FDA has tweaked its biosimilars guidances to give sponsors more information about how to bridge data, extrapolate from one condition, choose a study population, and conduct immunogenicity testing.

At the end of April, the agency issued three final guidances with modifications to draft documents published in 2012 Also see "FDA Biosimilars Guidances Address Immunogenicity Studies, European Bridge Data, Analytics" - Pink Sheet, 9 February, 2012.. And on May 13, FDA released a draft guidance on additional questions and answers regarding implementation of the Biologics Price Competition and Innovation Act, which established the 351(k) approval pathway for biosimilars.

The new Q&A provides advice on how to conduct pediatric assessments and addresses dosage formulation, among other things; comments are due by July 13. Together the guidances give sponsors more clarity as to the information they need to submit a 351(k) application.

They “reflect the evolution of FDA’s understanding” of biosimilars as it has worked with companies going through the process of getting an application, Stacie Ropka, counsel at Axinn, Veltrop & Harkrider, said. “Sometimes reality is a great teacher.”

“There are cases where a study population could be different from that in the clinical studies that supported the licensure of the reference product,” FDA guidance says.

FDA approved its first biosimilar, Sandoz Inc.’s Zarxio (filgrastim-sndz), a biosimilar to Amgen Inc.’s Neupogen (filgrastim), in March ([A#14150306001]). The launch has been delayed until the U.S. Court of Appeals for the Federal Circuit resolves litigation over the patent information exchange provisions of the BPCIA ([A#14150506004]).

One of the most notable changes in the guidances is the fact that FDA no longer requires that the study population used in a comparative clinical study to demonstrate biosimilarity be the same as that used by the reference product sponsor, Ropka said.

In its final guidance on scientific considerations in demonstrating biosimilarity to a reference product, FDA states that the choice of a study population should allow for an assessment of clinically meaningful differences between the proposed product and the reference product.

“Often the study population will have characteristics consistent with those of the population studied for the licensure of the reference product for the same indication,” the guidance states.

“However, there are cases where a study population could be different from that in the clinical studies that supported the licensure of the reference product. For example, if a genetic predictor of response was developed following licensure of the reference product, it may be possible to use patients with the response marker as the study population.”

Ropka said this is ethically a better way to go since you would not want to give a drug to someone you knew would not respond to it.

How To Build A Bridge To The U.S.

The agency also provides more details on the data necessary for a sponsor to use a non-U.S.-licensed product in animal or clinical studies to support biosimilarity to the U.S.-licensed reference product.

“As a scientific matter, the type of bridging data needed will always include data from analytical studies (e.g., structural and functional data) that directly compare all three products (i.e., the proposed biosimilar product, the U.S.-licensed reference product and the non-U.S.-licensed comparator product), and is likely to also include bridging clinical PK [pharmacokinetic] and/or PD [pharmacodynamic] study data for all three products,” the final Q&A guidance says. “All three pairwise comparisons should meet the pre-specified acceptance criteria for analytical and PK and/or PD similarity.”

The guidance says FDA also may consider whether the formulation, dosage form and strength of the U.S. reference product and non-U.S. comparator products are the same, their route of administration, and the scientific justification of the non-U.S. licensed comparator lots to establish the scientific bridge and how they relate to the material used in nonclinical and clinical studies.

The final guidance on quality considerations adds that a sponsor using a non-U.S. licensed comparator product may also need to address “comparative physicochemical characterization, biological assays/functional assays, degradation profiles under stressed conditions, and comparative clinical PK and, when appropriate, PD data, to address the impact of any differences in formulation or primary packaging on product performance.”

Extrapolating From One Indication To Another

FDA also expands its directions for companies that want to extrapolate clinical data to support biosimilarity for one condition of use to additional conditions of use for which the reference product has been approved.

In the final Q&A guidance, FDA recommends that in choosing a condition of use to study that would permit subsequent extrapolation of clinical data to other conditions, a sponsor consider choosing one “that would be adequately sensitive to detect clinically meaningful differences between the two products.”

In addition, the agency suggests a sponsor not choose a condition for which the reference product sponsor obtained accelerated approval and has not yet obtained verification of clinical benefit in postmarketing trials.

FDA also says that scientific justification for extrapolation should address the immunogenicity of the product in different patient populations.

And in the scientific considerations guidance, FDA says that in seeking to extrapolate immunogenicity findings for one condition of use to other conditions of use, “the sponsor should consider using a study population and treatment regimen that are adequately sensitive for predicting a difference in immune response between the proposed product and the reference product across conditions of use.”

The draft guidance had advised using a study population and treatment regimen this is “most sensitive” for predicting a difference in immune response.

Labeling To Make No Distinction Between Biosimilar And Interchangeable

FDA notes that it will address the issue of interchangeability of a biosimilar and reference product in a forthcoming guidance. But FDA did make a change with regard to labeling and interchangeability.

The scientific considerations draft guidance stated that labeling of a proposed product should include a statement that it has or has not been determined to be interchangeable with the reference product. That requirement was removed from the final guidance.

Republican Senators objected to this change in a letter to FDA Acting Commissioner Stephen Ostroff ([A#14150430003]).

But Axinn, Veltrop’s Ropka said dropping the interchangeability reference “could be a deletion without actual meaning.” She said that if FDA decides that a biosimilar must have a unique name rather than use the internationally recognized chemical name that “should signal to health care professionals that it’s a biosimilar and not interchangeable.”

FDA has yet to determine a naming policy. It gave Zarxio a “placeholder” nonproprietary name, attaching a suffix to the chemical name ([A#14150306005]).

FDA dropped a question on interchangeability from the final Q&A guidance and included it in the additional Q&A draft guidance. The agency reiterated that it can make the determination that a biosimilar is interchangeable in the 351(k) application or any supplement to the application but that “at this time, it would be difficult as a scientific matter” for an application to establish interchangeability in the original application.

In response to the draft guidances issued in 2012, some stakeholders criticized FDA’s demand for a higher standard of evidence to show interchangeability Also see "Biosimilar Interchangeability: Stakeholders Want More FDA Guidance, Fewer Hurdles" - Pink Sheet, 30 April, 2012..

Pros And Cons For Sponsors

James Shehan, of counsel with Hyman, Phelps & McNamara, said in an FDA Law Blog post that some of the changes in the guidances seem to make biosimilar approval easier while others potentially make it more difficult.

Among those beneficial to sponsors, he noted that the requirement that a sponsor compare its proposed biosimilar product directly with the U.S.-licensed reference product now includes the qualifier “unless it can be scientifically justified that such a study is not needed.” He said this opens the door to using products from outside the U.S.

In addition, Shehan said FDA reiterated its preference for a step-wise approach to demonstrate biosimilarity, but added that some tests could be performed “in parallel.” He also pointed to the change in choice of study populations and the direction that sponsors choose an indication to extrapolate from that is adequately sensitive rather than “most sensitive” as beneficial for biosimilar sponsors.

As for revisions that could possibly heighten biosimilarity standards, he noted several changes in the scientific considerations guidance pertaining to structural analyses, clinical studies and immunogenicity studies.

FDA wants Immunogenicity data for every clinical study – including PK and PD studies.

With regard to immunogenicity, the guidance states that FDA expects a sponsor to conduct comparative human PK and PD studies, if there is a relevant PD measure, and a clinical immunogenicity assessment.

“In certain cases, the results of these studies may provide adequate clinical data to support a conclusion that there are no clinically meaningful differences between the proposed biosimilar product and the reference product. However, if residual uncertainty about biosimilarity remains after conducting these studies, an additional comparative clinical study or studies would be needed to further evaluate whether there are clinically meaningful differences between the two products,” the guidance says.

FDA also “encourages that, where feasible, sponsors collect immunogenicity data in any clinical study, including human PK or PD studies.”

FDA recommends use of a comparative parallel design (i.e., a head-to-head study) in treatment-naïve patients as the most sensitive design for a premarketing study to assess potential difference in the risk of immunogenicity.

Depending on the clinical experience of the reference and proposed products, “a sponsor may need to evaluate a subset of patients to provide a substantive descriptive assessment of whether a single cross-over from the reference product to the proposed biosimilar would result in a major risk in terms of hypersensitivity, immunogenicity, or other reactions,” the guidance says.

In other changes, FDA says that process-related impurities in the proposed product should be assessed side-by-side with impurities in the reference product. And when a sponsor considers manufacturing changes after completing the initial analytical similarity assessment or after completing clinical testing, it should perform an additional analytical similarity assessment with lots manufactured by the new process and the reference product and establish comparability of the proposed product.

Lyophilized Powder Is Not Same Dosage Form As An Injection

The fourth guidance on additional questions and answers addresses dosage formulations. FDA poses the question: For biological products intended to be injected, how can an applicant demonstrate that its proposed biosimilar product has the same ‘dosage form’ as the reference product?”

The guidance says FDA considers “injection” (e.g., a solution) to be a different dosage form from “for injection” (e.g., a lyophilized powder).

“Thus, if the reference product is an ‘injection,’ an applicant could not obtain licensure of a proposed biosimilar ‘for injection’ even if the applicant demonstrated that the proposed biosimilar product, when constituted or reconstituted, could meet the other requirements for an application for a proposed biosimilar product,” the draft guidance states.

The guidance also advises sponsors how to satisfy the requirement for a pediatric assessment under the Pediatric Research Equity Act. The statute enables a sponsor to conduct studies in one population, such as adults or older pediatric populations, and extrapolate efficacy findings. The guidance also notes that sponsors should submit an initial pediatric study plan no later than 60 calendar days after the date of an end-of-Phase II meeting, or at another time agreed upon with FDA.

With regard to the importation of a non-U.S. licensed product to support a biosimilar development program, FDA says a sponsor does not need to submit a separate IND.

Exclusivity Still An Administrative Hurdle

The additional Q&A draft guidance includes the same question on exclusivity that appeared in the first Q&A document. The agency says a BLA applicant can include a request for reference product exclusivity in its BLA submission and FDA will consider the applicant’s assertions regarding the eligibility of its product for exclusivity.

Brand pharma and biotech stakeholders had objected to this approach in comments on the initial draft guidances. They said BLA sponsors should not have to request and justify the award of 12 years of innovator exclusivity Also see "FDA Biosimilar Guidances Stir Innovator Worries About BLA Exclusivity, Trade Secrets" - Pink Sheet, 30 April, 2012..

In August 2014, the agency issued a draft guidance specifying the types of information that sponsors of biological products need to submit to show that a product qualifies as the first licensed reference product ([A#14140804005]).

Amgen, Hospira Voice General Support For Guidances

Members of industry offered broad support for the four guidances.

“As a biosimilar sponsor, we are generally pleased with the approach the FDA is taking in its draft guidances and we encourage a continued trajectory of sound, patient-based decisions for a sustainable pathway,” Amgen said in a statement.

Hospira Inc. said it was pleased FDA issued the final guidance documents and pointed to two provisions as particularly noteworthy. It said the guidances reinforce the agency’s support of extrapolation across indications and confirm that a biosimilar sponsor may use data from a non-U.S. licensed comparator to support its application for biosimilarity.

Biosimilar Guidances: Broader Populations Permitted; More Immunogenicity Requested

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