President Obama announced during the recent State of the Union address that his administration would initiate an enhanced funding and policy focus on the field of precision medicine. Precision medicine is informed by the collection of genetic, proteomic, microbial and other biological data of a patient – and the end result is to more sharply define disease states and allow for treatment that is more personalized, with a higher likelihood of success. In the specific case of cancer, for example, a patient’s tumor cells can be analyzed genetically to develop a precise molecular characterization – and treatments can be customized accordingly. According to the White House release:
Launched with a $215 million investment in the President’s 2016 Budget, the Precision Medicine Initiative will pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.
The proposed funding is directed to the National Institutes of Health (NIH), the NIH’s National Cancer Institute and the Food and Drug Administration (FDA), and the National Coordinator for Health Information Technology (ONC). The initiative will focus on oncology-related objectives as a starting point:
The cancer-focused component of this initiative will be designed to address some of the obstacles that have already been encountered in “precision oncology”: unexplained drug resistance, genomic heterogeneity of tumors, insufficient means for monitoring responses and tumor recurrence, and limited knowledge about the use of drug combinations. Precision medicine's more individualized, molecular approach to cancer will enrich and modify, but not replace, the successful staples of oncology - prevention, diagnostics, some screening methods, and effective treatments - while providing a strong framework for accelerating the adoption of precision medicine in other spheres. The most obvious of those spheres are inherited genetic disorders and infectious diseases, but there is promise for many other diseases and environmental responses.
The breakdown of this investment is as follows:
$130 million to NIH for development of a voluntary national research cohort of a million or more volunteers to propel our understanding of health and disease and set the foundation for a new way of doing research through engaged participants and open, responsible data sharing.
The proposed investment of $215 million is actually quite small, when compared to an annual NIH budget of around $30 billion, and further still when it is divided among the target agencies. Congressional approval will also be needed, but that is probably likely, given ongoing bipartisan advocacy efforts in Congress to increase funding for “21st Century Cures.” However, apart from the financial aspects, the announcement does tie various policy architects together in the federal ecosystem of personalized medicine – imagining newly developed data from the NIH research cohort that is used to identify a new genetic marker for cancer diagnosis or susceptibility, leading to a new test devised by the NCI, which then enters the marketplace under a regulatory regime supervised by the FDA, and all emerging data points accountable in a more standardized electronic environment that the ONC has helped to develop. There are several regulatory sinkholes in this announcement, of course - what will it mean to launch a volunteer-sourced bio-database under government oversight, given a current minimalist privacy regime for genetic information (e.g., GINA). What regulatory scheme will prevail at the FDA with respect to LDTs and next-generation sequencing technologies (see recent post)?
$70 million to the National Cancer Institute (NCI), part of NIH, to scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment.
$10 million to FDA to acquire additional expertise and advance the development of high quality, curated databases to support the regulatory structure needed to advance innovation in precision medicine and protect public health.
$5 million to ONC to support the development of interoperability standards and requirements that address privacy and enable secure exchange of data across systems.
Myriad Genetics has ended its patent infringement litigation against its competitors over the patents on the BRCA1 and BRCA2 genes in the breast cancer genetic testing field. Myriad’s long campaign to enforce its patents is well known, and led to landmark patentable subject matter litigation that considered whether patent claims to isolated genes were valid. In the Supreme Court’s 2013 decision in AMP v. Myriad, the Court invalidated some of Myriad’s patent claims to isolated BRCA1 and BRCA2 genes. After that decision, a number of biotech companies immediately jumped into the BRCA1 and BRCA2 testing field, offering competitive genetic testing services. Myriad shifted its focus to allege new infringement allegations against a number of mostly smaller biotech companies, asserted different patent claims from the Supreme Court case, and the next round of litigation ensued. Last month, the Federal Circuit upheld a lower court’s decision that the second round of Myriad patent claims asserted against Ambry Genetics – to primers and isolated genes – were not patentable subject matter (see earlier post). Now, the company has ended its litigation against the other genetic testing companies after that ruling. One company is Pathway Genomics and they issued a statement:
Under the agreement, Myriad Genetics, Inc., the University of Utah Research Foundation, HSC Research and Development Limited Partnership, Endorecherche, Inc., and the Trustees of the University of Pennsylvania (the “Patent Owners”) and Pathway dismiss their respective claims and counterclaims against one another in the BRCA patent litigation. Additionally, the Patent Owners granted a covenant to not sue Pathway under the patents asserted in the litigation proceedings.
As one of the lead plaintiffs in the Supreme Court litigation, the ACLU reacted to the decision to end litigation:
Patients who need access to life-changing genetic testing should not be caught in the legal battle that Myriad Genetics has unfairly waged against competing laboratories, nor should scientists face the threat and cost of patent litigation. Myriad’s decision reinforces the basic principle that patents should never permit one company to lock up a product of nature, such as our own genetic information.
The breast cancer testing field has only diversified in the nearly two decades since BRCA1 and BRCA2 were discovered and then patented; as thousands of mutations in these genes have been identified, the identification of clinical risk has become more complex. Scientists have identified other genes that may contribute to breast cancer susceptibility and testing for mutations in those genes could be equally important to determining clinical risk. Even Myriad recognizes a more complex genetic picture for patients; it now offers a 25-gene panel test that discerns cancer susceptibility to breast cancer and other cancers in one round of testing.
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.
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.
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.
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.