February 22, 2015

FDA Issues Marketing Approval for 23andMe Direct to Consumer Bloom Syndrome Genetic Test

Federal regulation of the expanding genetic testing marketplace is beginning to take shape. The FDA has issued a formal approval for the marketing of a direct-to-consumer (DTC) genetic test to 23andMe, a leading personal genomics company based in Mountain View, CA. This is the first such decision by the FDA. As discussed here earlier, the FDA has been slowly enlarging its management of in vitro diagnostics to include most genetic tests, which are offered as laboratory-derived tests (LDT). 23andMe has tussled with the FDA over the last several years regarding whether and how its portfolio of DTC tests would be regulated by the FDA. In 2013, the FDA ordered the company to cease its marketing of over 200 unregulated health-related genetic tests through its Personal Genome Service. Finally, 23andMe signed on to FDA involvement by submitting a formal 510(k) application for the Bloom Syndrome Carrier Status test in 2014 (Bloom syndrome is a serious autosomal recessive genetic disorder caused by mutations in the BLM gene). For background on the submission: 
Section 510(k) of the Food, Drug and Cosmetic Act requires device manufacturers who must register, to notify FDA of their intent to market a medical device at least 90 days in advance. This is known as Premarket Notification - also called PMN or 510(k). 
The 23andMe submission was then converted to a de novo application, signalling the lack of a predicate test for comparison (but now potentially serving as a benchmark for future evaluations). Now, the FDA has announced its approval for 23andMe to market its DTC Bloom syndrome test, taking notice of any potential risk while also identifying the benefit of this type of test: 
FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information. Today’s authorization and accompanying classification, along with FDA’s intent to exempt these devices from FDA premarket review, supports innovation and will ultimately benefit consumers. 
In a sign that an overarching regulatory scheme is slowly emerging, the FDA further announced a classification of this subset of genetic tests:
Along with this authorization, the FDA is also classifying carrier screening tests as class II. In addition, the FDA intends to exempt these devices from FDA premarket review. The agency plans to issue a notice that announces the intent to exempt these tests and that provides a 30-day period for public comment. This action creates the least burdensome regulatory path for autosomal recessive carrier screening tests with similar uses to enter the market. 
It’s important to note that the Bloom syndrome test is not a test that provides either diagnostic or therapeutic information on which a patient may be making decisions regarding medical care; it is a report on Bloom syndrome carrier status and it will be used in reproductive decisions. The FDA’s concern with 23andMe’s (or other companies) offerings of health-related genetic information was largely focused on the likelihood that consumers would receive their genetic information accompanied by the companies’ assessment of risk or susceptibility, leading them to structure medical decisions (surgery, medications) on shaky or dubious representations. Because the approved test can be sold directly to consumers over the counter, the FDA did attach requirements for 23andMe to make consumers aware of genetic counseling options.

In parallel, the FDA is also building out oversight of foundational technologies that underlie genetic testing and analysis, most directly in its efforts to develop a regulatory program for next-generation sequencing (NGS) (see here). The FDA held its first public hearing on NGS oversight last week.

February 9, 2015

CDC Reports on Ebola Virus and Anthrax Safety Lapses in Its Laboratories; Federal Audit Results

Over the last year, reports of biosafety lapses in federal laboratories conducting research on anthrax, smallpox and Ebola virus elicited strong reactions in the scientific community and generated official responses to reduce the likelihood of similar events (see here for overview of CDC, NIH and FDA incidents). As the nation's signature public health agency, the incidents at the CDC laboratories were especially troublesome. In general, laboratories conducting microbiological research are designed to accommodate the safety requirements attendant to the threat of the pathogen itself. The safety evaluation will mandate the appropriate facilities, procedures and trained personnel based on the level of risk Laboratories are classified in a tier of biosafety levels (BSL1-4), with a BSL-4 designation describing the highest level containment environment:
Biosafety Level 4 is required for work with dangerous and exotic agents that pose a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no vaccines or treatments, or a related agent with unknown risk of transmission. Agents with a close or identical antigenic relationship to agents requiring BSL-4 containment must be handled at this level until sufficient data are obtained either to confirm continued work at this level, or re-designate the level. Laboratory staff must have specific and thorough training in handling extremely hazardous infectious agents. Laboratory staff must understand the primary and secondary containment functions of standard and special practices, containment equipment, and laboratory design characteristics. All laboratory staff and supervisors must be competent in handling agents and procedures requiring BSL-4 containment. 
Now, the CDC has issued its internal report on the December, 2014 Ebola incident in which a lab worker was possibly exposed to live Ebola virus. The report is detailed, and it is clear that human error explains the incident where Ebola virus may have been unintentionally transferred from a BSL-4 lab to a BSL-2 lab, which would lack the same degree of protection for potentially exposed workers. An earlier internal CDC report on the June, 2014 anthrax incident, involving transfer of a biological sample from a BSL-3 to a BSL-2 lab also identified personnel errors, as well as gaps in the overall containment protocols. In August, 2014, as a result of the pattern of safety lapses, the White House ordered a stand-down for federal laboratories to pause and review their biocontainment policies and practices, as well as perform an audit of pathogens and select agents. Reports now issued by the CDC and NIH detail the result of the stand-down, detailing the scale and site of research with the most dangerous pathogens, and identifying instances where undocumented biological samples have been left behind from earlier investigations. Overall, the stand-down produced a real-time status report on pathogen storage and handling in the leading federal labs; it is clear from the specific incidents reports, however, that human error can still override the most carefully planned containment measures.

February 6, 2015

Three-Parent Assisted Reproductive Technology Nears Approval in U.K.

The U.K. House of Commons approved a bill this week that would allow the use of a novel assisted reproductive technology (ART) to proceed. In current media coverage, the technique has been called three-parent reproduction, and it has been developed to offer a route to reproduction for women who are likely to transmit genetically inherited mitochondrial disease. Offspring inherit their mitochondria from the egg of the mother, and can be at risk from any mitochondrial disease that has occurred to the mother or the maternal family. The proposed intervention is known as mitochondrial replacement therapy. The three parents are the father and two mother donors: the nucleus is removed from the egg of the intended but genetically impaired parent and it is inserted into the egg of a healthy female donor, whose mitochondria are not defective. The reengineered egg undergoes in vitro fertilization with the father’s sperm, and is then implanted. This week, the U.K. House of Commons approved the use of the 3-parent mitochondrial replacement technique, in amending the Human Fertilisation and Embryology Act of 2008. The House of Lords is expected to follow suit. Unlike the U.S., the U.K. has an oversight body for ART – the Human Fertilisation and Embryology Authority (HFEA) -  which regulates fertility treatments and other reproductive technologies. The U.S. has no specific regulatory agency targeting reproductive technologies, but the FDA claims a regulatory role based on its general regulation of reproductive tissues in commerce (eggs, sperm) and the agency did shut down earlier work using MRT in the late 1990's. In the U.S. the FDA and the Institute of Medicine (IOM) are considering whether the technique should be approved for use in the U.S: 
An FDA Advisory Committee (AC) met on February 25 and 26, 2014, to discuss the science regarding assisted reproductive methods involving genetic modification of eggs and zygotes for the prevention of  mitochondrial disease. FDA has requested that the Institute of Medicine produce a consensus report regarding the ethical and social policy issues related to genetic modification of eggs and zygotes to prevent transmission of mitochondrial disease.
The FDA committee agreed that any proposed clinical trials with humans could be premature:
The Committee generally agreed that there is not sufficient animal data (particularly with regard to follow-up of offspring) to support the use of the mitochondrial manipulation technologies in first-in-human clinical trials. It was also acknowledged that the use of somatic cell nuclear transfer (SCNT) following by intracytoplasmic sperm injection (ICSI) had to be weighed against alternative methods for preventing the transmission of mitochondrial diseases to offspring, including adoption, oocyte donation, and cytoplasmic/mitochondrial transfer. 
The IOM began its study last month, holding its first meeting on the subject. In general, the U.S. is lagging behind the U.K. in considering official approval of this technique; in 1978, in vitro fertilization was first used in the UK before it migrated to the U.S. soon afterward. To date, there are pro and con views on whether MRT could be a viable option for prospective parents. Critics point to safety concerns as well as fears regarding a slippery slope toward allowing other genetic interventions to produce either healthier or “better” offspring. Supporters of MRT point out that the technique offers women with mitochondrial disease to have children that are genetically related but free of the genetic defect imparting serious disease. My own view is that there might be latent genetic incompatibilities that would not be overtly evident but perhaps manifest developmentally or subtly in a way that comprises the health of an MRT-derived offspring. Looking at regulatory moves in the future, there is always the possibility of legislative action that would either allow or prohibit the use of the technique – it’s too early to have such initiatives started, but such moves would echo ongoing Congressional and state responses to the possibility of human reproductive cloning that emerged in 1997, following the creation of the cloned sheep, Dolly.

January 31, 2015

Obama Announces Funding and Policy Focus on Precision Medicine

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.

$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. 
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)?

January 30, 2015

Myriad Genetics Ends Patent Infringement Litigation Against Breast Cancer Testing Competitors

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.