Sets Forth Clinical, Pharmacology Data Sufficient to Support Biosimilarity
By Kevin E. Noonan --
The Food and Drug Administration has released the first new Guidance relating to its evolving standards for satisfying the biosimilarity requirements of the Biologics Price Competition and Innovation Act (BPCIA) since its release in February 2012 of three basic Guidances that left many if not most of the relevant details unclear. This most recent Guidance is more specific, being directed particularly to the type and amount of clinical pharmacology data the Agency will require to demonstrate biosimilarity to a reference product but is expressly "being distributed for comment purposes only" and thus how the FDA will administer the BPCIA remains a work in progress.
The provisionality of the Guidance is acknowledged from the Introduction (Section I), where it is described as being antecedent to a Guidance "in its final form" that will be "one of a series" comprising how the Agency will implement the BPCIA. This Guidance "discusses some of the overarching concepts related to clinical pharmacology testing for biosimilar products, approaches for developing the appropriate clinical pharmacology database, and the utility of modeling and simulation for designing clinical trials."
The Guidance establishes (in Section II) the relevance of clinical pharmacological data to the question of biosimilarity, stating that "[c]linical pharmacology studies are normally a critical part of demonstrating biosimilarity by supporting a demonstration that there are no clinically meaningful differences between the proposed biosimilar and the reference product." These data are related to the "degree of similarity in drug exposure" between the reference drug product and the putative biosimilar. The Guidance also notes that such data typically include pharmacodynamics endpoints and pharmacometric analyses that can reveal "clinically meaningful differences," and thus "can add to the totality of the evidence, reduce residual uncertainty, and thus guide the need for and design of subsequent clinical testing to successfully support a demonstration of no clinically meaningful differences in the overall demonstration of biosimilarity." Which types of such studies are meaningful in any particular reference biologic product/biosimilar comparison will depend, inter alia, on the "residual uncertainties" remaining when all other types of comparison evidence are considered (e.g., structural, mechanistic and other physicochemical comparisons).
The Guidance sets forth "three key concepts" as being "especially relevant" to their assessment of the similarity of biosimilar products:
• Exposure and response assessment (Section III.A)
• Evaluation of residual uncertainty (Section III.B)
• Assumptions about analytical quality and similarity (Section III.C)
With regard to exposure and response assessment, the Guidance asserts that these data are "important for the determination of safety, purity, and potency of any biological product, as well as for the determination of any potential clinically meaningful difference between two products." But this assessment is "particularly challenging" in the biosimilar context, because what is being assessed is not a comparison between an active product that is a single molecule and its breakdown products but "a mixture of closely related, complex biological substances." The Guidance defines "exposure" to related to pharmacokinetic parameter, including dose, drug concentrations in blood, plasma and other biological fluids, and related variable including Cmax, Cmin , Ctrough,ss, and area under the curve (AUC). Response, on the other hand, is defined in the Guidance as pharmacodynamics, "a direct measure of the pharmacological or toxicological effect of a drug," the assessment of which includes single or multiple biomarkers (where using "broader" biomarker panels are preferred if they "capture multiple pharmacological effects of the [biosimilar] product." In this regard, the Guidance cites "time of onset" of the marker relative to the combination of the time of onset, the "dynamic range" of the marker, how sensitive the marker is to differences between the reference drug and the biosimilar, relationships between changes in the marker and clinical outcomes, and the relevance of the marker on the mechanisms of action of the molecule.
The Guidance on evaluating residual uncertainty is less expansive, merely setting forth the FDA standard of assessing the "totality of the circumstances" on the evidence and suggesting that this evidence be collected and submitted "in a stepwise manner," including the PK and PD data "obtained in conjunction with clinical pharmacology studies."
Assumptions regarding analytical quality and similarity are defined in the context of such a "stepwise assessment of biosimilarity," wherein "extensive and robust comparative structural and functional studies (e.g. bioassays, binding assays, and studies of enzyme kinetics) should be performed to evaluate whether the proposed biosimilar product and the reference product are highly similar." This in turn depends on the state of the art regarding analytical assays, including those related to measuring molecular weight, post-translational modifications, heterogeneity, impurity and degradation profiles and functional properties of the biosimilar.
The differences between the reference drug product and biosimilar and the "type, nature, and extent" of those differences need to be supported by relevant information and experimental data, and if necessary additional data, and the Guidance explicitly notes that "certain differences in the results of the analytical characterization may preclude a determination by FDA that the proposed biosimilar product is highly similar to the reference product" and that, as a result the Agency will not approve the biosimilar application.
The Guidance also sets forth four different assessments decisions along a "developmental phase continuum":
• Not similar: Certain differences in the results of the analytical characterization may lead to an assessment of "not similar" and further development through the 351(k) regulatory pathway is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that is likely to lead to a highly similar biological product.
• Similar: Further information is needed to determine if the product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product. As an example, glycosylation plays an important role in the PK of certain protein products. Manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product help resolve that some differences in glycosylation identified in the analytical studies would be within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.
• Highly similar: The proposed biosimilar product meets the statutory standard for analytical similarity. The results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.
• Highly similar with fingerprint-like similarity: The proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. The results of these fingerprint-like analyses permit a very high level of confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.
The Guidance then sets forth a section (Section III.D) describing the "integrity" of the methods used in PK and PD studies (not surprisingly noting that these "should be accurate, precise, specific, sensitive, and reproducible"). These include (for PK studies) that the analytical method(s) used should be able to detect the active product and not just the total product in the formulation, and (for both PK and PD studies) that the assays chosen should be capable of providing the Agency with data that "are meaningful and reflective of drug exposure, the biological activity, and/or the PD effect of the proposed biosimilar product and the reference product." A rationale for the choice of assay and its relevance should also be provided. The Guidance then sets forth considerations regarding a number of specific assays, including:
• Ligand binding assays (differentiating between receptor/ligand and antibody/antigen binding assays);
• Concentration and activity assays (particularly with regard to enzyme replacement); and
• PD assays (noting that the measured activity "should be relevant to the clinical outcome").
With regard to safety and immunogenicity (Section III.E), the Guidance reiterates the caution from the earlier Guidances with regard to immune-mediated toxicity and the extent to which clinical pharmacologic data may be important to indicate differences requiring additional studies and appropriate study types, and that in certain circumstances the results of these studies may indicate that additional studies should not be pursued (because the differences are sufficient for the Agency to deny the biosimilar application). And the Guidance further cautions that, should the publicly available information on the reference drug product indicate a propensity for immune-mediated toxicity the biosimilar applicant should include assays "capable of detecting binding antibodies (and their neutralizing potential) [] in advance to analyze samples obtained from PK and PD studies, so that immunogenicity may be evaluated in real time" (the Guidance further references its prior FDA guidance for industry Bioanalytical Method Validation).
As it has in earlier Guidances, the Agency urges stakeholders to consult, especially with "critical study design issues," including crossover and parallel designs, which are of "particular relevance" (Section IV.A). The "preferred design" for PK similarity assessments, according to the Guidance, is a single-dose, randomized, crossover study, particularly with products having a "short" half-life (less than 5 days), "rapid" PD response ("onset, maximal effect, and disappearance in conjunction with drug exposure"), and multiple dosing regimes where "the PD effect is delayed or otherwise not parallel to the single-dose drug PK profile." Parallel study designs are recommended for biologic drugs having a long half-life and that elicit immunogenic responses. Regarding the reference drug product used in these studies (set forth in Section IV.B), the Agency states that "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" but also 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" the Agency will likely require can include structural and functional analytical data, and PK and PD study data comparing all three products (US reference drug product, non-US reference drug product, and biosimilar).
With regard to appropriate study populations (Section IV.C), the Guidance sets forth the pros and cons for each alternative (healthy volunteers vs. patients affected by the relevant disease or disorder) and the considerations that can be dispositive for the choice of population (generally, those that would provide data that is "the most informative for detecting and evaluating differences in PK and PD profiles between the proposed biosimilar product and the reference product"). Safety (with regard to healthy volunteers) and the possibility for immunogenicity or "known toxicity" (for affected patients) are noted as relevant considerations, and the Guidance also mentions the possible importance of demographics in instances where a particular patient demographic group would be "most likely to provide a sensitive measure of differences between the proposed biosimilar product and the reference product" (while requiring a biosimilar applicant to justify these choices). In other parts of the Guidance the Agency sets forth relevant considerations for dosing, which include (not surprisingly) a dose that is "most likely to provide clinically meaningful and interpretable data" (wherein the approved dose for the reference product being perhaps the right dose for studies involving affected patients). Alternative dose choices are also provided (see Section IV.D).
Other aspects of clinical pharmacologic studies set forth in the Guidance include route of administration (the same as the reference drug product; Section IV.E) and the types of pharmacokinetic (Section IV.F) and pharmacodynamics (Section IV.G) measurements that should be considered, as well as the "appropriate pharmacodynamics time profile" (Section IV.H) and statistics used for comparing PK and PD results from the biosimilar and reference drug product (Section IV.I).
The Guidance also contains a section (Section V) relating to "simulation tools" as part of study design and data analysis. The Guidance asserts that these tools can be useful in making many study choices set forth in earlier portions of the Guidance, and particularly notes the importance of making comparisons on the steep portion of a dose-response curve (which will more readily show differences between the biosimilar and the reference drug product) rather than in the "plateau" potion (which will not). The Guidance also suggests that a biosimilar applicant who does not have access to exposure-response data on the reference drug product can use such tools to produce a "small study to determine an optimally informative dose" or other alternatives.
The Guidance concludes with a reminder that the Agency has decided that it will assess biosimilarity between a putative biosimilar product and a reference drug product based on the totality of the evidence" (as set forth extensively in earlier Guidances).
One aspect of this Guidance, in addition to its (somewhat) greater specificity, is that what may constitute evidence that the biosimilar should not be approved is more explicitly recited (or at least that non-approval is an outcome dependent on evidence of differences between the reference drug product and the biosimilar). Generally, however, this Guidance provides an relatively small, specific, incremental advance in setting forth the Agency's course in providing a biosimilar approval pathway under the statute.
As set forth on the first page of the Guidance:
Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Sandra Benton at 301-796-2500, or (CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 301-827-1800.
Copies of the Guidance can be found here.
Interested readers should take the Agency up on this offer; unlike other governmental Guidances, the FDA appears genuinely interested in working with its stakeholders to address their legitimate concerns regardinh how the Agency will administer the law.
Top Stories of 2014: #10 to #7
By Donald Zuhn --
10. While FDA Accepts First Biosimilar Application, Some Biosimilar Applicants Try to Bypass BPCIA
In July, Sandoz announced that the U.S. Food and Drug Administration had accepted its application to market a version of the protein filgrastim. The reference product is Amgen's NEUPOGEN®. Sandoz markets a biosimilar filgrastim outside the U.S. under the brand name ZARZIO®. Interestingly, in October, Amgen announced the results of a Phase III clinical trial of its own biosimilar drug (designated ABP 501) for moderate-to-sever plaque psoriasis conducted in comparison with adalimumab (sold by AbbVie as Humira®). Amgen and Sandoz were both involved in a BPCIA dispute that was resolved by the Federal Circuit in December. In what some perceived as an attempt to sidestep the requirements of the BPCIA, Sandoz filed a declaratory judgment action against Amgen and Roche related to its etanercept biosimilar drug product, which it developed to compete with Amgen's Enbrel® TNF inhibitor. In Sandoz v. Amgen, the Federal Circuit affirmed the District Court's dismissal of Sandoz's suit because "Sandoz did not allege an injury of sufficient immediacy and reality to create subject matter jurisdiction." In other biosimilar developments, the FDA issued a "Guidance for Industry" in August entitled "Reference Product Exclusivity for Biological Products file under Section 351(a) of the PHS Act." The Guidance provides some grounds for determining the term of market exclusivity under the BPCIA (12 years; Sec. 351(k)(7), codified at 42 U.S.C. 55 262(k)).
For information regarding this and other related topics, please see:
• "Celltrion Healthcare Co. v. Kennedy Trust for Rhematology Research (S.D.N.Y. 2014); Hospira Inc. v. Janssen Biotech Inc. (S.D.N.Y. 2014)," December 11, 2014
• "Sandoz Inc. v. Amgen Inc. (Fed. Cir. 2014)," December 9, 2014
• "Amgen Poised to Enter Biosimilars Market," October 8, 2014
• "FDA Releases Another Prospective Guidance," August 13, 2014
• "Finally, A Biosimilar Application Has Been Accepted By The FDA ," July 28, 2014
• "FDA Releases Draft Guidance on Biosimilars," May 14, 2014
• "Indiana Governor Signs Biosimilar Substitution Bill," April 10, 2014
9. Congress and Tech Sector Wage Battle Against Patent Trolls
Despite having passed patent reform legislation -- the Leahy-Smith America Invents Act -- in September 2011, many in the patent community expected Congress to pass another piece of patent reform legislation in 2014 -- this time addressing patent litigation and the problem of so-called patent trolls. However, after taking up and tabling legislation in March and April, Senator Patrick Leahy (D-VT), Chairman of the Senate Committee on the Judiciary, announced that he was taking the Patent Transparency and Improvements Act of 2013 (S. 1720) off the Committee's agenda because of a lack of "sufficient support behind any comprehensive deal." Meanwhile, the tech sector continued to lobby for patent litigation reform. Congress may take up patent reform again this year.
For information regarding this and other related topics, please see:
• "More Misinformation Regarding the Patent System and Non-Practicing Entities," December 18, 2014
• "Patent Litigation Reform -- Will the Outcome of the Mid-Term Elections Matter, and Is Reform Still Necessary?" October 30, 2014
• "Teva v. Sandoz -- Is Deferential Review a Boon for Patent Trolls?" October 14, 2014
• "House Tries One More Time: Targeting Rogue and Opaque Letters Act of 2014 ("TROL Act")," July 17, 2014
• "Patent Reform Legislation Off The Table -- For Now," May 21, 2014
• "Senate Judiciary Committee Tables Patent Reform, Again," April 3, 2014
• "Stopping Bad Legislation -- The Innovation Alliance Speaks Out," April 2, 2014
• "Stopping Bad Patents -- Senator Schumer Takes on the "Patent Trolls"," April 1, 2014
• "New York Times Op-Ed Argues Law Takes Misguided Approach to Software Patents," March 30, 2014
• "Senate Judiciary Committee Takes Up, Then Tables, Patent Reform," March 27, 2014
• "A Rebuttal to The Economist's "Stalking Trolls"," March 13, 2014
• "Senate Legislation Update -- The Commerce Committee Gets in the Act," March 5, 2014
8. Courts and PTAB Deal with Fallout of Alice Corp. v. CLS Bank
In June, the Supreme Court issued its opinion Alice Corp. v. CLS Bank International, affirming the Federal Circuit's per curiam opinion in CLS Bank International v. Alice Corp. (stay tuned for more on that decision as we move closer to the top three stories of 2014). However, the impact of the Supreme Court's Alice Corp. opinion on Federal Circuit and Patent Trial and Appeal Board decisions made it to #8 on the list. Patent Docs covered nine such decisions during the second half of 2014, and in only one case (DDR Holdings, LLC) did the Federal Circuit conclude that computer-implemented claims survive a § 101 challenge. Readers can look for more discussion of this top story, as well as the Supreme Court's Alice Corp. decision, during our live webinar on the "Top Patent Law Stories of 2014" on January 20, 2015.
For information regarding this and other related topics, please see:
• "DDR Holdings, LLC v. Hotels.com, L.P. (Fed. Cir. 2014)," December 8, 2014
• "Ultramercial Inc. v. Hulu LLC (Fed. Cir. 2014)," November 16, 2014
• "Ultramercial Inc. v. Hulu LLC -- Party Briefs," November 6, 2014
• "Cambridge Assoc., LLC v. Capital Dynamics (PTAB 2014); PNC Bank v. Secure Axcess, LLC (PTAB 2014)," October 16, 2014
• "U.S. Bancorp v. Solutran, Inc. (PTAB 2014)," September 10, 2014
• "Planet Bingo, LLC v. VKGS LLC (Fed. Cir. 2014)," August 27, 2014
• "I/P Engine, Inc. v. AOL Inc. (Fed. Cir. 2014)," August 18, 2014
• "Stewart Title Guaranty Co. v. Segin Software, LLC (PTAB 2014)," July 23, 2014
• "Digitech Image Technologies, LLC v. Electronics For Imaging, Inc. (Fed. Cir. 2014)," July 14, 2014
• "Cyberfone Systems, LLC v. CNN Interactive Group, Inc. (Fed. Cir. 2014)," March 3, 2014
• "SmartGene, Inc. v. Advanced Biological Laboratories, SA (Fed. Cir. 2014)," January 29, 2014
7. Supreme Court Addresses Fee Shifting Determinations in Exceptional Cases
In April, the Supreme Court issued opinions in Octane Fitness, LLC v. ICON Health & Fitness, Inc. and Highmark Inc. v. Allcare Health Mgmt. Sys., Inc. The issue in both cases centered on the attorney fee-shifting provision of 35 U.S.C. § 285. In Octane Fitness, a mostly unanimous court held that "an 'exceptional' case is simply one that stands out from others with respect to the substantive strength of a party's litigating position (considering both the governing law and the facts of the case) or the unreasonable manner in which the case was litigated," the Court leaving the determination of whether a case is "exceptional" to the discretion of the District Court judge. In Highmark, the Supreme Court determined that "an appellate court should apply an abuse-of-discretion standard in reviewing all aspects of a district court's §285 determination," even though "questions of law may in some cases be relevant to the §285 inquiry." The Supreme Court's decisions make it easier for a trial court to shift fees to the non-prevailing party if it believes that the litigation was brought or conducted in an abusive manner, and also make it more difficult for an appellate court to overturn such a determination.
For information regarding this and other related topics, please see:
• ""Standing Out" -- A Closer Look at the "Exceptional Case" Standard Articulated in Octane Fitness," April 29, 2014
• "Patent Trolls Beware -- Supreme Court Issues Decisions in Octane Fitness and Highmark," April 29, 2014
• "Oral Arguments in the Supreme Court Octane Fitness, LLC v. ICON Health & Fitness, Inc. Case," February 27, 2014
• "Supreme Court to Hear Oral Arguments in Attorney Fee Shifting Cases," February 25, 2014
• "Supreme Court Preview -- Highmark Inc. v. Allcare Health Mgmt. Sys., Inc.," February 19, 2014
• "Supreme Court Preview -- Octane Fitness, LLC v. ICON Health & Fitness, Inc.," February 13, 2014
Posted at 11:59 PM in Biosimilars, Federal Circuit, Food and Drug Administration, Media Commentary, Patent Legislation, Patent Trial and Appeal Board, Patentable Subject Matter, Supreme Court | Permalink | Comments (0)