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Biosimilars Law Blog

Posted in News & Events

Biosimilars Marching Forward as Planned

With the 5-4 decision from the U. S. Supreme Court upholding almost the entire Patient Protection and Affordable Care Act, for those who were hoping for a fresh opportunity to re-debate the biosimilars statute, and perhaps plug some holes or make some basic changes to the law, those hopes have been dashed for now.

While the merits of the Biologics and Price Competition Act were not in play during the Supreme Court’s evaluation of the constitutionality of PPACA, few changes to the approval and regulations of medicines in this country have had the potential for such a large effect on what medicines will be available to patients.  Prior to enactment, there was no abbreviated pathway for approval of biologic medicines under the Public Health Service Act. BPCIA, buried within PPACA, created that pathway in the U.S.

With Thursday’s (June 28, 2012) Supreme Court decision, any remaining legal debris has been cleared from the path and it looks like biosimilars in the U.S. will march ahead.

Posted in News & Events

Breaking decisions from the Supreme Court: Term in review

On Tuesday afternoon, three of Hogan Lovells’ Appellate practice partners will provide an analysis of some of the key decisions that will impact businesses as the Supreme Court concludes its current term.

Neal Katyal, former Acting Solicitor General of the United States and Appellate practice Co-Director, Cate Stetson, Co-Director of our Appellate practice; and Chris Handman, a seasoned Appellate partner, will conduct a 30-minute webcast on the ramifications of decisions handed down by the high court this term, which may include the Affordable Care Act, and how the three key cases challenging aspects of President Obama’s healthcare plan will be resolved.  As previously posted, the outcome of the decisions on the Affordable Care Act could have direct implications for the U. S. biosimilars pathway.

The half-hour program, which begins at 1 p.m. on June 26, will also provide essential background on the Supreme Court, including the composition, recent personnel changes, and background on the Justices, and explain the impact of these structures on the decisions.

Register online for the free webcast.

Posted in News & Events

Making U.S. Biosimilars a Reality – Everyone Seeks Clarity and Direction from FDA

The usual suspects from regulated industry, patient and physician groups turned out for the U.S. Food and Drug Administration’s public meeting on the biosimilars guidances.  Now that the draft guidances have been out for several months and the FDA has a stack of comments to consider, the dialogue has moved from the theoretical to the practical:  How is this really all going to work?

Stakeholders lined up for their turns at the podium at the Public Hearing held on May 11, 2012.  To be sure, there were the predictable disagreements among stakeholders on issues such as naming and interchangeability, in addition to the now-familiar (and sometimes conflicting) views on the need to protect patient safety, encourage product innovation, and create meaningful cost-savings.  However, the strong consensus that FDA should implement an education and communication plan about biosimilars was noteworthy.  For example, a speaker from the American Pharmacists Association said pharmacists don’t know what to expect or do when they start seeing prescriptions for biosimilar products. Patient advocates and physician groups also said their constituents will need additional educational materials and are interested in interactive presentations from FDA on the appropriate use of these new products. 

It’s not clear what steps FDA will take to articulate clear policy and provide guidance in these areas.  At the hearing, however, the agency asked speakers for details and supporting data, and encouraged everyone to submit these and other concrete suggestions on implementation to the docket (FDA-2011-D-0618), which is open until May 25th.

Posted in News & Events

SCOTUS review of the Patient Protection and Affordable Care Act and “the biosimilar thing”

While a Supreme Court ruling on the constitutionality of the healthcare reform law is not expected until June, sponsors and regulators continue to lay the groundwork for biosimilars in the U.S. An unintended consequence of embedding the Biologics Price Competition and Innovation Act within PPACA without a severability clause leaves the biosimilars law vulnerable to the fate of constitutional challenges to more controversial parts of the Affordable Care Act. 

The Supreme Court recently concluded three days of oral argument challenging the constitutionality of several provisions of PPACA. There was general agreement amongst the petitioners, defendants and the Justices that the biosimilars provisions are “peripheral” to the challenges under review by the Court.  Nevertheless, it remains possible that if the Court decides any one provision (such as the so-called “individual mandate”) is unconstitutional, rather than parsing out the constitutional bits, even those recognized to be peripheral to the provisions at issue, the Court could strike down the entire Act to let Congress sort it out.  So even though “the biosimilar thing,” as described by Justice Breyer, would seem to stand on its own without the other parts of the Act, the BPCIA could be swept into a sweeping decision that would invalidate the biosimilars pathway along with the rest of the Act.

The BPCIA was the result of significant bipartisan effort and support in both the House and Senate.  FDA reports (PDF) at least 35 requests for biosimilar pre-IND meetings as of February 15 and is holding a public meeting on the three issued draft biosimilar guidances in May.  If the Supreme Court throws out the BPCIA with the bath water, it is reasonable to expect that the law would be re-enacted as a stand-alone.  However, as we head into the presidential election season, the ability or will of Congress to enact any laws may come to a halt.  There is little profit here in speculation, but in terms of setting expectations, it is possible that the BPCIA would come off the books temporarily, leaving many interesting questions about the legal significance of the gap period if the law were re-enacted in, say, early 2013. 

Posted in News & Events

Awaiting FDA Guidance on Interchangeability for Biosimilars

The three draft Guidances recently released by the U.S. Food and Drug Administration on implementation of the Biologics Price Competition and Innovation Act of 2009 focus on how to demonstrate biosimilarity but don’t say much about demonstrating interchangeability.  FDA has asked for stakeholder input on biosimilar interchangeability at the agency’s upcoming one-day public hearing on the biosimilar draft Guidances to be held on May 11, 2012. Docket No. FDA-2011-D-0618. However, there are a few tidbits on interchangeability in the draft Guidances.

BPCIA—Interchangeability

By statute, to be found interchangeable, a biological product must:

  • Be biosimilar to the reference product;
  • Be expected to produce the same clinical result as the reference product in any given patient; and
  • If the product will be administered more than once to a patient, the risk (in terms of safety or diminished efficacy) associated with switching between the product and the reference product cannot be greater than the risk of repeated use of the reference product.

There are two potentially significant implications of FDA determining that a product is interchangeable with a reference product.  First, an FDA finding of interchangeability means the product “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”  An important unanswered question is how this federal statutory definition will intersect with state laws governing pharmacy substitution of prescribed drugs.  Second, the first biological product found to be interchangeable with a given reference product receives a period of exclusivity during which no other product can be approved as interchangeable to the same reference product.

Statements on Interchangeability in the Draft Guidances

For those awaiting guidance on interchangeability, the draft Guidances released in February provide remarkably little, but there are a few statements of interest.

FDA is not sure what data will be needed to demonstrate interchangeability

The Q&A Guidance (PDF) affirms the ability to file for and achieve an interchangeability determination in an initial 351(k) application, as well as in a supplement, and in the same paragraph states:

“At this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application given the statutory standard for interchangeability and the sequential nature of that assessment. FDA is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.” (Q&A I.14.)

Interchangeability applies to delivery device

Differences in products’ delivery devices or container closures may be relevant to interchangeability.

“(D)esign differences in the delivery device or container closure system used with the proposed biosimilar product may be acceptable. . . . Additional considerations apply for a proposed interchangeable product. For example, in reviewing an application for a proposed interchangeable product, FDA may consider whether the differences from the reference product significantly alter critical design attributes, product performance, or operating principles, or would require additional instruction to healthcare providers or patients, for patients to be safely alternated or switched between the reference product and one or more interchangeable products without the intervention of the prescribing healthcare provider. Additional performance data about the delivery device may also be necessary.” (Q&A I.4.)

Interchangeability (or not) should be stated in the label

In the section on labeling of the Scientific Considerations Guidance (PDF), mention is made that labeling should clearly indicate “This product (has or has not) been determined to be interchangeable with the reference product.” (Scientific Considerations at 21)

Foreign-reference product data not likely to support interchangeability

While elaborating on the considerations for sponsors in the use of comparative non-clinical and clinical data with a non-U.S.-licensed product, FDA notes that such data are unlikely to fulfill the additional requirements to support interchangeability.

“At this time, as a scientific matter, it is unlikely that clinical comparisons with a non-U.S.-licensed product would be an adequate basis to support the additional criteria required for a determination of interchangeability with the U.S.-licensed reference product.” (Q&A I.8)

*                       *                       *

So, although the Guidances provide significant information and direction regarding biosimilarity and biosimilar applications, FDA’s thinking on interchangeability – or at least what the agency is willing to say publicly about its thinking – is not as advanced.  The May 11 public hearing may be an opportunity to learn more, identify to FDA issues that need to be addressed, and perhaps propose how they should be addressed.

Posted in News & Events

Biosimilars: Who’s Who at FDA?

According to several recent presentations by U.S. Food and Drug Administration (FDA) officials, the agency has established three committees charged with discussing and coordinating issues related to biosimilars to ensure consistency in the regulatory approach and guidance to sponsors.  While FDA set up this infrastructure some time ago, with the issuance of the Draft Guidances and the upcoming Stakeholder Meeting, it is important to understand where the key policy and precedent-setting decisions will be made. 

Essentially, CDER and CBER have established a joint implementation committee, and CDER and CBER have each established their own review committees.   CDER, however, appears to be playing a lead role in managing the process, as sponsors are directed under the Biosimilars Q&A Document to contact CDER’s Office of Medical Policy to initiate any questions or dialogue with the joint implementation committee.

We also note that there will be one or more representatives from the Office of the Commissioner – which may include the Office of the Chief Counsel – on the joint implementation committee.  The Office of the Commissioner typically refrains from being directly involved in individual product development programs and reviews.  However, the Office of the Commissioner is now well positioned to play a role on cross-cutting decisions impacting biosimilars, particularly as issues arise at the Center level.  Whether the role of the Office of the Commissioner will be active or will be more that of an observer remains to be seen.

The FDA biosimilars committees are:

  • The Biosimilar Implementation Committee;
  • The CDER Biosimilar Review Committee; and
  • The CBER Biosimilar Review Committee

The CDER/CBER joint Biosimilar Implementation Committee is the agency’s forum for discussing overarching policy issues, while the review committees focus on product-specific and scientific issues related to biosimilars development programs. 

CDER/CBER Biosimilar Implementation Committee (BIC):

Janet Woodcock, M.D., and Karen Midthun, M.D, are the co-Chairs for the BIC (Dr. Woodcock is CDER’s Director, and Dr. Midthun is CBER’s Director).  The lead for the committee is Rachel Sherman, M.D., who leads CDER’s Office of Medical Policy.  This cross-center committee consists of staff from CDER, CBER, CDRH, and the Office of the Commissioner.

The BIC has been tasked with focusing on cross-center policy issues regarding implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCIA), including developing initial interpretations of the statute, policy development, and agency resource needs. 

CDER Biosimilar Review Committee & CBER Biosimilar Review Committee (BRC):

John Jenkins, M.D., Director of Office of New Drugs, is Chair of CDER’s BRC, and Robert Yetter, Ph.D, Associate Director for Review Management, is the Chair of CBER’s BRC, and both groups have members from both centers.  These committees have been tasked with product-specific issues related to biosimilars within CDER.

Compiled with assistance from Anne R. Mutashi.

Posted in News & Events

Public Comment on FDA Draft Biosimilars Guidances

Thoughts on the U.S. Food and Drug Administration’s recently issued biosimilar guidance documents?  The time to act is now.  As described in our earlier post , FDA must provide the public an opportunity to comment on the three recently issued biosimilars draft guidances.  42 USC 262(k)(8)(B)(i).  As described in the announcement notices in the Federal Register, FDA has opened a dedicated docket for each guidance:

FDA will accept comments to these dockets until April 16, 2012.

As the agency acknowledges in the Federal Register notices, FDA regulations allow the public to comment at any time on any guidance.  21 CFR 10.115(g)(5).  Nevertheless, we expect that all three of the guidance dockets will see a significant amount of input from industry stakeholders and all other interested persons.

With regard to the Q & A Guidance, FDA has also announced that:

“FDA intends to update this guidance to include additional Q&As as appropriate and intends to post information by Q&A number on FDA’s Web site regarding the publication date of draft guidance Q&As for comment, the comment period, and the publication date of final guidance Q&As.”

77 Fed. Reg. 8885, 8886 (February 15, 2012).  We will update you as soon as FDA issues any further draft Q&As for comment or finalizes any of the recently proposed ones.

Posted in News & Events

FDA’s Long-Awaited Biosimilars Guidances—The Prologue to Biosimilars in the U.S. has been published

The U.S. Food and Drug Administration released three draft Guidances on implementation of the Biologics Price Competition and Innovation Act of 2009. The Q&A, Scientific Considerations, and Quality Guidances cover the overall framework for biosimilar application requirements as envisioned by FDA. Notably, FDA has deferred guidance on how to establish interchangeability.

FDA emphasizes a “step-wise” approach for sponsors in their development plans for biosimilars and the Agency’s “totality of the evidence” approach to review of biosimilar applications. While there is little that is unexpected or unanticipated for those that have been following the public discourse, there are a number of things to note:

  • Potential flexibility on the choice of clinical endpoints to support a proposed biosimilar, including endpoints different from those used to support approval of the reference product.
  • Potential flexibility on use of data from non-U.S.-licensed products as part of the demonstration of biosimilarity.
  •  Important discussions on delivery devices that accompany biological products, on establishing the biosimilar has the same “strength” as the reference product, and on the possibility of post-market studies for biosimilars.
  • How biosimilars may be labeled to identify the corresponding reference product, indication(s), route of administration, and interchangeability (or lack thereof).
  • A discussion of what constitutes “publicly available” information regarding prior determinations that the reference product is safe, pure and potent, including how the FDA’s  “action package” for a Biologics License Application (BLA) product may be used.
  • Definitions of “protein” and “chemically synthesized polypeptide” that affect whether products are regulated under the Public Health Service Act or Food Drug and Cosmetic Act.

The draft Guidances will be open for comment and the process and deadlines for submitting comments – including the scheduling of any public meetings on the Guidances – will be published in the Federal Register. We note that FDA took roughly five years to finalize the regulations governing the 1984 Hatch-Waxman Act on generic drug products. How the agency will process the volumes of comments that are likely to follow the publication of these landmark draft guidance documents will be interesting and worthy of close attention.

Posted in Global Comparisons

EMA regulatory approval changes for biosimilars on the horizon in the E.U.?

As mentioned in a previous post, the EMA set the standard for regulatory approval of biosimilars* with the adoption of their overarching general guideline in 2005 (CHMP/437/04 — PDF), followed shortly thereafter by guidelines on quality issues (EMEA/CHMP/BWP/49348/2005 — PDF) and on non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 — PDF). The pathway for biosimilar approval was further delineated by the issuance of a number of product-class specific guidances, e.g., for epoetins and somatropins.

After more than five years of experience reviewing, approving and regulating biosimilars, the EMA has recently issued concept papers that articulate contemplated changes in the general biosimilars guidelines. While some may view these as a loosening of standards, others may view these contemplated changes as a refinement of the pathway. Either way, Europe’s experience with biosimilars is likely to color the U.S. Food and Drug Administration’s (FDA) implementation of the U.S. biosimilar pathway enacted in the Biologics Price Competition and Innovation Act of 2009 (PDF). FDA expects to issue initial guidance soon.

The comment period for the EMA concept paper on the revision of guidelines for biosimilars’ non-clinical and clinical issues (PDF) was open until December 31, 2011; the comment period for the concept paper on the revision of the general guidelines (PDF) is open until February 29, 2012. Draft revised guidelines are expected to be issued by the EMA in the first half of 2012.


*Called “similar biological medicinal products” under E.U. law (Directive 2001/83/EC)

Posted in Biosimilar Definitions

Biosimilars, biosimilarity—what does ‘highly similar’ mean?

It is largely up to the FDA.

In the U.S., what constitutes “highly similar” in the context of biosimilars is ultimately up to how the U.S. Food and Drug Admininstration applies the statutory language under the Biologics Price Competition and Innovation Act of 2009 (PDF). Demonstration that a biological product is “highly similar” to its reference product is a central tenet for biosimilarity under what is known as the 351(k) pathway, which establishes the abbreviated approval pathway for a biosimilar in the U.S. The statute reads, in part, as the initial step in demonstrating biosimilarity:

An application submitted under this subsection shall include information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies that demonstrate that the biological product is highly similar to the reference product nothwithstanding minor differences in clinically inactive components.

How the FDA interprets “highly similar” has far-reaching implications that may include:

  • Products that are similar enough to use the abbreviated 351(k) pathway but different enough to avoid IP protections of the reference biologic;
  • 12-year exclusivity for second generation biologic products;
  • “Improved” versions of a previously approved product.

In crafting the biosimilars legislation, Congress ceded a lot of scientific discretion to the FDA. To their credit, the FDA has convened a number of opportunities for stakeholder input both leading up to and after passage of the BPCIA.

In this approach, FDA has followed in the footsteps of their European counterparts. Europe has been ahead of the U.S. in both the legal authorization and regulatory guidance for biosimilars. As part of their ongoing dialogue with stakeholders in the E.U., the European Medicines Agency convened a stakeholder meeting in July 2009 to discuss guidelines for biosimilar monoclonal antibodies because the next wave of biosimilar applications is likely to include these products. As indicated in an unofficial meeting summary, innovator and biosimilar stakeholders generally agreed that amino acid differences should not be allowed. While noting that the U.S. and E.U. biosimilar schemes are not the same, the principle invoked here for biosimilarity is that the products should be as structurally similar as possible. Many aspects of structure, such as glysosylation, may not be completely controlled by the developer and manufacturer, but amino acid sequence can be controlled. And where such control is possible, it should be applied. Thus from a scientific perspective, there is no reason to tolerate differences in amino acid sequence between the reference and biosimilar product. Identical amino acid sequences may not be sufficient to demonstrate the products are “highly similar” but they are likely necessary.

As FDA develops its biosimilar guidances, it will be interesting to see whether such principles are embraced and articulated. The result will have a large impact on biosimilar applications and the ever-evolving definition of “highly similar.”