Patent Docs: Food and Drug Administration

Food and Drug Administration

April 06, 2016

FDA Releases Guidance on Biosimilar Labeling

The Biologic Price Control and Innovation Act (BPCIA), enacted as part of President Obama's Affordable Care Act (better known as "Obamacare," Public Law 111-148), provided for the first time in the U.S. a path for FDA approval of biosimilar drugs, i.e., "generic" versions of biologic drugs that, unlike generic versions of conventional small molecule drugs are not identical but similar. Congress did not, however, prescribe the standards for establishing biosimilarity or other aspects of the biosimilar pathway, leaving the details up to the FDA. As part of fulfilling its mandate under the BPCIA, the FDA has issued a series of Guidances (both in draft and final form) with respect to the procedural and scientific protocols to be followed in filing and pursuing a biosimilar drug application (see "FDA Releases 'Final' Guidances for Industry regarding the Biosimilar Approval Pathway"). On Friday, the FDA issued its latest Guidance, which has to do with labeling of biosimilar drugs. Far from being merely a technical aspect of the biosimilar program, this Guidance has been subject to pressures from both the innovator biologic drug makers and companies pursuing (or planning to pursue) their own biosimilar drugs. These pressures have everything to do with the hoped-for acceptance of these drugs (particularly by the U.S. government, the biggest payor for biologic drugs) and fears by innovator biologic drug companies that their drugs might be mistaken for a biosimilar version (especially in the event that a biosimilar is associated with an adverse event).

The Guidance (which is but a draft Guidance for now) on its face is being distributed "for comment only" and in this way reflects the manner in which the FDA has approached its task of implementing the Act, by soliciting public and industry feedback by issuing draft Guidances and holding hearings and other meetings. In a "black box" at the beginning of the document it states:

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

There are eight sections, providing the Background, General Principles, Specific Recommendations, FDA-approved Patient Labeling, Revised Biosimilar Product Labeling, instructions on how to submit initial and revised labeling, and a short section on Interchangeable Biological Products that does not provide labeling recommendations for interchangeable products (consistent with the agency's refusal to provide Guidance on obtaining approval for interchangeable versions of biologic drugs). In the short Background the agency explains the context of the biosimilar provisions of the Act and then moves immediately to the General Principles. There the FDA notes that the biosimilars pathway is provided "to demonstrate biosimilarity between the proposed [biosimilar] product and the reference product, not to independently establish safety and effectiveness of the proposed [biosimilar] product." Accordingly, the information on the biosimilar label should be the "relevant data and information from the reference product labeling, with appropriate product-specific modifications." Indeed, "[i]nformation and data from a clinical study of a proposed biosimilar product should be described in its labeling only when necessary to inform safe and effective use by a health care practitioner" and should not include "a description of these data," on the grounds that any clinical study undertaken by the biosimilar applicant should be aimed at establishing biosimilarity (defined as there being no clinically meaningful differenced between the biosimilar product and the reference product) and not at assessing the safety and efficacy of the biosimilar per se. The Guidance also recites several other labeling rules not limited to the biosimilar context that a biosimilar label is required to follow (see, 21 CFR 201.56(c)(1), 201.56(d) and 201.57, and 21 CFR 201.57(c)(9)(i) through (iii)).

With regard to the Specific Recommendations for biosimilar products, the Guidance accommodates circumstances where the biosimilar product label differs from the reference product label (for example, depending on whether the biosimilar applicant is seeking approval for all or just a subset of indications for which the reference product has been approved). The Guidance reaches the crux of the matter with regard to product identification; an earlier version of the agency's thinking in this regard was disclosed previously. The agency recommends using the biosimilar product name "[i]n sections where the information described is specific to the biosimilar product" and "[f]or directive statements and recommendations for preventing, monitoring, managing, or mitigating risks." The reference product name should be used "[w]hen clinical studies or data derived from studies with the reference product are described in biosimilar product labeling," particularly with regard to clinical studies and adverse reactions. The "core" name (which is the nonproprietary name without the source-specific suffix) should be used when the property or risk applies to both the reference and biosimilar products (exemplified in the Guidance as "BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS (Postmarketing Experience)" which would reflect the commonality of these properties for both products. The FDA also apprehends situations where "[t]here may be text appropriately based on the reference product labeling where more than one of these product identification approaches should be used to accurately convey information." For instances where a biosimilar has sought (and been approved for) fewer than all the indications approved for the reference product, information relating to these indications should not be included unless it is necessary for safety or efficacy (whilst ensuring that it is clear that the biosimilar is not approved for such uses).

The Guidance then recites the recommendation for specific language regarding a biosimilar:

[BIOSIMILAR PRODUCT'S PROPRIETARY NAME (biosimilar product's proper name)] is biosimilar* to [REFERENCE PRODUCT'S PROPRIETARY NAME (reference product's proper name)] for the indications listed.

The INDICATIONS AND USAGE section of the label "should be specific to the approved indications for the biosimilar product and should be consistent with language previously approved for the reference product for those indications" including text from the reference product related to Limitations of Use. The FDA also recommends specific language related to immunogenicity:

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to [reference product's proper name] in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Not surprisingly, the agency recommends that Patient Labeling follow the reference product except when differences are necessary to properly describe the biosimilar product.

The agency also recognizes that changes may arise during the life cycle of a biosimilar product and provides mechanisms for updating safety information, particularly when "new information" relating to use of the product under "more widely or [] diverse conditions." Specifically, "[a]s with any biological product, a biosimilar product application holder must promptly review all adverse drug experience information obtained or otherwise received from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological studies/ postmarketing adverse event surveillance, reports in the scientific literature, and unpublished scientific papers; and the biosimilar product application holder," citing 21 CFR 600.80. And if any information is found to be inaccurate, prompt correction is mandated by the statute (see, 21 CFR 601.12). The Guidance also provides for post-approval licensure for additional indications for which the reference product has been approved.

How such labeling information should be submitted is set out as requiring:

• A clean version of reference product labeling that was used to develop the biosimilar product labeling

• A tracked changes and annotated version of proposed biosimilar product labeling explaining the differences from the reference product labeling

• A clean version of the proposed biosimilar product labeling

Finally, the Guidance indicates that, while "FDA continues to consider the types of data and information that would support a demonstration that a biological product is interchangeable with a reference product" that Guidance will not be found here.

As noted above the FDA is soliciting comments; as the face of the Guidance states, "[c]omments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance," with electronic copies to be sent to http://www.regulations.gov and questions to Sandra Benton at 301-796-1042 or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.

Posted at 11:59 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

February 17, 2016

Sandoz Petitions for Certiorari over 180-day Notice Provision in BPCIA

By Kevin E. Noonan --

As reported earlier today in IP Law360, Sandoz has petitioned the U.S. Supreme Court for certiorari to review the Federal Circuit's decision that reversed the District Court in Amgen v. Sandoz. In its decision, two members of the Federal Circuit panel (Judges Lourie and Newman) held that the BPCIA required notice of commercial marketing of a biosimilar product be given by the biosimilar applicant to the reference product sponsor only after the FDA had given regulatory approval for the biosimilar. Judge Chen dissented, on the grounds that this constituted an extra 180 days of regulatory exclusivity beyond the 12 years expressly set forth in the statute.

Sandoz argues that this decision was outside the scope of the plain meaning of the statutory language, was inconsistent with the policy objectives of the BPCIA and in conflict with Supreme Court decisions on statutory interpretation. Specifically, Sandoz argues that Amgen's remedy to prevent commercial marketing immediately upon approval was to ask a district court for an injunction based on patent infringement, which Amgen has not done (and Sandoz pointed out to the Court). Indeed, Sandoz inferred that Amgen could not do so, based on SEC filings concerning whether Amgen owned an unexpired patent related to filgrastim.

Sandoz's petition also argues that the decision "disrupts the careful balance struck by Congress by delaying the launch of every biosimilar product by six months" (emphasis added). Again in this argument Sandoz maintains that the only remedy in the statute providing for an injunction was based on patent litigation, either pursuant to the "patent dance" or, according to its successful arguments below, as provided by the "remedies" in the statute when a biosimilar applicant refuses to provide the reference product sponsor with its application or relevant manufacturing methods. According to Sandoz, the statute is clear that "once the expressly granted [12 year] exclusivity period has run, the FDA's approval is 'made effective,' and the biosimilar applicant should be able to market immediately, absent the successful assertion by the sponsor of any valid patent claims."

The last portion of Sandoz statutory arguments contends that the Federal Circuit's interpretation "erroneously divorced the notice of commercial marketing provision from the patent resolution scheme and created an extra-textual injunctive remedy to enforce it." Sandoz characterizes the Federal Circuit's action as an extra-statutory judicial intervention into the process, by granting an injunction against commercial marketing (that was lifted 180 days after FDA approval, on September 4, 2015). Sandoz's point is that an "already approved biosimilar" was (and will be, for other biosimilars) kept off the market for an additional 180 days "without regard to whether the sponsor could show any valid patent rights or any irreparable harm." The argument with regard to the statutory scheme is as follows:

With the exception of the confidentiality provision -- which is not applicable here -- Congress did not make the provisions in Section 262(l) specifically enforceable. In other words, it created no cause of action for either the applicant or the sponsor to obtain an injunction to compel the other party to comply with any of the provisions in that subsection. In contrast, Congress expressly made the confidentiality provision enforceable by an injunction -- and that provision proves that Congress knew how to provide an injunctive remedy when it wished to do so.

Further:

As particularly relevant here, and consistent with the BPCIA's overall patent-based remedial approach, the remedy Congress provided for the failure to provide the notice of commercial marketing under subsection (l)(8)(A) is the ability to bring an artificial infringement suit. Specifically, when an applicant engages in the patent exchange process, yet does not provide notice of commercial marketing: "the reference product sponsor, but not the subsection (k) applicant, may bring" an action for a "declaration of infringement, validity, or enforceability" with respect to certain patents identified earlier in the patent exchange process.

Sandoz also noted that the Federal Circuit did not consider the "traditional equitable factors" involved in a decision to grant an injunction, which decision is in conflict with the Court's eBay decision.

The petition also makes the public policy argument that, left intact, the Federal Circuit's decision will impact not only Sandoz but every biosimilar applicant, supporting this argument with citations to the FTC's Report on biosimilars and other references regarding the importance of biosimilar drugs to patient accessibility to biologic drugs. This outcome will "disrupt[] the careful balance struck by Congress between competition and innovation" Sandoz asserts, in language certain to get the attention of at least some members of the Court.

The Court will take up the petition in due course (and in view of the public policy implications may solicit the Solicitor General's views), and of course Amgen will have the opportunity to oppose. There were a few amici who filed briefs supporting Sandoz's position on these issues in its petition for rehearing en banc, and briefs from those and any other amici will be due in the coming weeks.

Posted at 11:37 PM in Biosimilars, Food and Drug Administration, Supreme Court | Permalink | Comments (0)

February 09, 2016

Celltrion's Proposed REMICADE® Biosimilar Recommended for Approval

By Andrew Williams --

Earlier today, the FDA's Arthritis Advisory Committee recommended approval of biologics license application ("BLA") 125544 submitted by Celltrion, Inc. for CT-P13, a proposed biosimilar to Janssen Biotech Inc.'s REMICADE (infliximab) anti-TNF-α antibody. According to a press release from Celltrion, the committee voted 21-3 to recommend approval for all sought indications, including treatment of a variety of autoimmune diseases such as Crohn's disease, ulcerative colitis, and rheumatoid arthritis. This would be the second biosimilar ever approved in the United States (U.S.) pursuant to the Biologics Price Competition and Innovation Act (BPCIA), and the first biosimilar therapeutic monoclonal antibody. If the experience with Sandoz's Zarxio^TM biosimilar is any indication, the FDA should be expected to approve the application in the next couple of months. Marketing of the drug may be delayed, however, pending the outcome of Janssen's motion for partial summary judgment and a preliminary and permanent injunction. A key consideration of that case is the Federal Circuit's Amgen v. Sandoz decision and its interpretation, which may delay marketing for an additional six months because the Notice of Commercial Marketing cannot be effective until approval by the FDA.

Last week, in advance of today's meetings, staff at the FDA released a briefing document in which they reported that the data submitted by Celltrion showed "that CT-P13 is highly similar to US-licensed Remicade, notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between CT-P13 and US-licensed Remicade in terms of the safety, purity, and potency of the product." Importantly, much like Sandoz's experience with Zarxio, Celltrion benefited from the fact that CT-P13 has already been approved outside the U.S. for similar indications. For example, in the EU, South Korea, Japan, and India, Celltrion's biosimilar has been approved for all US-approved indications under the trade names Inflectra and Remsima (although no name has yet been assigned to the U.S. version of the drug). In Canada, however, the same drug has been approved for all indications except ulcerative colitis and Crohn's Disease. Because the development of CT-P13 occurred entirely outside of the U.S., Celltrion had to provide additional comparative data -- in order to "scientifically justify the relevance of that data by establishing an adequate scientific bridge between EU-approved Remicade, the US-licensed reference product and CT-P13." The FDA explained that this bridging data should always include results from analytical studies, such as structural and functional data that directly compares all products, and should also include bridging PK and/or PD clinical data.

The FDA's briefing document also said that Celltrion had "provided an extensive data package to address the scientific considerations for extrapolation of data to support biosimilarity to other conditions of use and potential licensure of CT-P13 for each of the seven indications for which US-licensed Remicade is currently licensed and for which CT-P13 is eligible for licensure." Celltrion is seeking to market CT-P13 for the following indications: (1) Crohn's Disease (CD), (2) Pediatric CD, (3) Ulcerative Colitis (UC), (4) Rheumatoid Arthritis, (5) Ankylosing Spondylitis, (6) Psoriatic Arthritis, and (7) Plaque Psoriasis. In addition, Celltrion is seeking approval for Pediatric CD, but according to the briefing, this indication is protected by orphan drug exclusivity until September 23, 2018. Unlike in Canada, the committee recommended approval for all sought-after indications in the U.S.

Once the FDA accepts the committee's recommendation and approves Celltrion's application, it may still be at least six months before the biosimilar drug can be marketed. Unlike Sandoz in the case of Zarxio, Celltrion provided Janssen with its aBLA after it was accepted by the FDA. Nevertheless, according to the Complaint filed by Janssen in the U.S. District Court for the District of Massachusetts, Celltrion refused to provide the requisite "other information" required by the BPCIA, which would describe the manufacturing process. Moreover, Celltrion served a notice of commercial marketing on February 5, 2015, indicating that it would begin selling the product as early as August 4, 2015. Of course, even though this notice occurred after Celltrion's application was accepted, it was significantly before actual approved (especially considering the biosimilar is not yet approved). Celltrion has responded to Janssen's injunction motions by alleging that the Notice-of-Commercial-Marketing provision of the BPCIA is not a stand-alone provision and that because it took part in the "Patent Dance," it is not required to give such notice. While Janssen's motion is pending, the Federal Circuit will be considering the almost identical issue in the Amgen v. Apotex case, which we will preview in an upcoming post.

Nevertheless, the committee's vote today is especially significant considering the intense interest focused on biosimilar therapeutic antibodies. Going into this meeting, there was a lot of uncertainty about just how much information the FDA would require in order for a biosimilar applicant to establish "no clinically meaningful differences" between its biosimilar drug and the reference product. Of course, Celltrion benefited from extensive data that it had already generated outside of the U.S. It therefore remains to be seen just how much data the FDA will require for biosimilar therapeutic antibodies that do not have such a history.

Posted at 08:37 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

January 04, 2016

May 11, 2015

FDA Releases "Final" Guidances for Industry regarding the Biosimilar Approval Pathway

By Kevin E. Noonan --

About three years ago, and less than two years after Congress passed and President Obama signed the Biologics Price Competition and Innovation Act (BPCIA) into law, the U.S. Food and Drug Administration issued a series of draft Guidances indicating how it was considering implementing the biosimilar approval pathway contained in the Act. The Guidances (see "FDA Publishes Draft Guidelines for Biosimilar Product Development" and "More on FDA Draft Guidelines for "Follow-on" Biologic Drug Approval Pathway") were expressly "draft" in nature, and were the subject of public hearings with the Agency welcoming industry input. This input was necessary; even a cursory review of the pathway provisions of the law would strike one with the frequency with which Congress delegated to the FDA the details of setting out the requirements for biosimilar approval. This did not come as a shock, it being rational that Congress should recognize that Agency expertise was particularly important in developing standards for approving drugs as complex as biosimilars under circumstances where the "follow-on biologic" drugs were frankly not identical to the approved reference biologic product.

In April the Agency released "final" Guidances that look remarkably like the originals; these Guidances are entitled:

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product [link]

• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product [link]

• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 [link]

The FDA has released an additional, more explicit Guidance related to the requirements for establishing biosimilarity since promulgating these first three (see "FDA Releases Draft Guidance on Biosimilars: Sets Forth Clinical, Pharmacology Data Sufficient to Support Biosimilarity") as well as a Guidance on market exclusivity (see "FDA Releases Another Prospective Guidance"). More importantly, the Agency recently approved the first biosimilar drug in the U.S. (see "FDA Approves Sandoz Filgrastim Biosimilar"). But as noted in the letter from several Senators discussed yesterday (see "Senators Send Letter on Biosimilars to FDA"), this progress has not come fast enough for some. In addition, the Agency has made at least one no-decision decision (using an "interim" non-proprietary name for Sandoz XARZIO^TM product (filgastrim–sndz)) and has not yet addressed the standards for interchangeability. However, such carping seems unfairly critical from the institution that left it to the Agency to actually develop a biosimilars pathway and, of course, be ready to take the blame for any problems arising along the way.

Posted at 10:45 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

April 15, 2015

Amgen Receives No Help from the FDA -- A Biosimilar Update

By Andrew Williams --

Near the end of last month, the U.S. Food and Drug Administration ("FDA") denied a citizen petition filed by Amgen in which it requested that action be taken to ensure that biosimilar applicants comply with the disclosure and exchange provisions described in the Biologics Price Competition and Innovation Act ("BPCIA"). Amgen had filed its petition on October 29, 2014, after Sandoz refused to disclose a copy of its biosimilar application related to Amgen's NEUPOGEN^® (filgrastrim) biologic drug product. More precisely, Sandoz had alleged that the disclosure provision of the BPCIA was not mandatory. Instead, as noted in the petition, Sandoz had independently offered to provide Amgen with the information, but with conditions and restrictions not found in the statute. Amgen requested in the petition that the FDA require all new biosimilar applicants to certify that they would comply with the disclosure provisions (in a manner similar to how an ANDA filer must provide a certification in the Hatch-Waxman context). However, the FDA denied this request because the provisions of the BPCIA do not in fact impose such a certification requirement, which stands in opposition to the explicit certification requirement for ANDA filers as found in the Hatch-Waxman statute.

Of course, this comes on the heels of the Northern District of California's denial of Amgen's motion for a preliminary injunction and partial judgement on the pleadings in the Amgen v. Sandoz case. As previously reported here, the Court in that case sided with Sandoz in determining that the disclosure provisions were not mandatory. In large part, the Court based its decision on the fact that, even though the BPCIA states that the biosimilar applicant "shall provide to the reference product sponsor a copy of the application," and other information related to the manufacturing process, the statute also provides the "penalty" for not so disclosing. Essentially, Sandoz was just opting for the penalty -- being subject to "an action under section 2201 of Title 28, for a declaration of infringement, validity, or enforceability of any patent that claims the biological product or a use of the biological product." 42 U.S.C. § 262(l)(9)(C). The obvious problem, however, is that a product sponsor will likely not be aware of which patents it can assert in the absence of such a disclosure.

In its citizen petition to the FDA, Amgen again alleged that the disclosure provisions and patent exchanges dictated by the BPCIA -- the so-called biosimilar "patent dance" -- were mandatory, not optional or discretionary. Amgen pointed to the text and the history of the statute for the support. In fact, without the initial disclosure by the biosimilar applicant, the "patent dance" cannot even begin. "All of these provisions quickly become nullities if biosimilar applicants are free to simply ignore the requirements of § 351(l)(2)(A)," Amgen asserted. This can become an even more serious issue when considering "interchangeable" biosimilar products. Such products earn a period of exclusivity tied in part to any potential litigation. As such, it would behoove a biosimilar applicant to delay, or even eliminate, any litigation by not disclosing its application or manufacturing information. Indeed, if a biosimilar applicant were not required to disclose that it had, in fact, filed an application, it could maintain the fact that it had filed an application secret. This could not have been what Congress intended, Amgen contended.

Momenta Pharmaceuticals also submitted a paper to the FDA in response to Amgen's citizen petition on November 25, 2014. This paper echoed Momenta's comments that it submitted to the FDA in May 2012, expressing concern that the "patent dance" provisions of the BPCIA would be converted to an FDA regulated regime. Instead, Momenta alleged that granting Amgen's petition would be contrary to the intent of Congress. Specifically, Momenta asserted that Congress intended:

• to separate the FDA from the patent resolution process;
• to allow applicants to choose to engage in the patent exchange process at the time a 351(k) Application is filed when appropriate;
• to provide reference biologic sponsors with procedural patent exchange protections should applicants elect to seek patent resolution early; and
• to allow for specific remedies should applicants elect not to seek patent resolution prior to commercial launch.

In the end, the FDA sided with Momenta and denied Amgen's petition. "Neither section 351(k) nor section 351(l) requires the FDA to impose certification requirements as part of the biosimilar review process." This is, again, in contrast to the Hatch-Waxman statute, which requires ANDA filers to certify regarding each patent listed in the FDA's Orange Book. "Viewed against the explicit requirements under the FD&C Act, the Petition's contention that FDA 'should' require a certification for biosimilar applications implicitly acknowledges that imposing such a requirement is a matter of regulatory discretion and not compelled under the PHS Act." With regard to that discretion, the FDA noted that the issue about whether the disclosure provisions were mandatory was being resolved in the Federal courts. Nevertheless, the FDA did provide Amgen with a glimmer of hope, if not for now than for the future: "In light of the ongoing litigation regarding interpretation of section 351(l) of the PHS Act, at this time, the Agency denies the request to exercise its discretion to require biosimilar applications to include a certification to FDA that the applicant will timely comply with section 351(l)(2)(A) of the PHS Act" (emphasis added). Of course, this likely provides little solace to Amgen, because if it does receive a favorable ruling on appeal in the Amgen v. Sandoz case, such FDA action will not be necessary.

Posted at 11:59 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

March 08, 2015

FDA Approves Sandoz Filgrastim Biosimilar

By Kevin E. Noonan --

On Friday, the Food and Drug Administration approved a biosimilar version of Amgen's Neupogen® (filgrastim) product for sale in the U.S. This is the first biosimilar to be approved under the provisions of the Biologics Price Competition and Innovation Act (BPCIA), which was part of the healthcare reform package passed in 2010 and commonly referred to as "Obamacare." Sandoz (a division of Novartis) will sell its biosimilar under the brand name Zarxio™.

The drug is a recombinantly produced version of human granulocyte colony stimulating factor (methionyl-human granulocyte colony stimulating factor or r-metHuG-CSF) and is used to stimulate neutrophil production in patients undergoing chemotherapy. Amgen has obtained FDA approval for Neupogen® for treating the following five conditions:

• Cancer patients receiving myelosuppressive chemotherapy;
• Cancer patients with acute myeloid leukemia receiving induction or consolidation chemotherapy;
• Cancer patients undergoing bone marrow transplantation;
• Patients undergoing autologous peripheral blood progenitor cell collection and therapy; and
• Patients with severe chronic neutropenia.

Sandoz provided the FDA with a wide variety of evidence of biosimilarity since it filed its application under Section 351(k) of the Public Health Service Act last July; this evidence included "structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data" and, importantly, an absence of immunogenicity in human subjects, together demonstrating the biosimilarity of Sandoz product Neupogen® according to the FiercePharma website. In particular, Sandoz performed a head-to-head comparison between its biosimilar drug and Neupogen® showing a level of biosimilarity sufficient for the FDA to approve Zarxio™ for all of Amgen's approved indications.

Neupogen® is a $1.2-1.4 billion dollar per year product for Amgen and part of the significance of FDA approval is economic. Industry estimates have Sandoz selling Zarxio™ for 15-30% less than Amgen's current price, which estimates are expected to reduce the cost of the drug by an equivalent amount once this biosimilar becomes accepted by physicians. Unlike conventional "generic," generally small molecule, drugs (which cause upwards of 90% reductions in drug prices from the innovator brand price), biosimilar drugs are both more complex than small molecule drugs and are administered by physicians (typically by injection) and thus continue to actively involve medical personnel during a course of treatment. Consequently, physician acceptance of biosimilar drugs is much more of an issue than for generic drugs and thus market penetrance is expected to be delayed for 1-5 years, even by Sandoz. These estimates are in line with industry expectations for biosimilar drugs in general; for example, Express Scripts has estimated that while U.S. healthcare costs may be reduced by about $250 million between 2015 and 2025, biosimilar sales worldwide will only increase from $1.3 billion to $35 billion by 2020, even taking into account the robust approval climate for biosimilar drugs on Europe (where the EMEA has approved 21 biosimilar drugs over the past 10 years; it should be noted that cost savings in Europe from biosimilars amount to about a 10% reduction).

(For those paying attention, another reason that marketing of Sandoz's Zarxio™ product may be delayed is that Amgen and Sandoz are embroiled in litigation over whether Sandoz is required to participate in the litigation provisions of the BPCIA); that case is ongoing (see "'No Clinically Meaningful Differences': The First Accepted Biosimilar Application Has Been Recommend for FDA Approval").

The other basis for considering approval of Zarxio™ to be significant is that, as the first biosimilar approved, it will be a bellwether for how well the FDA has implemented the BPCIA and performed in its role in protecting public health. The complexity of both biologic drugs themselves (which typically comprise thousands of atoms; the chemical formula of filgrastim for example is C₈₄₅H₁₃₄₃N₂₂₃O₂₄₃S₉) and the methods by which they are made (typically using recombinant cells expressing genetically engineered genes transferred from one organism (here, human) to another such as bacteria) provide much greater challenges for the agency in performing its review of safety, potency and efficacy. While the EMEA in Europe has successfully approved biosimilar drugs for a decade, in the U.S. doubts are likely to remain until experience (both the agency's and the public's) has shown them to be unfounded.

There is one aspect of the FDA's approval of Zarxio™ that remains controversial, and that is the non-proprietary (or common) name the agency has given to Sandoz's product. The name, filgrastrim-sndz, has been called a "placeholder" by the agency because it has not yet decided whether to give different names to biosimilar versions of branded biologic drugs (as innovator biotechnology companies have advocated to ensure that any adverse events be properly ascribed to the biosimilar) or to use the same name as the innovator biologic drug (as urged by groups like the Generic Pharmaceutical Association (GPhA) and health organization to minimize the chance of confusion by medical personnel). These sentiments were voiced on Friday by Ralph G. Neas, President and CEO of GPhA, who stated that his organization "reiterate[s] our stance that the Agency's departure from the currently accepted international nonproprietary name (INN) system could disrupt the ability to track and dispense these medicines, risking provider confusion and patient safety."

One thing the FDA did not do was approve Zarxio™ as an interchangeable product, because inter alia the agency has not yet developed standards for making this determination. In addition to the absence of "no clinically meaningful differences" required to be shown between the branded (or reference product sponsor's) product and the biosimilar drug for approval as a biosimilar, to be interchangeable there must be no differences in outcomes when a patient is switched to an interchangeable biosimilar drug product than occur when the innovator's product is administered. Interchangeability when achieved will have the advantage that switching to the interchangeable version will not require physician approval and will be eligible for at least a one-year exclusivity period for the successful interchangeable biosimilar applicant.

This is but the first of many biosimilar approvals waiting FDA action; these include applications by Apotex for its version of Neupogen® (which was accepted by the FDA last month and is sold in Europe under the name Grastofil) as well as a biosimilar version of Amgen's Neulasta® (a PEGylated version of the molecule). Pundits and politicians have pontificated about the benefits to be had by adopting a biosimilar approval pathway in the U.S., and those predictions have begun the process of being tested with approval of Zarxio™.

Posted at 11:41 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

February 23, 2015

23andMe Receives FDA Approval for Genetic Diagnostic Test

By Kevin E. Noonan --

Last Thursday the genetic diagnostic and DNA analysis company 23andMe announced that the FDA had granted the company approval to market a genetic diagnostic test for Bloom's Syndrome, the first such approval for this rare genetic disease. The news is tempered by the company's further announcement that it will not offer the test to consumers "until it completes the regulatory process for additional test reports and can offer a more comprehensive product offering."

Readers may recall that the FDA effectively stopped 23andMe from selling its genetic analysis kit, which the company marketed as Personal Genomic Services (PGS) in November 2013 by issuing a Warning Letter to the Company (see "FDA Threatens Agency Action Against 23andMe Over Personal Genetic Testing"). According to the FDA, genetic diagnostics assays fall under the agency's purview and authority because they are medical devices (21 U.S.C. § 321(h)). According to the letter, the testing service offered "is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body." At that time, the agency professed a desire to work with the company to assist in developing the type and quantity of evidence required for approval, but warned that it had spent "significant time" evaluating the PGS test and providing feedback to 23andMe. It appears that the company complied with the agency by submitting the evidence for approval of a much more limited test (i.e., limited to Bloom's Syndrome), compare to the tests offered previously (which included more that 250 "diseases and conditions" such as BRCA gene mutations, diabetes, coronary artery disease, an sensitivities to drugs such as warfarin, clopidigrel and 5-fluorouracil).

The test is described as a "spit test kit and a chip array platform," and approval is limited at this time to detecting genetic markers for Bloom's syndrome. Bloom's syndrome is a genetic disease inherited in an autosomal recessive manner, that predisposes individuals to certain cancers and is also associated with short stature, sensitivity to sunlight exposure and shortened lifespan. The locus of the mutation is in the BLM gene on chromosome 15 (at 15q26.1) and encodes a DNA helicase. Defects in this gene cause a dramatic (~ten-fold) increase in homologous recombination in cells from affected individuals, resulting in genomic instability. Genetic testing is the only way to predict risk for passing the disease to offspring, as parents having only one copy of the gene show no symptoms.

The FDA's decision to permit 23andMe to offer the test, while important to the company and to those individuals who may be at risk for passing on the Bloom's syndrome trait to their children, is also significant for the type of testing the FDA required and the evidence it mandated for approval. For example, 23andMe in an announcement stated that it "conducted extensive comprehension studies with consumers from different backgrounds, education levels and incomes," as well as test accuracy and validity.

The company's future in the genetic diagnostics space remains uncertain, however, in view of the following disclaimer on its website:

Updated February 19, 2015b: 23andMe provides ancestry-related genetic reports and uninterpreted raw genetic data only. We intend to add some health-related genetic reports in the future once we have a comprehensive product offering. At this time, we do not know which health reports might be available or when they might be available.

A disturbing note was struck by Alberto Guitierrez, Director of the Office of In Vitro Diagnostics and Radiologic Health in the agency's Center for Devices and Radiologic Health, who stated that "[t]he FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information," and that the FDA intended to "exempt these devices from FDA premarket review." How disturbing this sentiment may be will depend on how widespread access to genetic testing becomes and the extent to which providers such as 23andMe provide information to consumers receiving this information; indeed, the company's disclaimer suggests that FDA action has encouraged it not to provide any interpretation for the "raw genetic data" it supplies to consumers. For all the criticism that has been leveled against Myriad (some of which may have been justified) the company acted responsibly by ensuring that its customers had access to genetic counselors who explained the significance of their test results and provided options for accommodating the consequences of any propensities their genetics disclosed. Among all the negative press Myriad received there were two types of stories that did not appear: one, that the company had provided a misdiagnosis (of either type); and two, that someone had decided to end their life because they misinterpreted the results of their test or its implications on their health. Minimizing the risk of the latter outcome will depend even more heavily on adequate counseling as more individuals have more tests for more genetic diseases, particularly as those diseases expand to include those that are less determinative than tests like the BRCA test or 23andMe's Bloom's Syndrome test and as there are more opportunities for behavioral modifications that could modulate patient outcomes. Mr. Gutierrez is also reported to have said that authorization of 23andMe's test "supports innovation and will ultimately benefit consumers." But that innovation will be costly if it is not accompanied by the appropriate amount of interpretation so individuals can make the best-informed choices for themselves.

Posted at 11:59 PM in Food and Drug Administration | Permalink | Comments (6)

January 12, 2015

Guest Post: 41 New Drugs Approved in '14 -- A Random Spike or a Growing Trend of Drug Innovation?

By Cambria Alpha-Cobb* and Anthony D. Sabatelli** --

If innovation drives progress, then 2014 was the year of progress! During the past year the U.S. Food and Drug Administration approved 41 new drugs. That is 14 more than 2013 and the highest number in 18 years! What spurred this increase? And what challenges do these new drugs face in the 2015 market?

The FDA publishes the drug approval data based on New Molecular Entities (NMEs) [1]. These drugs can be both the traditional small molecule drugs in addition to newer high-molecular weight biologics. For information on NMEs and how they are classified, see "The Scorecard- Fewer New Drug Approvals in 2013: What's in store for 2014?" [2] a previous blog post by Dr. Anthony Sabatelli. Using data published annually from the FDA, we plotted the number of approved NMEs since the 1940s [1][3], below. After a dramatic peak in 1996, our plot shows a steady decline in approvals, followed by very little turnaround throughout the first decade of the 21st century and then a slow recovery in the past few years. Not only does this 2014 spike continue a slow upward trend, but also the new generation of drugs it embodies is believed to represent key advances in new drug development, suggesting a more broad-based recovery [4].

One of the main changes to the drug pipeline has been the expansion of treatment options. Many of the breakthrough discoveries from the past year are diverging from the traditional small molecules into whole new technologies and therapies. Nearly 4 out of 10 of the approved NMEs in 2014 were for biologics, a dramatic increase from 1 in 10 biologic NMEs approved in 2005 [5]. The 2014 NMEs spanned 10 therapeutic areas, up from 8 last year, with infectious diseases dominating with 12 approvals [4]. Next in line were approvals for cancer treatments (8) and rare disease drugs (5), emphasizing the industry's focus on specialized products [6].

Chart of New Molecular Entities approved: Annual approved NMEs based on data from [1] and [3].

While this innovation is helping restore our faith in the drug industry, these drugs are arriving into a market where high prices are coming under attack, and more competition will only increase these attacks. Fierce Pharma identified six therapeutic areas, including some rare diseases and cancer treatment, where increased competition could lead to heavy price competition [7]. This competition raises questions about future commercial prospects and could suggest reduced future development efforts due to these new pricing pressures [8].

As John Carroll, editor of Fierce Biotech, states, "Approvals aren't enough to determine whether a pipeline strategy is successful or not." [8] However 2014 was the best year since 1996, and the innovative technologies provide encouragement that this spike might be part of a long-lived trend. Competition in pricing may hinder the sales of some of these new drugs, however the future is promising as firms venture from their comfort zones and embrace these breakthrough discoveries [8].

* Dr. Cambria Alpha-Cobb is a Technology Specialist at Dilworth IP
** Dr. Sabatelli is a Partner with Dilworth IP

[1]http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm20025676.htm
[2]http://www.dilworthip.com/scorecard-fewer-new-drug-approvals-2013-whats-store-2014/
[3]http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SummaryofNDAApprovalsReceipts1938tothepresent/default.htm
[4]http://www.forbes.com/sites/bernardmunos/2015/01/02/the-fda-approvals-of-2014/
[5]http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ucm373420.htm
[6]http://in.reuters.com/article/2015/01/01/pharmaceuticals-approvals-idINL6N0UE2C120150101
[7]http://www.fiercepharma.com/story/limited-attention-span-focus-these-market-shake-ups-2015/2014-12-24
[8]http://www.fiercebiotech.com/special-reports/biopharma-posts-chart-topping-41-new-drug-approvals-2014/2015-01-02?utm_medium=nl&utm_source=internal

Posted at 11:59 PM in Food and Drug Administration | Permalink | Comments (2)

January 04, 2015

October 06, 2014

Guest Post: Will Purple Become The New Orange? FDA Publishes Long-Awaited Lists Governing Biologics

By Anthony Sabatelli* --

Some fashion trends may come and go, but in the not too distant future the majority of prescription drug sales will be purple.¹ For those of you not yet familiar with this latest trend, allow me to explain.

Most drug products are small, synthetically produced substances. The common pain reliever ibuprofen, for example, contains only 33 atoms and has a molecular weight of 206. In contrast, there is a whole new class of complex drug products that are isolated or produced from biological sources such as living cells. These biologically produced drugs, more commonly called "biologics," are orders of magnitude larger than their small molecule cousins and present special challenges in their preparation, isolation, and administration. Insulin is a common example of a biologic. It is a protein having a molecular weight of approximately 5800. Another example is the hormone erythropoietin (or "EPO"), which is used to treat anemia. EPO is a far larger biological drug with a molecular weight of nearly 35,000.

So what does this have to do with the color purple?

First, Enter The Orange Book

Small-molecule prescription drugs are approved by the US Food and Drug Administration (FDA). In 1984, Congress passed the Drug Price Competition and Patent Restoration Act (commonly known as "Hatch-Waxman") to bring low-cost prescription drug products to consumers, while balancing the competing interests of the branded pharmaceutical industry and generic drug manufacturers. Hatch-Waxman provided a unique statutory link between the patent and regulatory systems and established a framework under which generic drugs could be marketed. Hatch-Waxman requires the FDA to publish information on approved drug products with their therapeutic equivalence information. Also published are patent and other exclusivity information for the approved drugs, setting the grounds for the complex litigation that results when the interests of the branded and generic drug manufacturers clash. The FDA publication in which this drug and patent information appears is known, not by its lengthy title², but rather by its distinctive orange cover -- hence, the "Orange Book."

Now Enter the Purple Book

Fast forward to 2014, or rather first to 2010. In March of that year, President Obama signed into law the Patient Protection and Affordable Care Act (more commonly known as "Obamacare"). One of the Act's provisions was the Biologics Price Competition and Innovation Act ("BPCIA"), which created an abbreviated licensure pathway for biologics that are demonstrated to be either "biosimilar" to or "interchangeable" with the originally approved product.³In other words, the legislation created a regulatory pathway for the approval and marketing of the generic equivalent of a biological drug. This regulatory pathway is just getting off the ground. Even though biologics have been around for a long time (synthetic insulin was marketed in 1982), no biosimilar product has as yet been approved in the United States. In fact, it is believed that only two biosimilar applications are currently pending before the FDA. However, this will all soon change and the first biosimilars are expected to receive approval in 2015.

Since the passing of the BPCIA, the FDA has issued various announcements on biologics and biosimilars, including a long-awaited Draft Guidance that was published in August. The big news, however, is that the FDA just published its first edition of the Purple Book, with the lengthy title -- "Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations." This publication, like its Orange Book Counterpart, lists approved biological drug products and will eventually list biosimilar and interchangeable products as they are approved. The published information, however, is still not complete. For example the date of first licensure and the expiry of product exclusivity are only listed for three products. Clearly, the FDA has much work ahead to compile complete information.

Will There Be A Color Clash?

It will be interesting to see how the Purple Book will function. Will it clash with the Orange Book? After all, orange and purple are not exactly complementary colors. Only time will tell as biologics overtake the pharmaceutical market and the first biosimilar and interchangeable products begin receiving approval.

__________________________

[1] As explained in this article, biologically produced drugs ("biologics") will be governed by the US Food and Drug Administration's (FDA's) newly established "Purple Book." Depending on the source and how the data is analyzed, biologics accounted for just 10 percent of annual prescription drug sales in 2010. By 2017, that number could well surpass 50 percent. Notwithstanding the data, the trend is clear that biologics will account for a majority of prescription drug sales.

[2] Approved Drug Products with Therapeutic Equivalence Evaluations

[3] "Biosimilars" and "Interchangeables" are two different types of biological generic products.

* Dr. Sabatelli is a Partner with Dilworth IP.

For additional information regarding this topci, please see:

• "FDA Announces 'Purple Book'," September 16, 2014

Posted at 10:58 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

September 16, 2014

FDA Announces "Purple Book"

By Paul Tully --

The new phone book is here? No, but close. The Food and Drug Administration ("FDA") announced on Friday that it has published its first listing of approved biologic drugs. The list will be supplemented with approved biosimilar alternatives to the biologic drugs, termed the "List of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations." Inevitably given a "color" designation (following the tradition of the "Orange Book" of approved small molecule drugs), the new listing of biologics is colloquially called the "Purple Book." Both the Center for Drug Evaluation and Research ("CDER") and the Center for Biologic Evaluation and Research (CBER) have published their own versions of the Purple Book (CDER List of Licensed Biological Products; CBER List of Licensed Biological Products; FDA Purple Book webpage).

The new lists disclose all approved biologic drugs and the date a product was licensed, as well as "whether the FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act." The Purple Book is intended to permit users to determine whether the FDA has licensed a biosimilar and whether such a biosimilar is interchangeable with an already-licensed reference biological product (i.e., an already-licensed FDA biological product). Both biosimilar and interchangeable biological products will be listed with regard to the reference product to which biosimilarity or interchangeability was demonstrated. The agency further announced that these lists will be updated "periodically."

This new resource is certain to become a valuable tool for life-sciences professionals, but it remains to be seen whether relevant patent information will ultimately make its way into the Purple Book, as is prevalent (and required) in its Orange Book cousin. Stay tuned.

Posted at 11:59 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

August 13, 2014

FDA Releases Another Prospective Guidance

By Kevin E. Noonan --

On August 5th, the U.S. Food and Drug Administration issued a "Guidance for Industry" entitled "Reference Product Exclusivity for Biological Products file under Section 351(a) of the PHS Act." Before setting forth the first word of the Guidance, the Administration set forth the following caveat:

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's or the Agency's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance.

The term of market exclusivity under the BPCIA (12 years; Sec. 351(k)(7), codified at 42 U.S.C. 55 262(k)) requires that the agency identify the date from which to calculate the term. This Guidance, prefaced by the quote set forth above, provides some grounds for making that determination. However, as with many of the FDA's Guidances on provisions of the law, the tentativeness of the principles set forth are more akin to hints than rules and provide little other than further evidence that the Administration will act with utmost caution (a stance understandable when taken with regard to substantive grounds for biosimilar approval but somewhat less so in the context of this Guidance).

The critical date with which the Guidance is concerned is the "date of first licensure" of the reference product under PHSA Sec. 351(k)(7)(C). This date determines not only the length of the market exclusivity of the reference product but also the time (4 years) that a biosimilar applicant must wait before filing an application for biosimilar approval. The Guidance notes that "[n]ot every licensure of a biological product under 351(a) is considered a 'first licensure' that gives rise to its own exclusivity period," where some changes in "previously licensed" reference products, from either the same or "related" reference product sponsors are expressly excluded from being considered as a date of first licensure. Because the agency recognizes that it is the reference drug sponsor who will have "superior information" about such changes or such relationships between companies, the Guidance sets forth "the types of information that reference product sponsors should provide to facilitate FDA's determination of the date of first licensure for their products."

The Guidance then sets forth these types of "superior information." Typically, the date of first licensure is "the initial date the particular product at issue was licensed in the United States." But there are exceptions codified into the statute; these include

• a supplement for the biological product that is the reference product; or

• a subsequent application filed by the same sponsor or manufacturer of the biological product (or a licensor, predecessor in interest, or other related entity) for:

-- a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or

-- a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

(These can be seen as "anti-evergreening" provisions.) The Guidance notes that the Agency has "experience in construing other provisions that require examination of the relationships between business entities to determine eligibility of a new drug application for exclusivity" (citing "Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions" (patent and exclusivity final rule), published in the Federal Register of October 3, 1994 (59 FR 50338 at 50359 and 50362)). In view of this experience, the Guidance asserts that the Agency will construe certain terms of the statute consistently to its previous determinations. Thus:

• the term "predecessor in interest" will be "any entity that the sponsor has taken over, merged with, or purchased, or that has granted the sponsor exclusive rights to market the biological product under the 351(a) application, or had exclusive rights to the data underlying that application";

• a "licensor" will be "any entity that has granted the sponsor a license to market the biological product, regardless of whether such license is exclusive" and shall "include, for instance, entities that continue to retain rights to develop, manufacture, or market the biological product, and/or rights to intellectual property that covers the biological product"; and

• one corporate entity will be considered an "other related entity" "if (1) either entity owns, controls, or has the power to own or control the other entity (either directly or through one or more other entities) or (2) the entities are under common ownership or control" or "if the entities are or were engaged in certain commercial collaborations relating to the development of the biological product(s) at issue." In this regard, the FDA "expects to consider not only ownership and control of the investigational new drug application (IND) and the BLA, but also the level of collaboration between the entities during the development program as a whole."

Regarding the statutory proscriptions against considering for the date of first licensure situations wherein there is "a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength" unless there are "modifications in the structure of the biological product" that results in a change in "safety, purity or potency," the Agency will need to determine what qualifies as "modifications in the structure of the biological product" that satisfy the statute. To do so, "a sponsor seeking to assist FDA in determining the date of first licensure for a reference product licensed under 351(a), should describe the structural similarities and differences between its proposed product and any previously licensed biological product that was the subject of a 351(a) application filed by the same sponsor or manufacturer (or its licensor, predecessor in interest, or other related entity)." Specifically, for a protein product the reference drug sponsor should describe "any differences in amino acid sequence, glycosylation patterns, tertiary structures, post-translational events (including any chemical modifications of the molecular structure such as pegylation), and infidelity of translation or transcription, among others." In addition, the Agency will perform a structural comparison of the reference drug product and the modified product, including "whether the modified product affects the same molecular target as the previously licensed product." For changes in cell lines to make the reference product, the Agency asserts that "modification of the structure will not simply be presumed" but rather require the product sponsor to submit relevant evidence that establishes the change.

In addition, according to the statute, the reference product sponsor will be required by the Agency to show the structural modification "results in a change in safety, purity or potency" (or alternatively and interchangeably, "safety and effectiveness"). The Agency will do this on a "case-by-case basis" based on scientific data (as provided by the sponsor). The Agency is willing to presume such a change if the sponsor establishes that the modified "product demonstrates that it affects a different molecular target than the original product" (where the Guidance defines "a difference molecular target" to mean any molecule in the body whose activity is modified by the product, resulting in a desirable therapeutic effect," including "receptors, enzymes, ion channels, structural or membrane transport proteins, nucleic acids, and pathogens, among others").

The final section of the Guidance sets forth expressly the information the Agency "suggests" the reference product sponsor should submit to support its date of first licensure. This information includes:

1. A list of all licensed biological products that are structurally related to the biological product that is the subject of the 351(a) application being considered. This list should include products that share some of the same principal molecular structural features of the product being considered, but generally can be limited to products that affect the target should be included. Where specific molecular targets have not been defined, this list should include products that share the narrowest target that can be characterized. This may be a pathway, cell type, tissue, or organ system. If this assessment results in the conclusion that no product that has the same molecular target or shares some of the same principal molecular structural features has been licensed, a sponsor should provide an adequate justification to support the assertion that there are no previously licensed products that are relevant for purposes of determining the date of first licensure.

2. Of those licensed biological products identified in item 1 above, a list of those for which the sponsor or one of its affiliates, including any licensors, predecessors in interest, or related entities, are the current or previous license holder.

3. Description of the structural differences between the proposed product and any products identified in item 2 above. For protein products, this should include, but is not limited to, changes in amino acid sequence, differences due to post-translational events, infidelity of translation or transcription, differences in glycosylation patterns or tertiary structure, and differences in biological activities.

4. Evidence of the change in safety, purity, and/or potency between the proposed product and any products identified in item 2 above. This should include, but is not limited to, a description of how the structural differences identified in item 3 above relate to changes in safety, purity, and/or potency.

And, of course, "any other information and data that would assist the FDA in making its determination."

Finally, the Guidance notes that it "is reviewing options for making information publicly available regarding reference product exclusivity and dates of first licensure" and will provide the information to the public on its website when the Agency decision has been made.

Posted at 11:59 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

May 14, 2014

FDA Releases Draft Guidance on Biosimilars

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 C_max, C_min , C_trough,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.

Posted at 11:55 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

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