September 30, 2015

CRISPR Gene-Editing Technology: UK Application Filed, More Official Statements, International Summit

Over the last year, several ad hoc and professional organizations have continued to weigh in on whether the CRISPR/Cas9 gene-editing technology should be subject to any pauses in its adoption as a method of genome alteration or correction (see here). The advent of CRISPR/Cas9 technologies, beginning with the first publication in 2012, has accelerated scientific interest in gene editing because the technique has offered a more efficient approach than previous genome-altering methodologies. Here is an overview of the directions such research can take:  
Genome editing has tremendous value as a tool to address fundamental questions of human and non-human animal biology and their similarities and differences. There are at least four categories of basic research involving genome editing technology that can be distinguished: 1) research to understand and improve the technique of genome editing itself; 2) genome editing used as a tool to address fundamental questions of human and nonhuman animal biology; 3) research to generate preliminary development of human somatic applications; and 4) research to inform the  plausibility of developing safe human  reproductive applications. 
However, the CRISPR age is encountering fits and starts. Most controversially, the specter of  CRISPR becoming a novel reproductive technology to perform gene editing on a human embryo has raised the most attention and concern. Earlier, this year, two groups of American scientists issued cautionary statements (see earlier post here); the NIH then reiterated its ban on any federal funding of research on gene-editing in embryos. More recently, other international bodies are weighing in. The U.K. Wellcome Trust has now issued a statement: 
Research using genome editing tools holds the potential to significantly progress our understanding of many key processes in biology, health and disease and for this reason we believe that responsibly conducted research of this type, which is scientifically and ethically rigorous and in line with current legal and regulatory frameworks, should be allowed to proceed. We will continue to support the use of genome editing in preclinical biomedical research as well as studies that progress and refine these technologies. Within the UK, this research may involve the use of somatic (non-reproductive) or germ cells, including human embryos up to 14 days old - within the confines of the HFE Act 2008 - where appropriately justified and supported by rigorous scientific and ethical review. 
Against that backdrop, a U.K. developmental biologist has applied to the Human Fertilisation and Embryology Authority (HFEA), for permission to edit the genome of a human embryo (there is no such agency in the U.S). The goal of the proposed research is to identify what genes in the developing embryo are active in the early post-fertilization stages; the research would use surplus embryos from IVF clinics where permission has been granted for such use. The license may be granted
The Human Fertilisation and Embryology Authority (HFEA) has yet to review her application, but is expected to grant a licence under existing laws that permit experiments on embryos provided they are destroyed within 14 days. In Britain, research on embryos can only go ahead under a licence from an HFEA panel that deems the experiments to be justified. 
In a separate development, The Hinxton Group, an international consortium centered on stem cell issues, published a statement calling for caution in possible reproductive applications, but not a moratorium:
Oversight structures must be in place prior to any attempts to use genome editing in human reproduction. Effective oversight requires the development of appropriate standards for preclinical data (e.g., What are acceptable thresholds for off-target events and mosaicism? What are appropriate methods for determining  the impact of off-target events?). Initial attempts should be conducted only in the context of formal clinical research or trials. In addition, the health and well-being of participants, developing fetuses, and pregnancy outcomes should be monitored carefully. The health and well-being of those born should also be monitored in long-term follow-up and research, albeit with a mind toward the burdens this would impose. 
Finally, in an event that will likely feature a spectrum of viewpoints, the Chinese Academy of Sciences (CAS) and the Royal Society (the science academy of the U.K.) are joining the U.S. National Academy of Sciences (NAS) to hold a highly anticipated international summit on human gene-editing on December 3, 2015 in Washington, D.C. A preliminary meeting (and webcast) to organize the summit will be held next week on October 5, 2015; details here.

September 12, 2015

Financial Toxicity: Oncologists Call for Drug Pricing and Patent-Related Measures to Reduce Cost of Biotech Cancer Drugs

In an unusual foray into advocacy involving the pharmaceutical marketplace, a coalition of oncologists has published a call to action in the Mayo Clinic Proceedings regarding the high price of cancer drugs; the physicians advocate for a number of regulatory and legislative measures to reduce the cost of cancer drugs, increase market competition, and ultimately improve patient access. It has been evident for a while that while molecular research has resulted in the development of new therapeutic approaches to cancer – especially targeted biotech drugs – the price of some of these drugs has well exceeded both patient and physician expectations; hence, the term "financial toxicity." In just one example, the Amgen drug Blincyto, an immunotherapy for leukemia, can cost about $178,000 for a course of treatment. The recent attention to funding research on "precision medicine" from the NIH and the White House focused on how cancer treatment (new drugs) is one of the chief beneficiaries of these efforts. In the published commentary, the oncologists make several points: 
In 2014, all new US Food and Drug Administration (FDA) approved cancer drugs were priced above $120,000 per year of use.
For a patient with cancer who needs one cancer drug that costs $120,000 per year, the out-of-pocket expenses could be as high as $25,000 to $30,000—more than half the average household income and possibly more than the median take-home pay for a year. Patients with cancer then have to make difficult choices between spending their incomes (and liquidating assets) on potentially lifesaving therapies or foregoing treatment to provide for family necessities (food, housing, education). 
The commentary specifically calls for the following measures:
(1) Creating a post-FDA drug approval review mechanism to propose a fair price for new treatments, based on the value to patients and heath care.
(2) Allowing Medicare to negotiate drug prices.
(3) Allowing the Patient-Centered Outcomes Research Institute, created through the Affordable Care Act initiatives to evaluate the benefits of new treatments, and similar organizations to include drug prices in their assessments of the treatment value.
(4) Allowing importation of cancer drugs across borders for personal use (e.g., prices in Canada are about half of prices in the United States).
(5) Passing legislation to prevent drug companies from delaying access to generic drugs (pay-for-delay).
(6) Reforming the patent system to make it more difficult to prolong product exclusivity unnecessarily (patent “evergreening”).
(7) Encouraging organizations that represent cancer specialists and patients (e.g., American Society of Clinical Oncology, American Society of Hematology, American Association for Cancer Research, American Cancer Society, National Comprehensive Cancer Network) to consider the overall value of drugs and treatments in formulating treatment guidelines. 
A number of the suggested measures are familiar tactics, although not all in force. For example, the patent recommendations overlap with ongoing efforts to improve either patent quality or forestall dubious attempts to extend the term of lucrative patents (the “evergreening” phenomenon, for example, has been countered using patent law theories of double patenting). The phenomenon of “pay for delay” in which brand name companies pay would-be generic competitors to stay out of the market has encountered the Supreme Court’s Federal Trade Commission (FTC) v. Actavis decision in 2013 which endorsed antitrust inquiries into such arrangements; the Federal Trade Commission actively monitors such agreements. The call for the FDA to incorporate a pricing determinant in the drug approval process runs counter to any agency mandate to consider such questions in its regulatory work. Federal legislation to allow patients to import prescription drugs from Canada has been introduced, but not enacted. The call for the government to allow Medicare to negotiate bulk pricing with drug companies has been a political football for more than a decade since the enactment of Medicare Part D prohibited that option; the Obama administration has endorsed such negotiations, but the realities of Congress today make that unlikely. With respect for the calls to professional organization, the American Society for Clinical Oncology (ASCO) is actively pursuing methods for drug valuation that incorporate pricing. Despite these particulars, the Mayo commentary lines up with other public acts of priced-based resistance from the oncology community, such prescribing refusals based on cost (e.g., Sloan-Kettering oncologist practices) or cost-consciousness in prescribing practices. The article further endorses a consumer petition drive which seeks patient support for these efforts. A critical mass of attention is developing to the high pricing of new biotech cancer drugs; the British medical journal Lancet published a recent editorial: 
It therefore seems depressingly clear that industry's inflated pricing of new cancer drugs is contributing to a failure of health systems to offer promising new therapies to the very people for whom the drugs are created—cancer patients worldwide.
It should be noted that despite the Lancet's pessimism, the U.K. did actually establish a Cancer Drugs Fund under the National Health Service to target assistance to those needing expensive cancer drugs; however, as just announced, the fund is over-budget and now restricting which drugs will be covered.

September 4, 2015

Zarxio Becomes the First Biosimilar Drug to Enter U.S. Market

The first biosimilar drug has entered the U.S. market, with the launch of the Sandoz product Zarxio, which is a biosimilar of the Amgen reference product Neupogen; it received the first FDA approval for a biosimilar drug earlier this year (following expert panel approval). The biologic drug Neupogen, used to restore white blood cell function for cancer patients undergoing chemotherapy, has been one of the most successful biotech drugs of the biotechnology industry. In general, biologics are produced from living systems, such as microorganisms or cells, rather than from direct chemical synthesis; a biosimilar is a product that is "similar" to the originally approved biologic. Under the biosimilar drug approval pathway established under the Biologics Price Competition and Innovation Act of 2009 (enacted as part of the Affordable Care Act), the FDA was empowered to receive applications from companies wishing to offer a biosimilar drug that could replace and/or compete with the reference product. Importantly, a distinction is made between “biosimilar” and “interchangeable.” The FDA explains: 
A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products. 
An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product.
FDA requires licensed biosimilar and interchangeable biological products to meet the Agency’s rigorous standards of safety and efficacy. That means patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.
To date, the FDA has not established the formal guidelines for a biosimilar to earn the designation of “interchangeable;” Sandoz, among others, has called for such action. As a result, the full market scope of market competition contemplated for an age of “biotech generics” awaits further regulatory developments from the FDA. This contrasts with the fate of Zarxio in the European Union, where the biosimilar has been approved since 2009 and where an approval by the the European Medicines Agency (EMA) means that a physician could decide that a biosimilar is interchangeable as a function of professional judgment, rather than regulatory designation.

The entry of Zarxio into the U.S. market has been accompanied by a patent-related dispute between Sandoz and Amgen regarding what level of information exchange between biosimilar applicant and reference product sponsor is required by the BCPIA (the so-called "patent dance"). In 2014, Sandoz provided notice to Amgen that it had filed a Biologics License Application (BLA) with the FDA to produce a biosimilar of Neupogen. A legal scuffle followed this notice, with Amgen claiming that Sandoz did not provide the actual BLA application as required by the BCPIA. The district court agreed with Sandoz that the statute did not require the application to be provided, but it did recognize an obligation of the application to provide notice of commercial marketing to the sponsor after FDA approval. In July of this year, the Federal Circuit subsequently sided with Sandoz and did not require it to provide the application to Amgen, and interpreted the BCPIA to establish that the notice to Amgen triggered a 180-day delay of marketing for Sandoz, which is why Zarxio has just entered the market now despite its approval in March.The growing pains for the age of biotech generics continue on another front, as the FDA has just released proposed naming guidelines to distinguish follow-on products from the original reference drug.

August 28, 2015

More States See Legislation That Conditions Abortion Rights on the Genetic Status of the Fetus

The ongoing legal battles over the scope of reproductive rights protected by the 14th Amendment  – with claims of constitutionally protected values of liberty and privacy invoked – continue, going back to the signature case of Roe v. Wade in 1973 and furthered tailored by Planned Parenthood v. Casey (1992), among other cases. Other arguments for the protection of reproductive autonomy are grounded in gender equality. Fast forwarding to the rapidly developing technological landscape of genetic testing, reproductive medicine has steadily refined the options available for prenatal testing to provide prospective parents with ever more accurate – and earlier obtained – medical information. The most dramatic development has been the availability of non-invasive prenatal diagnosis (NIPD) that relies on obtaining fetal DNA (cell-free detal DNA, cffDNA) from maternal blood as early as 4 weeks into gestation and to test for a number of genetic/chromosomal disorders, including Down syndrome (attributed to the presence of an extra chromosome 21, leading to a trisomy). NIPD has reduced the need for invasive procedures, such as chorionic villi sampling and/or amniocentesis. As prenatal testing becomes more sophisticated, an ongoing political battle rages over whether abortion rights should be restricted based on the intent or rationale of the mother for seeking the procedure. This has led to both state and federal efforts to restrict abortion when it is sought on the basis of gender, race or genetic anomaly (e.g., Down syndrome). Currently, a bill, HB 135, is pending in Ohio that would ban any abortion that is sought sought because prenatal testing reveals Down syndrome. North Dakota enacted a similar bill in 2013 (that same bill would have prohibited abortions about as early as 6 weeks; that portion was struck down by the Eighth Circuit in July of this year). To date, there are no reports of enforcement of these selective bans on abortion. Yet they raise not only the most obvious legal issue of whether such laws impinge on the constitutional right enshrined by Roe (or present the “undue burden” prohibited in Casey). They raise a novel issue of whether the legal rights accorded to the mother can vary according to genetic status of a fetus. Beyond that, express litigation over the constitutional concerns of the fetus itself would lead into the legal personhood legal battles that have been fought already (and overwhelmingly seen the defeat of attempted personhood ballot initiatives and legislation) (see earlier posts here and here). Thus, an indirect genetically-determined legal climate of maternal rights emerges if these laws work as intended – with the twist that the relevant genetic information is derived from the fetus. While is appears that these laws are unworkable as a practical matter, these bills can formally require the provider to question the mother about her motives and can impose felony charges on a physician violating the ban. The Ohio bill is likely to pass, and join the North Dakota bill alone in targeting maternal rights on the basis of a fetal genetic anomaly. Proponents of these bills have argued that, for example, the current climate of genetic testing only encourages the elimination of offspring with detectable genetic abnormalities, with the result that Down syndrome births become increasingly uncommon, and they invoke a kind of disability discrimination argument in support of these measures (however, that leads back to the fetal personhood debate). Opponents argue that the Roe-based constitutional right to seek an abortion – while certainly cabined by many modern legislative limitations – is not conditioned on maternal motive or the genetic status of the fetus, but is simply motivated by a desire to limit women's reproductive choices.

August 19, 2015

Sequenom Seeks En Banc Rehearing After Federal Circuit's Denial of Prenatal DNA Testing Patent

In June, the Federal Circuit ruled that a prenatal testing method for detecting fetal DNA in maternal serum was not patentable, violating the prohibition against the patenting of natural phenomena (see here). In the case, Ariosa Diagnostics, Inc. v. Sequenom Inc. (2015), a representative claim from U.S. Patent No. 6,258,540 is as follows:
1. A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.
In the invalidity challenge asserted by Ariosa when the company was sued for patent infringement by Sequenom, Ariosa argued that the method claim effectively covered (or preempted) all uses of the newly observed natural phenomenon - namely, the presence of fetal DNA in maternal blood. The method is centered on that discovery - detect the fetal DNA and perform genetic assessments on that sample, thereby avoiding more risky invasive prenatal procedures. The trial court, and then the Federal Circuit, concluded that the method patent claims were invalid, that they did attempt to patent a natural phenomenon, not an actual invention. As the Federal Circuit stated: 
Thus, in this case, appending routine, conventional steps to a natural phenomenon, specified at a high level of generality, is not enough to supply an inventive concept. Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art. 
Now, Sequenom has filed a petition at the Federal Circuit, asking for an en banc review of the court's panel decision in June. Sequenom challenges the panel's application of a test for patent eligibility derived from the Supreme Court's 2012 decision in Mayo v. Prometheus. Further, Sequenom argues that the impact of the patent denial on future method patent claims that center on a newly discovered natural phenomena is devastating to future innovation:
The full Court’s intervention is particularly necessary because, if this Court does not step in and draw this line, the panel’s rule threatens to swallow many more meritorious inventions along with this one. The core of nearly every major innovation is the discovery of a fact about the natural world that motivates inventors to combine existing techniques to achieve new practical results. Accordingly, the panel’s test would threaten an invention implementing the discovery that a certain form of Ebola virus provokes an immune response that prevents infection (to take just one timely example). Nearly all vaccines have this problem: The hard part is determining the natural law that a given attenuated virus creates lasting immunity; once you know that, the rest is “routine.” The same goes for future holy-grail discoveries like simple, non-invasive methods of detecting early-stage cancer— ironically, the cheaper and simpler the method discovered, the less patentable it will be. In truth, the problem goes well beyond diagnostics or even medicine: If combining conventional techniques in an unconventional fashion, motivated by a discovery about nature’s laws, is unpatentable subject matter, it is hard to see how any process claim can survive. 
The Ariosa decision particularly impacts method claims, not composition of matter claims (which were already severely impacted by AMP v. Myriad in 2013). Whether the Federal Circuit decides to accept the petition and rehear the case en banc is unknown; what is known, however, is that the Ariosa decision does jeopardize the validity of similar method claims to the detection of many biochemical or molecular relationships, just at a time when much of modern biotech research is devoted to uncovering exactly that kind of information.