March 14, 2015

FDA Approves First Biosimilar Drug to Enter U.S. Market

The FDA has approved its first biosimilar drug, opening up an era of market competition for biologic drugs (drugs produced in living cells rather than chemically synthesized).. Sandoz (a division of Novartis) submitted an application for Zarxio, which is a biosimilar to Amgen’s drug Neupogen, used to stimulate the immune system and reduce the likelihood of infection, particularly for cancer patients undergoing chemotherapy. In January of this year, the FDA's Oncologic Drugs Advisory Committee (ODAC) recommended approval (see here), and the full agency has now issued its formal approval: 
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, called the “reference product.” This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data. 

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards. 

The FDA’s approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen. Zarxio has been approved as biosimilar, not as an interchangeable product. Under the BPCI Act, a biological product that that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. 
The FDA has not approved Zarxio as an interchangeable product, so a prescribing physician will need to specify the biosimilar drug when prescribing. As the agency further develops its biosimilar approval processes, it will need to contend with the determination of interchangeability for a biosimilar to fully compete (or substitute) for the reference product. Nonetheless, the Zarxio approval shows that the FDA is now willing and able to evaluate biosimilar applications; more applications will follow. Now the field of biologic drugs begins to have its own long-awaited version of a “generic” approval pathway. Will price savings result? Biosimilars have been available in Europe for several years; results to date indicate that Zarxio has been priced around 25% less than the reference product. In general, the relatively high cost of biologic drugs and the resulting effect on access has created a strong demand for competition to emerge; this inaugural biosimilar approval is a start.

March 4, 2015

NIAID Announces Joint U.S.-Liberia Clinical Trial for Ebola Virus Antiviral Drug

The Ebola virus disease crisis continues in western Africa. To date, in the hardest-hit countries of Liberia, Guinea and Sierra Leone, at least 23,913 cases are reported by the World Health Organization (WHO), with 9,714 deaths. At the height of the Ebola outbreaks on several continents last fall, the experimental biotech drug, ZMapp, made by Mapp Biopharmaceutical of San Diego, and comprised of several humanized monoclonal antibodies, was given to several U.S. health care workers who had contracted the virus while working in western Africa, with positive results. Although no drug had received formal approval for treating Ebola virus disease, WHO assembled an expert panel to consider the ethical implications of using non-approved, but potentially promising drugs (including ZMapp) during the expanding Ebola crisis; a summary of their consultation stated: 
In the particular circumstances of this outbreak, and provided certain conditions are met, the panel reached consensus that it is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects, as potential treatment or prevention. 
Now, the first formal clinical trial for ZMapp has been announced by the National Institute of Allergy and Infectious Disease (NIAID)
In partnership with the Liberian government, the National Institute of Allergy and Infectious Diseases (NIAID) today launched a clinical trial to obtain safety and efficacy data on the investigational drug ZMapp as a treatment for Ebola virus disease. The study, which will be conducted in Liberia and the United States, is a randomized controlled trial enrolling adults and children with known Ebola virus infection.

“Although ZMapp has been used to treat several Ebola-infected patients in recent months, we cannot determine if the drug actually benefitted those patients because it was not administered within the context of a clinical trial,” said Anthony S. Fauci, M.D., director of the NIAID, at the National Institutes of Health (NIH). “This clinical trial will help us determine if ZMapp and other treatments are safe and effective for use in the current devastating outbreak in West Africa as well as in future outbreaks. 

ZMapp, developed by Mapp Biopharmaceutical Inc., based in San Diego, is composed of three different proteins called monoclonal antibodies. ZMapp is designed to prevent the progression of Ebola virus disease within the body by targeting the main surface protein of the Ebola virus. The antibodies comprising ZMapp are produced in tobacco plants specially bioengineered to produce large quantities of these proteins. Studies in nonhuman primates demonstrated that ZMapp has strong antiviral activity and rescued the animals from death as late as five days after infection with Zaire ebola virus. The drug has not yet been tested in human clinical trials, but was administered under emergency use authorization to nine infected patients in Africa, the United States, and Western Europe. 
The current picture for containing Ebola virus is mixed; while western Africa is still a focus of public health and relief efforts, there are warnings regarding the possibility that other countries with poor public health infrastructure could be susceptible to future outbreaks. Furthermore, there is still no vaccine available, although some promising candidates are in development. From the U.S. perspective, the American troops committed to public health assistance in western Africa are being withdrawn. The Ebola "czar" has now finished his term, and has called for improving the WHO response capacity, decreasing reliance on overburdened NGOs and establishing a formal international public health responder force ready to be deployed in similar crises. The Ebola crisis illustrates a paradox of modern public health management: specific therapeutic options may originate in cutting-edge biotechnology, but the overall containment of any infectious disease crisis is equally dependent on the availability of basic, old-fashioned public health infrastructure.

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.