FDA Publishes New Draft Guidance on Biosimilars As Congress Raises Questions About FDA’s Use of Draft Guidance Documents

Jun 03, 2014   

As we previously reported here, here, and here, the U.S. Food and Drug Administration (“FDA”) has been drafting guidance regarding the regulation of biosimilars since as early as 2011. A biological product is biosimilar if it is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and if 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.” See section 351(i)(2) of the PHS Act here. The biosimilar approval process is an abbreviated pathway for FDA licensure of biological products that are demonstrated to be biosimilar to or interchangeable with an FDA-licensed reference product under the Biologics Price Competition and Innovation Act (“BPCIA”).

In 2012, the FDA released three guidance documents, which outlined its expectations for submitting applications for biosimilar products to FDA pursuant to the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). Together, these three draft guidances provided industry with general questions and answers regarding the implementation of BPCIA, as well as scientific and quality considerations for demonstrating biosimilarity to a reference product. The following year, the FDA released a fourth draft guidance document outlining the procedures for formal meetings that occur between the FDA and sponsors or applicants during the development phase of a biosimilars. Since then, manufacturers of biological products have eagerly anticipated the FDA’s release of final guidance.

On May 14, 2014, instead of issuing final guidance on biosimilars, the FDA issued yet another draft guidance document, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. According to the FDA, this draft guidance is “intended to assist biological product sponsors with the design and use of clinical pharmacology studies to support a showing that a proposed therapeutic biological product is ‘biosimilar’ to its reference product under [BPCIA].” This draft guidance specifically applies to products for which pharmacokinetic (“PK”) and pharmacodynamic (“PD”) data are required to help demonstrate biosimilarity.

Summary of FDA’s Draft Guidance on Clinical Pharmacology Data to Support a Demonstration of Biosimilarity

Although the information set forth in the FDA’s newest draft guidance is extensive, much of the information covered here was previously addressed in the draft guidances issued in 2012 and 2013.  Unfortunately for industry, the FDA’s newest draft guidance does not offer much insight into the FDA’s regulation of biosimilars, the specific requirements for submitting a biosimilar application (“§351(k) application”), nor the likelihood of success of obtaining approval through this pathway. (For coverage of the FDA’s recent draft guidance, please click here, here, and here.)

Similar to the draft guidances issued by the FDA in 2012, FDA’s 2014 guidance explains the step-wise process for demonstrating biosimilarity. This draft guidance emphasizes the “critical” role of pharmacological studies in the demonstration of biosimilarity because they “support[] a demonstration that there are no clinically meaningful differences between the proposed biosimilar and the reference product.” Moreover, clinical pharmacology studies are important because they “add to the totality of the evidence, reduce residual uncertainty, and thus guide the need for and design of subsequent clinical testing” in the overall demonstration of biosimilarity. Id. When developing proposed biosimilar products, the FDA identified three key concepts that must be addressed in any §351(k) application: (1) exposure and response assessment, (2) evaluation of residual uncertainty, and (3) assumptions about analytical quality and similarity.

–          Exposure and Response Assessment: The FDA explains that exposure-response information is important for determining the “safety, purity, and potency of any biological product.” For the purposes of this guidance document, exposure refers to PK variables, including input of all active components of a biological product as measured by dose and drug concentrations in plasma and other biological fluids. Response, on the other hand, refers to PD variables, or the direct measures of the pharmacological or toxicological effects of a drug on the body.

–          Evaluation of Residual Uncertainty: The FDA intends to use a risk-based approach in evaluating the data provided in a sponsor’s § 351(k) application. Specifically, the FDA announced that it will consider the “totality of the data and information submitted,” including data from structural and functional characterization, nonclinical evaluations, human PK and PD studies, clinical immunogenicity testing, and investigation of clinical safety and clinical effectiveness.

–          Assumptions About Analytical Quality and Similarity: The FDA directs sponsors to conduct “extensive and robust comparative structural and functional studies (e.g. bioassays, binding assays, and studies of enzyme kinetics)” to evaluate whether the proposed biosimilar and the reference product are highly similar. The capabilities and limitations of these “state-of-the-art analytical assays” should be fully described in the § 351(k) application’s analytical assessment. Interestingly, the FDA encourages applicants to compare the quality attributes of the proposed biosimilar product with those of the reference product using a “meaningful fingerprint-like analysis algorithm” that “covers a large number of product attributes and their combinations with high sensitivity using orthogonal methods.” In using this “fingerprint-like analysis algorithm,” the FDA expects sponsors to reach one of four assessments about their product: not similar, similar, highly similar, and highly similar with fingerprint-like similarity. “Not similar” products are not recommended for the biosimilar pathway unless, for example, modifications are made to the manufacturing process that are likely to lead to a highly similar biological product. “Similar” products require additional data or studies to determine if the differences are acceptable to consider the proposed product as highly similar to the reference product. Proposed biosimilars that are “highly similar” and “highly similar with fingerprint-like similarity” permit high or very high confidence that the proposed product meets the statutory standard for biosimilarity and allow sponsors to “conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.”

Furthermore, the FDA explains that using “accurate, precise, specific, sensitive, and reproducible” bioanalytical methods of evaluating PK and PD properties of a proposed biosimilar and its reference product is “critical” to evaluating clinical pharmacology similarity. The draft guidance document goes on to detail the requirements for these data types, including specific information regarding ligand binding assays, concentration and activity assays, and pharmacodynamics assays that should be included in an application. In addition to these bioanalytical evaluations, the FDA recommends that applicants collect safety and immunogenicity data to supplement the overall assessment of biosimilarity.

Lastly, the guidance document encourages applicants to discuss crucial aspects of their clinical pharmacology development plan with the FDA. Specifically, the draft guidance outlines nine different study design areas that industry should consider in those discussions: crossover design, parallel design, the reference product, study population, dose selection, route of administration, pharmacokinetic measures, pharmacodynamic time profile, and the statistical comparison of PK and PD results.

The FDA is accepting comments on this draft guidance until the August 12, 2014. Comments can be submitted electronically to http://www.regulations.gov [Docket No. FDA-2014-D-0234].

FDA Under Scrutiny for Draft Guidances

In its 2014 biosimilars draft guidance, the FDA reiterates that, once finalized, this guidance will be a part of a series of guidance documents intended to implement the BPCIA. It will be interesting to observe how swiftly the FDA issues final guidance on biosimilars, especially in light of the recent scrutiny the FDA has faced regarding its policies on and use of draft guidances. One week before the most recent draft guidance was issued, the FDA received a letter from the U.S. Senate Committee on Health, Education, Labor and Pensions (the “Senate HELP Committee”), expressing “significant concern about the [FDA’s] use of draft guidances to make substantive policy changes.” (The full text of the Senate HELP Committee’s letter to FDA can be accessed here, courtesy of Hyman, Phelps, & McNamara, P.C.) In its letter to FDA, the Senate HELP Committee voiced its concern that “that these draft guidances are not being revised, finalized, or withdrawn in a timely manner.” As a result of the FDA’s failure to finalize guidances in a timely manner, FDA review staff, patients, clinicians, and FDA-regulated companies “feel compelled to follow draft guidances as if they were final” because these drafts are the only information available on the agency’s most current thinking on important issues.

Furthermore, the Senate HELP Committee expressed concern that the FDA “issues guidance that seemingly does not take into account, or may even conflict with, the scientific community.” In order to better understand the FDA’s use of guidance to effectively communicate with FDA-regulated entities seeking advice on how to bring life-saving medical products to patients, the Senate HELP Committee has requested FDA to provide additional information about all Level 1 Draft Guidances, including the date issued, and the timeline with which the FDA plans to withdraw, revise, or finalize each guidance. The Senate HELP Committee also requested the FDA to provide an update on FDA-wide activities to implement the “best practices” to make the finalization of guidance more efficient and expeditious. In addition, the letter asked the FDA to produce information on the average amount of time that FDA has taken to finalize draft guidances in the last five years, and to explain how it ensures that FDA staff does not follow the guidance in the absence of any other policy or final guidance.


Given that the FDA is operating under the Senate’s microscope, it is difficult to speculate exactly when industry should expect the FDA to publish final guidance on biosimilars. It remains to be seen whether issuing the recent draft guidance shortens FDA’s timeframe for releasing final guidance or tolls FDA action in asking for public comment. The attorneys at Fuerst Ittleman David & Joseph, PL will continue to monitor any developments in the FDA’s regulation of biosimilars. For more information, please feel free to contact us by email at contact@fidjlaw.com or by phone at (305) 350-5690.