Leah Christl, Ph.D., Associate Director for Therapeutic Biologics and lead of the Therapeutic Biologics and Biosimilars Staff in the Office of New Drugs, discusses new guidance for developing interchangeable biological products
Therapeutic biological products
A therapeutic biological product may be approved as an originator, biosimilar, or interchangeable product. In an earlier From our perspective article, I compared the type of data and information needed to support approval of an originator product with that needed to support approval of a biosimilar product. In short, an originator product is approved based on a full profile of nonclinical and clinical data that demonstrate its safety and effectiveness, and a biosimilar product’s approval is based on an array of comparative data that show it is highly similar to and has no clinically meaningful differences from the reference product (an originator product may serve as a reference product for a biosimilar).
New guidance for developing interchangeable biological products
With the release of the draft Guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” we have now presented our recommendations on the data and information expected for a product to meet the standard for interchangeability.
To support a demonstration of interchangeability, the data and information submitted to FDA must show that a proposed interchangeable product is biosimilar to the reference product and that it can be expected to produce the same clinical results as the reference product in any given patient. Also, for products that will be administered more than once, the data and information must show that switching a patient back and forth between the reference product and the proposed interchangeable product presents no greater risk to the patient in terms of safety or diminished efficacy when compared to treating them with the reference product continuously.
Building confidence and increasing access
Although the data requirements for approval of originator, biosimilar, and interchangeable products vary, all biological product applications are reviewed based on the data and information provided by the applicant, and approved only after they meet FDA’s rigorous approval standards. The approval standards that apply to each category of product ensure that a product is safe and effective. Patients can be assured that an FDA-approved interchangeable biological product has been thoroughly tested.
FDA’s high standards for approval should also assure healthcare professionals that they can be confident in the safety and effectiveness of an interchangeable product, just as they would be for a reference product. The availability of biosimilar and interchangeable products in the U.S. marketplace will provide more treatment options, which will hopefully drive down costs to give more patients access to treatment.
Prescribing biological products
Corresponding with their standard practices, we advise healthcare professionals to review the product’s labeling before prescribing to be sure that a product is appropriate for their patient’s needs. Generally speaking, providers can prescribe biosimilar and interchangeable products just as they would prescribe other medications, by writing the product’s proprietary or nonproprietary name on the prescription.
Biological product substitution
A product approved as an interchangeable may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. Patients and healthcare professionals should be aware that once interchangeable biological products are available in the United States, some states may permit an interchangeable product to be substituted for the reference product – a practice commonly called pharmacy-level substitution.
Many states and state boards of pharmacy have passed laws or regulations that address the pharmacy-level substitution of products, and substitution laws and regulations may vary from state-to-state. FDA encourages healthcare professionals to maintain familiarity with the available biological products and with state laws and regulations regarding substitution to be aware of the potential for their patients to encounter a pharmacy-level product substitution.
Online resources for biological product information
FDA has published the “Purple Book” as an online resource for healthcare professionals and patients to locate information about currently approved biological products. Its official title is “Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations,” and as the name suggests, it will tell readers if a biological product of interest is an originator, biosimilar, or interchangeable product.
Another dependable online resource for product-specific information is our Drugs@FDA website. Patients and healthcare professionals who want to dive deep into FDA’s review of the data that were used to support approval of a biological product can search the Drugs@FDA database for this information.
To show that a biological product is interchangeable with its reference product, applicants can build upon a demonstration of biosimilarity. The complex nature of biological products means that there is no one-size-fits-all approach across the product landscape to the data needed to demonstrate biosimilarity. It follows that the data needed to demonstrate interchangeability are also determined on a case-by-case basis depending on considerations such as the complexity of the product, the reference product’s indications and the potential for immune system complications.
The data that support biosimilarity generally include a thorough structural and functional characterization of the product; any necessary animal studies; a comparative evaluation of pharmacokinetics (measures of drug exposure); and when appropriate, pharmacodynamic (measures of drug effect at a given drug exposure), clinical immunogenicity assessments and any necessary clinical safety and effectiveness studies. In addition to demonstrating biosimilarity, a sponsor of a proposed interchangeable product must submit data and information to show that the biological product can be expected to produce the same clinical result as the reference product in any given patient. As described in the newly released draft guidance, FDA expects that sponsors will submit data and information to support a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in all of the reference product’s licensed conditions of use. These data and information may vary depending on the nature of the proposed interchangeable product, and can include an evaluation of the data and information already generated to support a demonstration of a biological product’s biosimilarity.
For biological products that are administered to an individual patient more than once, the applicant must also provide data and information to demonstrate that the risk in terms of safety or diminished efficacy of switching between the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without switching. FDA expects that applications generally will include data from a switching study or studies in one or more appropriate conditions of use to assess the risk, in terms of safety and diminished efficacy, of alternating or switching between the products. Applications may also include a scientific rationale to extrapolate data and information supporting a demonstration of interchangeability in an appropriate condition of use to the remaining conditions of use for which the reference product is licensed and for which licensure is sought for the interchangeable product.
In addition, depending on the product, data showing that patients or caregivers can appropriately use the interchangeable product delivery device without additional training may be needed.
As with the step-wise generation and evaluation of data to demonstrate biosimilarity, we recommend that applicants use a step-wise approach to address any residual uncertainty about interchangeability when developing and testing their proposed interchangeable product.
As you can see, there are a variety of factors that influence the amount of data and information that may be needed to demonstrate interchangeability. There is no single data package that will work for all proposed interchangeable products. With this in mind, we recommend that applicants developing a proposed interchangeable product meet with FDA early in their development process to discuss their plans.
Share your thoughts
The draft guidance that we’ve published outlines the considerations for demonstrating interchangeability, and represents our current thinking on development and testing for proposed interchangeable products. If you are interested in commenting, visit the draft guidance docket and provide your thoughts on our approach. We are also seeking comments on the topics addressed in the Notice of Availability on the draft guidance document, including post-approval regulation of these products once they are available in the United States.
As we gain more experience with biosimilars and interchangeable products, it is inevitable that new information and questions will emerge. As always, we’ll work with the community to find answers, reevaluate our approaches, when appropriate, and reinforce public confidence in the safety, quality and effectiveness of FDA-approved products.
Biography for Leah Christl
Dr. Christl is the Associate Director for Therapeutic Biologics in the Office of New Drugs (OND) in the FDA's Center for Drug Evaluation and Research. Dr. Christl leads the Therapeutic Biologics and Biosimilars Staff (TBBS) in OND. TBBS is responsible for ensuring consistency in the scientific and regulatory approach and in advice to sponsors regarding development programs for proposed biosimilar products and related issues regarding development programs for therapeutic biologics. Prior to joining the FDA, Dr. Christl received her Ph.D. in Molecular and Cellular Biology and Pathobiology – Marine Biomedicine and Environmental Science, from the Medical University of South Carolina in Charleston. She also spent two years at the University of South Carolina as an Associate Research Professor.