A Review of the Status of Biosimilars in the U.S.

The Biologics Price Competition and Innovation (BPCI) Act of 2009 was enacted as part of the Patient Protection and Affordable Care Act to establish an abbreviated pathway for the licensure by Food and Drug Administration (FDA) of biological products demonstrated to be biosimilar to or interchangeable with a FDA-licensed reference product. We at the BRIC Wall Blog decided to review the current status of biosimilars in the U.S.

FDA Guidances

Since the BPCI Act was signed into law on March 23, 2010, the FDA has issued six guidances relating to biosimilars or reference biological products. These guidances are:

1.  Guidance for Industry on Biosimilars: Q & A’s Regarding Implementation of the BPCI Act of 2009 – issued February 9, 2012.

2.  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product – issued February 9, 2012.

3.  Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product – issued February 9, 2012.

4.  Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants – issued March 29, 2013.

5.  Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (Clinical Pharmacology Guidance) – issued May 13, 2014.

6.  Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (Exclusivity Guidance) – issued August 4, 2014.

A detailed examination of the Clinical Pharmacology Guidance and Exclusivity Guidance, the two guidances released in 2014, is provided below.

Clinical Pharmacology Guidance

Clinical pharmacology studies are a critical part of demonstrating biosimilarity and are used to support a demonstration that there are no clinically meaningful differences (in terms of safety, purity and potency) between a proposed biosimilar product and a reference product. The Clinical Pharmacology Guidance provides information for proposed biosimilar products for which pharmacokinetic (PK) and pharmacodynamic (PD) data are required as part of the stepwise approach in developing the data and information necessary to support a demonstration of biosimilarity. Specifically, this guidance discusses 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.

According to the guidance, in the step-wise assessment of biosimilarity, extensive and comparative structural and functional studies (such as, 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. The guidance describes four possible assessments of biosimilarity. These are:

1.  Highly similar with fingerprint-like similarity: Under this assessment, 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 result of the analysis permits a high level of confidence in the analytical similarity of the proposed biosimilar and the reference product. Thereupon, under this assessment, it is appropriate for the sponsor to use a more targeted and selective approach to conduct animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity. This is the gold standard.

2.  Highly similar:   Under this assessment, the proposed biosimilar product meets the statutory standard for analytical similarity. Specifically, the results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it is appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

3.  Similar: Under this assessment, information is needed to determine if the proposed biosimilar product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if the observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product. The example provided in the guidance is glycosylation. Glycosylation plays an important role in the PK of certain protein products and manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product would be helpful in resolving whether some of the differences in glycosylation identified in the analytical studies are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.

4.  Not similar: Under this assessment, differences in the results of the analytical characterization may lead to an assessment of “not similar” for the proposed biosimilar product. In this instance, further development under the 351(k) regulatory pathway (namely, the regulatory pathway for biosimilars) is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that are likely to lead to a highly similar biological product.

According to the guidance, the outcome of the comparative analytical characterization provides information to the sponsor regarding the next steps needed to demonstrate biosimilarity.

Exclusivity Guidance

The Exclusivity Guidance describes how the FDA will determine the date of first licensure of a reference product and the types of information reference product sponsors should provide to facilitate FDA’s determination of the date of first licensure for their products. The guidance states that in most instances, the date of first licensure will be the initial date the particular product at issue was licensed in the U.S. However, the 12-year exclusivity period does not apply if the licensure is for:

1.  A supplement for the biological product that is the reference product; or

2.  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.  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

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

Moreover, according to the guidance, the burden is on the sponsor to demonstrate that a new licensure meets the standards for exclusivity.

For biological products that may or may not be entitled to reference product exclusivity, the FDA suggests a four-step process for sponsors to provide certain relevant information.  Specifically, the FDA suggests that sponsors provide the following:

1.  A list of all the licensed biological products that are structurally related to the biological product that is the subject of the 351(a) application (namely, a biologics license application (BLA)) being considered.  This includes products that share the same molecular target or have some of the same principal molecular features.  Where molecular targets have not been defined, the list should include products that share the narrowest target that can be characterized (this may be a pathway, celltype, tissue or organ system).  If a sponsor determines there are no licensed products that fall into these categories, it must provide an “adequate justification” to support this assertion.

2.  Of the licensed products from item 1, a list of those which the sponsor or one of its affiliates, including any licensors, predecessors in interest, or related entities, are the current or previous license holder.  The term “licensors” is defined broadly to include “any entity that has granted the sponsor a license to market the biological product, regardless of whether such license is exclusive”. This definition includes 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. The term “predecessors in interest” has been interpreted by FDA to mean an entity (such as a corporation) that the sponsor has taken over, merged with, or purchased, or from which the sponsor has purchased all rights to the drug (namely, the reference product). Additionally, the FDA has construed the term “predecessor in interest” to include an entity which has granted to the sponsor exclusive rights to a new drug application or the data upon which exclusivity is based, which may include licensors, assignors, and joint venture partners, depending on the circumstances of a case. Moreover, the FDA will consider 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 a BLA application, or had exclusive rights to the data underlying the application to be a predecessor in interest. 

The BPCI Act does not define the term “other related entity”. Nonetheless, the FDA generally considers a sponsor to be a “related entity” if: (i) either entity owns, controls or has the power to own or control the other entity (either directly or thorough one or more other entities) or (ii) the entities are under common ownership or control. According to the guidance, the FDA expects to consider not only ownership and control of the investigational new drug application (IND) and BLA, but also the level of collaboration between the entities during the development of the program as a whole.

3.  A description of the structural differences between the proposed biological product and any products identified in item 2.  For protein products, sponsors are asked to discuss “differences in amino acid sequence, glycosylation patterns, tertiary structures, 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 biological product and any products identified in item 2. Such evidence should include a description of how the structural differences identified in item 3 relate to changes in safety, purity and/or potency.

The FDA encourages sponsors to provide this information at the time of 351(a) application is submitted (as correspondence to the application) or as an amendment to an application.

What is in a (biosimiliar) name?

There have been several reports that the FDA has completed a draft guidance document on the naming of biosimilar products. However, the reason the draft guidance has not yet been released is a delay by the Department of Health and Human Services in completing its review of the document. In fact, in August 2014, two of the Senate’s high ranking legislators on healthcare, Lamar Alexander (R-TN) and Orrin Hatch (R-UT), called for the release of FDA’s biosimilar naming guidance. Unfortunately, despite the Senators urging, the guidance has still not yet been released and the time table for release is unknown.

The Purple Book

In September 2014, the FDA began publishing the “Purple Book”, the biologic counterpart to the Orange Book for “small molecule” drugs. The book is split into two parts, one for products approved by the Center for Drug Evaluation and Research (CDER) and the other for products approved by the Center for Biologics Evaluation and Research (CBER). Information included in the Purple Book includes:

1.  BLA number;

2.  Product (Proper) Name;

3.  Proprietary Name;

4.  Date of Licensure;

5.  Date of First Licensure;

6.  Reference product Exclusivity Expiry Date;

7.  Interchangeable or biosimilar; and

8.  Withdrawn.

Unfortunately, the published information presently contained in the Purple Book is not very complete. Specifically, the date of first licensure and the date of expiration of product exclusivity is provided for only a very small number of products. Also, unlike the Orange Book, the Purple Book does not list any patent information.

Awaiting Approval

As readers may recall, in July 2014, Sandoz announced that it had filed a 351(k) application for a biosimilar version of filgrastim. Sandoz’ biosimilar of filgrastim is marketed in more than 40 countries under the brand name ZARZIO®. Approximately one month later, Celltrion announced the filing of its 351(k) application for a biosimilar of infliximab (Remicade®). The industry is anxiously awaiting news regarding the approval of these products.

This post was written by Lisa Mueller of Michael Best & Friedrich.

First Mailbox Appeal to be decided by the Federal Court of Appeals in Brazil: An Update

 

This is an update to our post on October 14, 2014. Yesterday, reporting Appellate Judge Messod Azulay from the 2nd Specialized Panel of the Federal Court of Appeals for the 2nd Circuit postponed the hearing of the first mailbox appeal. The reason for the postponement was due to the filing of an amicus brief by Abifina (Association of the Generic Industry). The Judge will summon the other parties to present a reply to Abifina’s brief. 

The BRIC Wall will continue to provide updates on this matter as they become available.

This post was written by Lisa Mueller and Roberto Rodrigues of Licks Attorneys.

 

 

First Mailbox Appeal to be decided by the Federal Court of Appeals in Brazil

This is an update to our post of September 22, 2014 regarding ongoing litigation in Brazil regarding the invalidity of 222 mailbox patents (namely, patent applications filed between January 1, 1995 and May 14, 1997, under the terms of Article 70.8 of the TRIPS Agreement). According to the Brazilian Patent and Trademark Office (INPI), these patents should have received a term of 20 years from their filing date. However, these patents mistakenly received a term of 10 years from the date of grant.

Since June 2014, three mailbox cases have been decided by the Federal Judges (Judges) in Brazil. Two Judges ruled in favor of the patent holders and one against. Not surprisingly, the Judges each conveyed different points of view regarding the inefficiency of the INPI to examine patent applications in a reasonable time and to deal with its current backlog.

The Judges ruling in favor of the patent holders stated INPI violated the IP Statute when it failed to comply with the rule requiring examination of mailbox applications before 2004 (as required by the IP Statute). The Judges also stated that the lawsuits filed by INPI to invalidate these patents were a violation of the constitutional principle of “legitimate expectation,” which requires a certain amount of predictability and trust in the acts of the Public Administration.

The Federal Court of Appeals will hear the first appeal of a mailbox case on October 21, 2014. The appeal was filed by the INPI against the decision rendered by Judge Brandão who rejected the lawsuits stating that the suits were a violation of the “legitimate expectation” principle.  The panel will comprise the Reporting Appellate Judge Hon. Messod Azulay from the 2nd Panel of the Court of Appeals. The panel will also include Judges André Fontes and Ivan Athié.

It is anticipated that Judge Fontes will decide against the patent.  Moreover, he might go as far as to suggest “killing” the entire patent rather than just correcting its term.  In addition, Judge Athié, a member of the 1st Panel and is replacing Appellate Judge Simone Schreiber (who is on vacation), has previously rendered some decisions against patents.  For example, in 2013, Judge Schreiber decided against a 2nd medical use patent covering Strattera (from Eli Lilly) for a lack of inventive activity.  Additionally, he voted for the invalidity of a patent covering Kaletra (from then Abbott Laboratories) due to a lack of novelty.   Thus, it will not be surprising if the Judges Athié and Fontes join forces in deciding against the mailbox patent.

Based on the composition of the panel, the odds are against a favorable outcome for the patent.  In fact, Reporting Appellate Judge Azulay may represent the the last hope for the patent.  The parties and Interfarma (Brazilian Research-based Pharmaceutical Manufacturers Association), which has not yet submitted an amicus brief in connection with this lawsuit, will have to act fast next week if they hope to avoid an unfavorable outcome.

The BRIC Wall Blog is pleased to announce that Roberto Rodrigues of Licks Attorneys will be attending the hearing on October 21st.  Mr. Rodrigues will be sending live updates from the court which we will post as quickly as possible on October 21st.

This post was written by Lisa Mueller and Roberto Rodrigues of Licks Attorneys.

Patent Term Adjustment: Not available solely in the U.S.

Patent term adjustment (PTA) is a process of extending the term of a U.S. patent as a result of delays caused by the U.S. Patent Office (USPTO) during the prosecution.  The total PTA is added to the 20 year term of a patent.  The PTA provisions of the American Inventors Protection Act of 1999 allow for term adjustment if:  (1) the USPTO fails to initially act on an application within fourteen months of its filing date; (2) the USPTO fails to respond to a reply or appeal by applicant within four months of the reply or appeal; (3) the USPTO fails to act on an application within four months of a Board of Patent Appeals and Interferences or court decision in an application containing allowable claims; (4) the USPTO fails to issue a patent within four months of the date the issue fee was paid; (5) the USPTO fails to issue a patent within three years of its filing date; (6) the issuance of a patent is delayed due to imposition of a secrecy order; (7) the issuance of a patent is delayed due to an interference proceeding; or (8) the issuance of a patent is delayed due to successful appellate review.  A patent term is extendible for a period equivalent to the delay.

PTA can be complicated and requires both the USPTO and Patentee to monitor several events during prosecution.  The USPTO calculates PTA and includes a notification of the PTA in the Notice of Allowance.  The PTA is printed on the cover sheet of the patent.  A Patentee must file a request for reconsideration of the PTA within two months from the date the patent was granted (although this due date is extendible with the payment of extension fees).

Unlike the U.S., Europe, Canada, Mexico, Japan, Russia, China, Australia and India do not provide any PTA for patent office delays.  However, South Korea, El Salvador and Columbia provide PTA for delays caused by their respective patent offices in issuing a patent.

PTA in South Korea

In 2012, the South Korean Patent law was amended to introduce a PTA system pursuant to the provisions of the Korea-U.S. Free Trade Agreement.  Specifically, PTA is available for any patent application filed after March 15, 2012 if the registration of a patent is delayed more than:

1.  Four years from the filing date of the application; or

2.  Three years from the date of filing a request for examination.

A patent term is extendible for a period equivalent to the delay. Any delays attributable to the applicant (such as delays by the applicant in responding to a notice from Korean Intellectual Property Office (KIPO)) will not be included in the PTA period.  Also, unlike the U.S., PTA is not automatically granted by the KIPO, but is only awarded after request by the Patentee.  Such a request must be filed within three months from the date of issuance of a patent.

PTA in El Salvador

As a result of the ratification by El Salvador of the DR-CAFTA Dominican Republic – Central America Free Trade Agreement (DR-CAFTA), it is possible to request PTA of a patent in El Salvador for up to an additional 550 days due to delays in the granting of a patent by the Patent Office in El Salvador.  Specifically, PTA is available for any patent application filed after January 20, 2006, if the registration of a patent is delayed more than:

  1. Five years from the filing date of the application; or
  1. Three years from the date of filing a request for examination.

A Patentee must request file a request for extension of a patent term that includes the circumstances and reasons that lead to the delay in registration.

PTA in Columbia

On September 29, 2014, the Columbian government issued Decree 1873 providing “compensation” (namely, PTA) in the event of unjustified delay by the Columbian Patent Office in issuing patents.  Unfortunately, this compensation does not apply to pharmaceutical patents.  According to the decree, a patent term is extendible for each day of “unreasonable delay” in the granting of a patent.  An “unreasonable delay” exists when a decision to grant a patent takes longer than:

1.  Five years from the filing date of the application; or

2.  Three years from the date of filing a request for examination.

A Patentee must request restoration of the patent term within two months of the date of issuance of a patent.

Please watch the BRIC Wall Blog for further updates on patent term adjustment.

This post was written by Lisa Mueller.