February 28, 2015

Presidential Bioethics Commission Reviews Federal Response to Ebola Virus Crisis

The Presidential Commission for the Study of Bioethical Issues (Bioethics Commission) has released a brief, titled Ethics and Ebola: Public Health Planning and Response, following its consideration of specific ethical questions that emerged while the U.S. government was responding to the Ebola virus outbreak in western Africa. Ebola virus cases in the U.S. began to appear last fall, the but Guinea, Sierra Leone and Liberia experienced significant outbreaks during 2014, and the World Health Organization reports an ongoing struggle in these countries. The commission advanced several recommendations to improve international responses, as well as the U.S. domestic response and capabilities: 
Strengthening the capacity of the World Health Organization to respond to global health emergencies through the provision of increased funding and collaboration with other international, national, and non-governmental public health organizations. 

Identifying and empowering a single U.S. health official accountable for all federal domestic and international public health emergency response activities. 

Strengthening the deployment capabilities of the U.S. Public Health Service, including by streamlining command structure for deployment and providing appropriate resources to train and maintain skills needed for emergency response.
The Commission also highlighted the need to embed ethical considerations into disease management and responses in a coordinated ethics framework: 
In addition, the Bioethics Commission recommend[s] that ethical principles be integrated into timely and agile public health decision making processes employed in response to rapidly unfolding epidemics. It call[s] for qualified public health ethics expertise to be readily available to identify ethical considerations relevant to public health emergencies and responses in light of real-time available evidence. Specifically, it recommends that a single U.S. health official should be accountable for ethics integration. 
While recognizing that public health measures can compromise individual liberty in emergency situations, the Commission addressed the need for possible quarantine
On the contentious issue of quarantine and other policies related to movement restrictions, the Bioethics Commission recommend[s] that governments and public health organizations employ the least restrictive means necessary—based on the best available scientific evidence—when implementing restrictive public health measures. 
The Commission recognized that clinical trials during a public health emergency can pose ethical choices regarding trial design, and particularly regarding the use of placebos, but did not rule out their use
Clinical research during a serious communicable disease epidemic creates a stark ethical dilemma: On one hand, using placebo controls appears to deny some patients the possibility—however small and uncertain—of a benefit from experimental interventions; on the other hand, research that does not yield conclusive results about an intervention’s safety or effectiveness could exacerbate the tragedy of the epidemic by providing misleading and potentially harmful information. Navigating this tension requires careful analysis of the range of possible trial designs coupled with a commitment to core principles of research ethics. 
In upcoming work, the Bioethics Commission will further consider “the importance of democratic deliberation and public education in bioethics.” While the role of the Bioethics Commission is deliberative and advisory, it has a broad and singular mandate to consider how the government ethically responds to the emergence of new life science technologies and ethically reacts to medical or health crises that necessitate competent and agile federal involvement.

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.