The three draft Guidances recently released by the U.S. Food and Drug Administration on implementation of the Biologics Price Competition and Innovation Act of 2009 focus on how to demonstrate biosimilarity but don’t say much about demonstrating interchangeability. FDA has asked for stakeholder input on biosimilar interchangeability at the agency’s upcoming one-day public hearing on the biosimilar draft Guidances to be held on May 11, 2012. Docket No. FDA-2011-D-0618. However, there are a few tidbits on interchangeability in the draft Guidances.
By statute, to be found interchangeable, a biological product must:
- Be biosimilar to the reference product;
- Be expected to produce the same clinical result as the reference product in any given patient; and
- If the product will be administered more than once to a patient, the risk (in terms of safety or diminished efficacy) associated with switching between the product and the reference product cannot be greater than the risk of repeated use of the reference product.
There are two potentially significant implications of FDA determining that a product is interchangeable with a reference product. First, an FDA finding of interchangeability means the product “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” An important unanswered question is how this federal statutory definition will intersect with state laws governing pharmacy substitution of prescribed drugs. Second, the first biological product found to be interchangeable with a given reference product receives a period of exclusivity during which no other product can be approved as interchangeable to the same reference product.
Statements on Interchangeability in the Draft Guidances
For those awaiting guidance on interchangeability, the draft Guidances released in February provide remarkably little, but there are a few statements of interest.
FDA is not sure what data will be needed to demonstrate interchangeability
The Q&A Guidance (PDF) affirms the ability to file for and achieve an interchangeability determination in an initial 351(k) application, as well as in a supplement, and in the same paragraph states:
“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&A I.14.)
Interchangeability applies to delivery device
Differences in products’ delivery devices or container closures may be relevant to interchangeability.
“(D)esign differences in the delivery device or container closure system used with the proposed biosimilar product may be acceptable. . . . 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.” (Q&A I.4.)
Interchangeability (or not) should be stated in the label
In the section on labeling of the Scientific Considerations Guidance (PDF), mention is made that labeling should clearly indicate “This product (has or has not) been determined to be interchangeable with the reference product.” (Scientific Considerations at 21)
Foreign-reference product data not likely to support interchangeability
While elaborating on the considerations for sponsors in the use of comparative non-clinical and clinical data with a non-U.S.-licensed product, FDA notes that such data are unlikely to fulfill the additional requirements to support interchangeability.
“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&A I.8)
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So, although the Guidances provide significant information and direction regarding biosimilarity and biosimilar applications, FDA’s thinking on interchangeability – or at least what the agency is willing to say publicly about its thinking – is not as advanced. The May 11 public hearing may be an opportunity to learn more, identify to FDA issues that need to be addressed, and perhaps propose how they should be addressed.