January 20, 2015

FDA Advisory Committee Approves First U.S. Biosimilar Application

The FDA advisory committee that recently considered the first U.S. application for a biosimilar drug filed pursuant to the Biologics Price Competition and Innovation Act of 2009 (BPCIA) concluded that the application should proceed (see here). The FDA’s Oncologic Drugs Advisory Committee (ODAC) was asked to consider the following question regarding the Sandoz submission of EP2006 as a biosimilar to Amgen’s blockbuster biologic drug Neupogen, which is used to boost the immune system for cancer and other patients: 
Does the committee agree that based on the totality of the evidence, EP2006 should receive licensure for each of the 5 indications for which US-licensed Neupogen is currently licensed?  
Following a day-long public meeting that heard from diverse stakeholders, the ODAC unanimously approved the submission. This meeting and its vote shows that the pathway for biosimilar approval has officially been activated in the U.S., but these initial questions of biosimilarity for approval are not the only hurdles in the regulatory scheme. Left for another day is the key question of whether an approved biosimilar will be greenlighted as “interchangeable” with the approved brand name product, thus making it available for substitution when filling prescriptions. The FDA defines interchangeability:  
An “interchangeable” biological product is biosimilar to the reference product, and can be expected to produce the same clinical result as the reference product in any given patient.  If administered more than once to an individual (as many biological products are), the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product will not be greater than the risk of using the reference product without such alternation or switch. Once determined “interchangeable” two biological products will thus be able to be substituted for each other (i.e., interchanged) by a pharmacist without the intervention of the health care provider. Pharmacists will be responsible for knowing which biological products are interchangeable and which will require prescriber prescription before substitution. 
Substitution laws for pharmaceuticals are state laws, and because biosimlar substitution is now on the radar screen, some states have already seen legislative action which is quite early considering that no biosimilars have completed regulatory review and will not for some time. Obviously, the standards for substitution will govern whether any approved biosimilar can compete for distribution with an already approved and well-known original biologic. The logic of any generic drug marketplace is to offer lower-cost options to high-priced brand-name drugs; for the scheme to work, a proposed substitute must provide the same therapeutic benefit to a consumer. In contrast to traditional chemically-based pharmaceutical synthesis, biologic drugs are produced in biological systems, which can introduce some differences in various cycles of production; any differences in a biosimilar must not degrade the overall clinical benefit in order to replace the existing pioneer biologic. That requirement and its implementation will surely test how well the BPCIA was designed to establish a true biosimilar approval process that results in a more competitive marketplace for biologics.

January 5, 2015

Biosimilars Arrive at the FDA: Market Competition for Biologics Begins with Today's Preliminary FDA Staff Approval

This is a watershed week for biotech drugs (more formally known as biologics). Biotech drugs represent the culmination of molecular investigations into disease processes in order to identify when the use of a natural molecule (e.g., an antibody) offers a targeted treatment to specifically selected patients (e.g, Herceptin for breast cancer, Gleevec for leukemias). In 2014, the FDA issued 41 new drug approvals, a relatively high volume as compared to previous years. Biologics comprise a significant sector of drug approvals: these biotech drugs are often developed as targeted therapies and generally produced with biological processes, rather than chemical synthesis. Biologics have been available for several decades and often command significant (and sometimes unaffordable) prices; in general, there has been no "generic" market competition for a pioneer biologic in the U.S. (reproducing a biologic with high fidelity is more challenging than for standard chemically synthesized pharmaceuticals because the biologic is produced by biological processes). However, 2014 was the year in which the U.S. saw the opening moves in the efforts to bring biosimilars (or follow-on biologics) to the market. With the passage of the Affordable Care Act (ACA), the Biologics Price Competition and Innovation Act of 2009 (BPCIA), as part of that legislation, took effect in 2010. The BPCIA designed an abbreviated approval pathway for products shown to be biosimilar to or interchangeable with the original reference biologic product
Under the BPCI Act, a sponsor may seek approval of a “biosimilar” product under new section 351(k) of the PHS Act.  A biological product may be demonstrated to be “biosimilar” if data show that the product is “highly similar” to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency. 

In order to meet the higher standard of interchangeability, a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product. Interchangeable products may be substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider.
The recent law is somewhat similar in concept (if not exact details) to the Hatch-Waxman Act of 1984, which designed a generic drug approval process for standard pharmaceuticals. The BPCIA contains the kind of tradeoffs that were seen in Hatch-Waxman, where the generic follower can rely on clinical data developed by the first manufacturer and thus avoid de novo clinical trials, while the first company is rewarded with one or more periods of market exclusivity. From the date of first licensure of the licensed biologic referenced in the biosimilar application, there is a 12-year market exclusivity period accorded to the first biologic. This period is independent of any patent rights that may pertain to the product. Several key developments related to the BPCIA occurred in 2014. In July of last year, the FDA received its first biologics license application (BLA) for a biosimilar version of Amgen's biologic Neupogen, filed by Novartis. The Oncologic Drugs Advisory Committee of the FDA will meet this week to take up the Novartis application. Today's release of a preliminary approval by the FDA staff of the proposed biosimilar ("there are no clinically meaningful differences in the effectiveness") is a watershed development that precedes the meeting this week. 

In another recent legal development, the BPCIA lays out a complicated set of patent-related information exchanges between the first biologic manufacturer and the biosimilar follower. In the recent opinion from the Federal Circuit, Sandoz v. Amgen, the court affirmed a district court’s refusal to entertain allegations of irregularities in the patent information scheme by the biosimilar entrant (Sandoz) against the pioneer manufacturer (Amgen). The Federal Circuit did not find declaratory judgment jurisdiction where Sandoz had not yet made a formal biosimilar application to the FDA, and would not consider its allegations out of turn from the sequence of events dictated by the BPCIA. With these recent moves from the FDA and the Federal Circuit,  the age of biosimilars in the U.S. - anticipated for some years - will begin to take concrete shape in 2015.

December 29, 2014

FDA's 2015 Regulatory Targets in Genetic Testing: Laboratory-Derived Tests and Next-Generation Sequencing

The FDA is holding two upcoming public workshops in the next several months that consider several areas of genetic test regulation which may be the subject of upcoming FDA actions. The FDA derives authority for any proposed oversight of genetic testing from its general mandate to regulate medical devices; one category of device is the in vitro diagnostic (IVD), a term that generally captures tests and assays that are used in the diagnosis (or treatment) of disease, including genetic tests. The ongoing issue of whether laboratory-derived tests (LDT) should be directly regulated by the agency continues to be unresolved. Because LDTs constitute the majority of commercially available genetic tests in the U.S., the absence of regulation regarding the utility and/or validity of these tests means that most of the genetic tests in the U.S. are not subject to FDA oversight (however, general certification of laboratories does occur under the Clinical Laboratory Improvement Amendments (CLIA). The FDA published its Framework for Regulatory Oversight of Laboratory Developed Tests last fall, and generally proposed a risk-based classification and regulatory structure for LDTs. The agency’s rationale for increasing its involvement in this genetic testing sector was provided: 
LDT’s are important to the continued development of personalized medicine, but it is important that in vitro diagnostics are accurate so that patients and health care providers do not seek unnecessary treatments, delay needed treatments, or become exposed to inappropriate therapies.The FDA has generally not enforced premarket review and other applicable FDA requirements because LDTs were relatively simple lab tests and generally available on a limited basis. But, due to advances in technology and business models, LDTs have evolved and proliferated significantly since the FDA first obtained comprehensive authority to regulate all in vitro diagnostics as devices in 1976.
The public workshop for discussion of the LDT framework will be held on January 8-9, 2015; public comments to the online document can still be filed until until February 2, 2015.

The FDA is also considering how it might interface with the field of next generation sequencing (NGS), a term applied to high-throughput methods for generating multiple DNA sequences in parallel; such methods can produce whole-genome or exome-only DNA sequences efficiently and quickly. Typically, the sequencing operation does not start with a particular clinical goal in mind or a particular gene or mutation of interest; the approach is clinically neutral and aims to produce genome-wide DNA sequences. NGS sequencing therefore creates high-volume data that requires serious computational analysis in order to create meaningful, useful results for clinical application. NGS can generate data that reveals rare and previously unknown genetic variants. Because of the broad-brush nature of whole-genome sequencing, it has the potential to reveal incidental (undirected) findings; the ethical management of such information by medical personnel has been the subject of bioethical and academic debate. The FDA has issued a discussion paper which highlights specific concerns and possible standardization for NGS technologies: 
NGS tests are unique among existing IVDs in the amount of data that can be generated, the lack of an a priori definition of what will be detected, and the number of clinical interpretations that can be made from a single patient sample. In order to continue to support the development of useful medical information, FDA believes the most efficient possible approaches to regulating NGS tests should be considered. Among the possibilities, a standards-based approach to analytical performance of NGS tests and the use of centralized curated databases containing up-to-date evidence to support clinical performance are under discussion.
The public workshop on NGS regulation will be held on February 20, 2015; the agency will  receive comments until March 20, 2015.

December 22, 2014

Myriad Genetics Loses Latest Round of BRCA Genetic Testing Litigation at the Federal Circuit

In 2013, the Supreme Court considered whether isolated genes qualified as patentable subject matter in AMP v. Myriad (see here for analysis). That case centered on Myriad Genetics' patent claims to isolated BRCA1 and BRCA2 genes which are used to provide genetic testing to detect an increased genetic susceptibility to developing breast and/or ovarian cancer. The Court rejected the patent claims to the isolated genes, noting that:
[S]eparating that gene from its surrounding genetic material is not an act of invention. 
After the Court’s opinion was issued, several genetic testing companies immediately moved into the marketplace, offering diagnostic genetic testing for mutations in the BRCA1 and BRCA2 genes (Ambry Genetics and others, see here). At that time, Myriad still held other patent claims that had not been challenged in the earlier litigation. Therefore, following the Supreme Court decision, Myriad promptly filed suit against the new entrants, asserting remaining patent claims to DNA primers (short sequences used to amplify/copy a BRCA1/2 sequence) and to testing methods. Myriad sought a preliminary injunction against Ambry Genetics. In University of Utah Research Foundation et al. v. Ambry Genetics, issued earlier this year, a federal district court denied a preliminary injunction to Myriad, basing its decision on a conclusion that Myriad could not show a reasonable likelihood of success on the merits of the litigation because the asserted patent claims were likely not patentable subject matter. Now, on appeal, the Federal Circuit has upheld the denial of the preliminary injunction, in In re BRCA1-And BRCA2-Based Hereditary Cancer Test Patent Litigation, issued last week. With respect to the patent claims to the primers (short DNA strands that initiate the synthesis of a longer DNA molecule, such as a gene) the court stated: 
The primers before us are not distinguishable from the isolated DNA found patent-ineligible in Myriad and are not similar to the cDNA found to be patent-eligible. Primers necessarily contain the identical sequence of the BRCA sequence directly opposite to the strand to which they are designed to bind. They are structurally identical to the ends of DNA strands found in nature. 
In this recent litigation, Myriad had also asserted several method claims that captured the basic process of comparing the sequence of a patient’s BRCA1 or BRCA2 genes with a wild-type (normal) DNA sequence of the relevant gene. In its analysis of these claims, the Federal Circuit rejected the claims, not because of a natural phenomenon or law of nature, but rather relying on the “abstract idea” exception to patentable subject matter (this exception most recently discussed by the Supreme Court in Alice Corp. v. CLS earlier this year):
Here, under our earlier decision, the comparisons described in the first paragraphs of claims 7 and 8 are directed to the patent-ineligible abstract idea of comparing BRCA sequences and determining the existence of alterations. The methods, directed to identification of alterations of the gene, require merely comparing the patient’s gene with the wild-type and identifying any differences that arise. 
In this second round of litigation over the DNA primers, the Federal Circuit relied on the Supreme Court’s reasoning regarding isolated genes to invalidate the DNA primer claims (the Federal Circuit had initially upheld the patent claims to isolated genes in 2012, only to be reversed by the Supreme Court). With respect to the method claims, the Federal Circuit relied on the abstract ideas exception as it had in its rejection of similar method claims in its 2012 decision preceding the Supreme Court case. This decision is the latest round in Myriad’s attempts to restrict competition in the BRCA1 and BRCA2 genetic testing field through assertion of patent claims, and Myriad has now lost on patent claims to isolated genes, DNA primers, and basic genetic testing methods (only claims to cDNAs were upheld). Ambry hailed the Federal Circuit's decision. Also last week, the United States Patent and Trademark Office (PTO) has issued its 2014 Interim Guidance on Patent Subject Matter Eligibility. This updated guidance follows an unusually high number of Supreme Court cases to examine patentable subject matter in life science, business method and software patents over the last 6-7 years, and the PTO has been publishing its evolving thinking on these issues. The PTO is seeking public comment on the Interim Guidance until March 16, 2015, and it will hold a public forum on these issues in January 2015.

November 26, 2014

November Biotechnology Ballot Measures: GMO Labeling, Fetal Personhood, GMO Cultivation

The 2014 midterm elections contained a number of state ballot measures on policy issues involving biotechnology. Not surprisingly, the issue of whether foods containing genetically engineered ingredients should be labeled appeared on two state ballots. In Oregon, Measure 92 was apparently narrowly defeated (50% to 49%) (Oregon had also rejected a similar ballot measure in 2002). However, the narrowness of the vote has now resulted in this week's order of a recount. With respect to Colorado's proposed labeling measure, the vote was not so close: Proposition 105 was defeated 65%-34%. These defeats mean that the current status of state labeling measures is that Vermont has fully passed a labeling law that takes effect in 2016; Connecticut and Maine have also passed labeling laws but their implementation is conditionally linked to a trigger where neighboring states passing similar measures (which has not yet occurred). A second issue with implications for biotechnology on the ballots this month was the issue of fetal personhood: two such initiatives on the ballots in North Dakota and Colorado would have declared personhood to begin at the moment of conception; these and similar measures have been crafted by anti-choice groups in order to elevate the constitutional status of the unborn and effectively criminalize abortion as a result. However, conception-triggered personhood also has implications for the field of human embryonic stem cell (hESC) research: the use of such cells requires their removal from an early-stage embryo, and under a fetal personhood statute, effectively becomes a criminal act against a legally-declared person. As a result, these initiatives have also threatened hESC research. The measures in North Dakota and Colorado were both rejected (by almost identical margins of 65% to 35%). To date, all fetal personhood ballot measures in the states have failed. A third issue on the November ballots was agricultural, relating to the presence of genetically engineered crops: several county-wide ballot measures that would ban the planting and cultivation of genetically engineered crops (on the ballots as "genetically modified organisms") were passed in Humboldt County, California and Maui County, Hawaii.  Lastly, a bond measure in Maine to authorize funding
"to discover genetic solutions for cancer and the diseases of aging" passed overwhelmingly. The 2014 elections continued the ongoing attention to GMO labeling and fetal personhood initiatives as the most contentious state-based legislative  battles affecting biotechnology.