.I.6.
Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?
A.I.6.
(Proposed Answer): Yes, an applicant is not required to obtain licensure for all presentations for which the reference drug is licensed. However, if an applicant seeks licensure for a particular indication or other condition of use for which the reference product is licensed and that indication or condition of use corresponds to a certain presentation of the reference product, the applicant may need to seek licensure for that particular presentation (see also responses to Q4 and Q5).    
Q.I.7.Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?
A.I.7.(Proposed Answer): Yes, a biosimilar applicant generally may obtain licensure for fewer than all conditions of use for which the reference product is licensed. The 351(k) application must include information demonstrating that the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling submitted for the proposed biosimilar product have been previously approved for the reference product (see section 351(k)(2)(A)(i)(III) of the PHS Act).
Q.I.8. Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is biosimilar to the reference product?
A.I.8.(Proposed Answer): Yes, a sponsor may use a non-U.S.-licensed comparator product in certain studies to support a demonstration that the proposed biological product is biosimilar to the U.S.-licensed reference product. However, as a scientific matter, analytical studies and at least one clinical pharmacokinetic (PK) study and, if appropriate, at least one pharmacodynamic (PD) study, intended to support a demonstration of biosimilarity must include an adequate comparison of the proposed biosimilar product directly with the U.S.-licensed reference product. We note, however, that for certain complex biological products, a modified approach may be needed.
 
If a sponsor seeks to use data from an animal study or a clinical study comparing its proposed biosimilar product to a non-U.S.-licensed product to address, in part, the requirements under section 351(k)(2)(A) of the PHS Act, the sponsor should provide adequate data or information to scientifically justify the relevance of these comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product. The type of bridging data needed likely would include a clinical PK and/or PD study conducted with the U.S.-licensed reference product.
 
Issues that a sponsor may need to address to use a non-U.S.-licensed comparator product in a biosimilar development program include, but are not limited to, the following:
 
  • the relevance of the design of the clinical program to support a demonstration of biosimilarity to the U.S.-licensed reference product for the condition(s) of use and patient population(s) for which licensure is sought;
  • the relationship between the license holder for the non-U.S.-licensed product and BLA holder for the U.S.-licensed reference product, including whether the non-U.S.-licensed product, and/or any components thereof, are manufactured in the same facility(ies) as the U.S.-licensed reference product during the relevant time period; 
  • whether the non-U.S.-licensed product was manufactured in a facility(ies) licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA (e.g., International Conference on Harmonisation (ICH) countries);
  • whether the non-U.S.-licensed product was licensed by a regulatory authority that has similar scientific and regulatory standards as FDA (e.g., ICH countries) and the duration and extent to which the product has been marketed; and
  • the scientific bridge between the non-U.S.-licensed product and the U.S.-licensed reference product, including comparative physico-chemical characterization, bioassays/functional assays, and comparative clinical and/or nonclinical PK and/or PD data, as appropriate, and data to address any differences in formulation or primary packaging.
 
A sponsor also should address any other factors that may affect the relevance of comparative data with the non-U.S.-licensed product to an assessment of biosimilarity with the U.S.-licensed reference product.
 
A sponsor may submit publicly available information regarding the non-U.S.-licensed product to justify the extent of comparative data needed to establish a bridge to the U.S.-licensed reference product. Sponsors are encouraged to discuss with FDA during the development program the adequacy of the scientific justification and bridge to the U.S.-licensed reference product. A final decision about the adequacy of this scientific justification and bridge will be made by FDA during review of the 351(k) application.
 
At this time, as a scientific matter, it is unlikely that clinical comparisons with a non-U.S.-licensed product would be an adequate basis to support the additional criteria required for a determination of interchangeability with the U.S.-licensed reference product.
Q.I.9.Is a clinical study to assess the potential of the biological product to delay cardiac repolarization (a QT/QTc study) or a drug-drug interaction study generally needed for licensure of a proposed biosimilar product?
A.I.9.(Proposed Answer): No. In general, a proposed biosimilar product may rely upon the reference product’s clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential and drug-drug interactions.  
Q.I.10.How long should sponsors retain reserve samples of the biological products used in comparative clinical PK and/or PD studies intended to support a 351(k) application?
A.I.10.
(Proposed Answer): The requirements in 21 CFR 320.38 and 320.63 for retention of reserve samples of the products used in bioavailability and bioequivalence studies apply to applications submitted under section 505 of the FD&C Act. However, FDA recommends that the sponsor of a proposed biosimilar product retain reserve samples in the same manner and for the same time period (at least 5 years) as described in 21 CFR 320.38 and 320.63 following a comparative clinical PK or PD study of the reference product and the proposed biosimilar product (or other clinical study in which PK or PD samples are collected) that is intended to support a submission under section 351(k) of the PHS Act. Retention of samples used in a comparative clinical PK or PD study or other clinical study in which PK or PD samples are collected would serve the same purpose described in the Final Rule for the cited regulations (58 FR 25918, April 28, 1993). Specifically, reserve samples establish the identity of the products tested in the actual study, allow for confirmation of the validity and reliability of the results of the study, and facilitate investigation of further follow-up questions that arise after the studies are completed.
Q.I.11.Can an applicant extrapolate clinical data intended to support a demonstration of biosimilarity in one condition of use to support licensure of the proposed biosimilar product in one or more additional conditions of use for which the reference product is licensed?
A.I.11. (Proposed Answer): Yes. If the proposed product meets the statutory requirements for licensure as a biosimilar product under section 351(k) of the PHS Act based on, among other things, data derived from a clinical study sufficient to demonstrate safety, purity, and potency in an appropriate condition of use, the potential exists for the biosimilar product to be licensed for one or more additional conditions of use for which the reference product is licensed. However, the applicant would need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarity for each condition of use for which licensure is sought. 
 
Such scientific justification for extrapolation should address, for example, the following issues for the tested and extrapolated conditions of use:
 
  • the mechanism(s) of action in each condition of use for which licensure is sought; this may include:
    • the target/receptor(s) for each relevant activity/function of the product;
    • the binding, dose/concentration response and pattern of molecular signaling upon engagement of target/receptors;
    • the relationships between product structure and target/receptor interactions;
    • the location and expression of the target/receptor(s);
  • the PK and bio-distribution of the product in different patient populations (relevant PD measures also may provide important information on the mechanism of action);
  • differences in expected toxicities in each condition of use and patient population (including whether expected toxicities are related to the pharmacological activity of the product or to “off-target” activities); and
  • any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which licensure is sought.
Q.I.12.How can an applicant demonstrate that its proposed injectable biosimilar product has the same “strength” as the reference product?
A.I.12. (Proposed Answer): Under section 351(k)(2)(A)(i)(IV) of the PHS Act, an applicant must demonstrate that the “strength” of the proposed biosimilar product is the same as that of the reference product. As a scientific matter, there may be a need to take into account different factors and approaches in determining the “strength” of different types of biological products. 
 
In general, we expect injectable biological products to have both the same total content of drug substance (in mass or units of activity in a container closure) and the same concentration of drug substance (in mass or units of activity per unit volume) as the reference product to have the same “strength” under section 351(k)(2)(A)(i)(IV) of the PHS Act. We note, however, that for certain complex biological products, a modified approach may be needed.
 
The total content of drug substance generally should be expressed using the same measure as the reference product. For example, if the strength of the reference product is expressed as milligrams (mg) per total volume in a container closure, for example mg/5 milliliters (mL), the proposed biosimilar product generally should also describe its strength in mg/5 mL, rather than units per 5 mL. If the total content of drug substance is expressed in units of activity (e.g., international units (IU) or units per total volume in a container closure), the units of the proposed biosimilar product should be the same as the reference product.
 
The concentration of the drug substance (in mass or units of activity per unit volume) generally should be expressed using the same measure as the reference product. The extinction coefficient used to calculate the concentration of a protein drug substance should be determined experimentally, and a justification for the experimental method should be provided.  If the proposed biosimilar product is a dry solid (e.g., lyophilized) from which a constituted or reconstituted solution is prepared, then the 351(k) application should contain information demonstrating that the concentration of the proposed biosimilar product, when constituted or reconstituted, is the same as that of the reference product.
 

The requirement for a 351(k) application to contain information demonstrating that the proposed product and the reference product have the same “strength” applies to both biosimilar products and interchangeable products. 

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Q.I.13.What constitutes “publicly-available information” regarding FDA’s previous determination that the reference product is safe, pure, and potent to include in a 351(k) application?
A.I.13.
(Proposed Answer): “Publicly-available information” in this context generally includes the types of information found in the “action package” for a BLA (see section 505(l)(2)(C) of the FD&C Act). However, FDA notes that submission of publicly available information composed of less than the action package for the reference product BLA will generally not be considered a bar to submission or approval of an acceptable 351(k) application.
 
FDA intends to post on the Agency’s Web site publicly available information regarding FDA’s previous determination that certain biological products are safe, pure, and potent in order to facilitate biosimilar development programs and submission of 351(k) applications. We note, however, that the publicly available information posted by FDA in this context does not necessarily include all of the information that would otherwise be disclosable in response to a Freedom of Information Act request.
Q.I.14.
Can an applicant obtain a determination of interchangeability between its proposed product and the reference product in an original 351(k) application?
A.I.14. (Proposed Answer): Yes. Under the BPCI Act, FDA can make a determination of interchangeability in a 351(k) application or any supplement to a 351(k) application. An interchangeable product must be shown to be biosimilar to the reference product and meet the other standards described in section 351(k)(4) of the PHS Act. At this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application given the statutory standard for interchangeability and the sequential nature of that assessment. FDA is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.                          
Q.I.15.Is a pediatric assessment under the Pediatric Research Equity Act (PREA) required for a proposed biosimilar product?

A.I.15. 

(Proposed Answer): Under the Pediatric Research Equity Act (PREA) (section 505B of the FD&C Act), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain a pediatric assessment to support dosing, safety, and effectiveness of the product for the claimed indication unless this requirement is waived, deferred, or inapplicable. 

Section 505B(n) of the FD&C Act, added by section 7002(d)(2) of the Affordable Care Act, provides that a biosimilar product that has not been determined to be interchangeable with the reference product is considered to have a “new active ingredient” for purposes of PREA, and a pediatric assessment is required unless waived or deferred. An interchangeable product is not considered to have a “new active ingredient” for purposes of PREA. If a biological product is determined to be interchangeable with the reference product, a pediatric assessment of the interchangeable product is not required.  

FDA encourages prospective biosimilar applicants to submit plans for pediatric studies during the investigational new drug (IND) stage of product development. See also the guidance for industry, How to Comply with the Pediatric Research Equity Act.