Several years of turbulence around the legitimacy and value of research that alters the genetics of highly dangerous pathogens in order to determine the relationship between DNA and function are the backdrop to a surprising announcement from the Obama administration regarding government funding of such research. Experiments that introduce genetic changes into the genomes of dangerous pathogens in order to study both transmissibility and pathogenicity may confer new or enhanced functions on a pathogen that make them more dangerous than in the native state. These are termed the “gain-of-function” (GOF) studies, a category of dual-use research of concern (DURC). Controversy ensued in 2011 over the publication of some of these experiments with highly pathogenic H5N1 influenza viruses. New federal policies regarding funding and oversight of DURC life science research were published, but those events presupposed the continuation of such research. Now the administration has issued a moratorium on federal funding of such research, asserting that more consideration is required as to the biosafety and biosecurity issues raised by this research:
Gain-of-function studies, or research that improves the ability of a pathogen to cause disease, help define the fundamental nature of human-pathogen interactions, thereby enabling assessment of the pandemic potential of emerging infectious agents, informing public health and preparedness efforts, and furthering medical countermeasure development. Gain-of-function studies may entail biosafety and biosecurity risks; therefore, the risks and benefits of gain-of-function research must be evaluated, both in the context of recent U.S. biosafety incidents and to keep pace with new technological developments, in order to determine which types of studies should go forward and under what conditions. In light of recent concerns regarding biosafety and biosecurity, effective immediately, the US.Government (USG) will pause new USG funding for gain-of-function research on influenza, MERS or SARS viruses, as defined below. This research funding pause will be effective until a robust and broad deliberative process is completed that results in the adoption of a new USG gain-of-function research policy.
The statement calls on the National Science Advisory Board for Biosecurity (NSABB) and the National Research Council to undertake more formal evaluative reviews of the pros and cons of these experiments. The NSABB held a public meeting last week to begin that work. This announcement did not occur in a vacuum: in the wake of the Ebola virus disease outbreaks and the recent reports of widespread biosafety lapses at high-profile federal laboratories, attention has focused on the status of research into pathogens that cause infectious diseases and into vaccines and drugs for prevention and treatment. The scientific community has been divided over the specific issue of GOF research; both sides have gone public with the formation of professional advocacy groups that support or oppose such research. The control of federal funding for research can be subject to executive branch discretion. An earlier high-profile example of an executive branch dictate is the Bush-era policy of refusing to fund the establishment of new embryonic stem cell lines. This announcement is directed to a pause in funding and the encouragement of what appears to have been missing for the past several years: official acknowledgement that the funding of such controversial research required a formal deliberative process that should precede, not follow, official decisions to allow the work. The statement also calls on those providing private funds for such research to implement a voluntary pause, pending the upcoming reviews.
The FDA is now seeking public comment on a guidance document, Framework for Oversight of Laboratory Tests, that will launch the agency’s entry into a new role regulating a sector of laboratory testing, known as laboratory-derived tests, or LDTs. These tests are offered as services from commercial laboratories, and are developed by the company itself. With respect to the field of genetic testing, LTDs are the predominant form of testing available to the public, where a consumer can send a biological sample to a lab for testing (direct to consumer tests), or provide a sample to a health care provider who mediates the testing process (see here). For years, the FDA has declared that while it has the legal authority to regulated such tests, it has exercised “enforcement discretion" – deciding not to require premarket approval from labs seeking to offer such services. As this marketplace has grown, the agency has moved closer to establishing a more formal role over the quality of these tests, and now has done so with its announcement of how it will require the industry to engage with the FDA in order to offer these tests (see here for the agency's new notification requirements for laboratories). The new proposed framework contains the following observations from the FDA as to why it needs to step up now:
LDT’s are important to the continued development of personalized medicine, but it is important that in vitro diagnostics are accurate so that patients and health care providers do not seek unnecessary treatments, delay needed treatments, or become exposed to inappropriate therapies.
The FDA has generally not enforced premarket review and other applicable FDA requirements because LDTs were relatively simple lab tests and generally available on a limited basis. But, due to advances in technology and business models, LDTs have evolved and proliferated significantly since the FDA first obtained comprehensive authority to regulate all in vitro diagnostics as devices in 1976. Some LDTs are now more complex, have a nation-wide reach and present higher risks, such as detection of risk for breast cancer and Alzheimer’s disease, which are similar to those of other IVDs that have undergone premarket review.
The FDA has identified problems with several high-risk LDTs including: claims that are not adequately supported with evidence; lack of appropriate controls yielding erroneous results; and falsification of data. The FDA is concerned that people could initiate unnecessary treatment or delay or forego treatment altogether for a health condition, which could result in illness or death. The FDA is aware of faulty LDTs that could have led to: patients being over- or undertreated for heart disease; cancer patients being exposed to inappropriate therapies or not getting effective therapies; incorrect diagnosis of autism; unnecessary antibiotic treatments; and exposure to unnecessary, harmful treatments for certain diseases such as Lyme disease.
The House Energy and Commerce Committee Subcommittee on Health held a hearing on the proposed framework last month. The agency has the guidance document open for 120-day public comment period, which will last until February 2, 2015.
The urgency of calls for reliable and scaled public health responses to the magnitude of the international Ebola virus disease (EVD) outbreak is increasing; a media frenzy over the apparent emergence of Ebola in Dallas, TX is underway. At the present time, over 7,000 cases and over 3,300 deaths are attributed to the outbreak concentrated in West Africa, where the virus emerged earlier this year. The crisis requires a combination of public health resources (personnel, facilities, diagnostic capabilities) and effective countermeasures (vaccines, drugs). To date, the most effective drug against the virus appears to be ZMapp, an antibody-based treatment developed by Mapp Biotherapeutical. However, ZMapp supplies are limited, and efforts to scale up production, while necessary, will still not produce enough to meet demand. An expert consultation called by the World Health Organization this week to review vaccine candidates has identified two Ebola vaccines that are ready for Phase I clinical trials. Scheduled milestones for the testing and evaluation of these potential vaccines are now published. Even in a best case scenario, in which a vaccine candidate performs well enough to justify scaleup and distribution, WHO does not anticipate that a significant number of vaccines to be ready before around March, 2015. The WHO meeting participants noted the unprecedented severity and spread of this viral disease relative to other public health crises:
Participants also drew heavily on lessons learned, in the African setting, during trials for candidate malaria, HIV/AIDS, cholera, epidemic meningitis, hepatitis B, and other vaccines. As some experts noted, never again can the international community allow what boils down to “market failure” to create such catastrophic suffering for humanity in any country, in any region of the world. The sense of urgency and need for speed, without compromising the integrity of studies or the quality of their data, are fully justified by the dire situation in affected countries and the risk that other countries may soon experience their first imported cases. The Ebola outbreak currently ravaging parts of West Africa is the most severe acute public health emergency in modern times. Never before in recent history has a biosafety level 4 pathogen infected so many people so quickly, over such a wide geographical area, for so long.
The CDC has already estimated that 1.4 million cases of EVD could emerge by January next year. Case projections from WHO are smaller, but both agencies point out that a near-term ability to reverse the course of EVD will depend on successful public health efforts, including patient isolation and contact avoidance measures. Drugs and vaccines will not be produced fast enough in the short term to meet demand, but the efforts described above are good starts. More generally, as the WHO acknowledged with its reference to “market failure,” it is clear that government expenditures for research on countermeasures need to continue, but the development of a true pipeline from lab to clinic is still lacking. That is a translational failure here: the emergence of rare but deadly outbreaks of diseases like Ebola are not met with stockpiles of drugs. The U.S. Strategic National Stockpile maintains supplies of drugs for use in viral epidemics, but these are directed to the more familiar diseases such as influenza and anthrax. The current Ebola outbreak illustrates the consequences of focusing national resources too narrowly on the usual suspects in bioterrorism or pandemic crises, with the consequence that new or remote pathogens emerging in the U.S. are not met immediately with effective countermeasures that would contain disease outbreaks.