July 23, 2016

Congressional Impasse on Zika Virus Funding Impacts Public Health Efforts in Peak Summer Months

The Zika virus outbreak is spreading in the U.S., according to local public health authorities and the federal Centers for Disease Control (CDC); international Zika virus cases are also increasing. Infection occurs because of a mosquito bite that transmits the virus, and most public health interventions to date concentrate on limiting exposure to the mosquito (Aedes aegypti). As of yet, there is no vaccine or specific treatment for the Zika virus. The discovery that Zika virus infection in pregnant women can lead to birth defects, including microcephaly, raised the alarm about the spread of the virus in this population (see earlier post here). To date, there are about 1400 reported cases in the U.S; there are about 400 cases of Zika infection in pregnant women. Most cases in the U.S. are traced to individuals traveling outside the country, returning with the infection; Puerto Rico, Brazil and other Caribbean and Latin American countries are some of the hotspots of transmission. Now, however, there  appear to be are several cases of local transmission of the Zika virus in Florida, which means that the virus is gaining a foothold in the U.S. itself. As in most public health crises, the government is tasked with providing increased support to local authorities, funding for treatment developments, and other activities. Congress has been in a stalemate over emergency Zika virus funding over the last month. President Obama sought $1.9 billion in new dedicated funding; the House of Representatives approved $1.1 billion. On to the Senate, where several provisions inserted into the funding bill encountered opposition; most notably, an explicit ban on Planned Parenthood as the recipient of any new funds. As discussed in an earlier post, because of the risk that Zika virus infection poses to pregnant women, who are at risk to give birth to babies with developmental disorders (and not all are known at this point), access to contraception and other reproductive services would appear to be a key ingredient in minimizing the birth of Zika-affected babies. That’s where the usual political conflict over reproductive and family planning funding entered the Zika funding legislation, and created an impasse. So to date, the Senate has not approved the funding that the House approved, and Congress has taken its usual lengthy summer break without acting on emergency funding for Zika virus research and support. The 7-week hiatus in the Zika funding battle has dismayed federal public health officials. The American Medical Association  (AMA) faulted Congress
At a time when concerns continue to mount about the nation's readiness to protect the public from the Zika virus, the AMA is disappointed by Congress' failure to pass legislation before adjourning for summer recess that would provide the resources necessary for our country to respond to this looming public health crisis. Without ensuring there are sufficient resources available for research, prevention, control and treatment of illnesses associated with the Zika virus, the United States will be ill-equipped to deploy the kind of public health response needed to keep our citizens safe and healthy—especially since the spread of mosquito-borne illness is accelerated during the summer months.
Editorials in some of the hardest hit areas of the country noted how the impasse would adversely affect their regions; here is the Palm Beach Post from Florida on the local impact: 
Congress has left the building. And in its dysfunctional wake, it leaves yet another failed effort at passing crucial emergency funding to fight the spread of the dreaded Zika virus. For at least the next seven weeks, Florida — which has distinguished itself as ground zero for cases of the mosquito-borne virus — will just have to hope that the worst part of the rainy storm season doesn’t translate into more infections. (Palm Beach County has seen about 12 cases of travel-related Zika.) It may be a long, hot summer. Mosquitoes that carry the Zika virus breed year-round here, and the number of infections in the continental United States is mounting. On Monday, the state Health Department reported 13 new cases of the Zika virus in Florida - the most reported cases of the virus in a single day. Moreover, federal officials say they will have to postpone a slew of anti-Zika actions. For example, the U.S. Centers for Disease Control and Prevention will have “limited capacity” to help with efforts to counter mosquito populations in the continental U.S. and territories. 
Yes, it should be noted that the CDC is now dispersing about 60 million dollars currently to localities to augment public health efforts, but these are “stopgap” awards that will not approach the scale of the demand. Congress returns on September 6th.

July 17, 2016

Congress Passes Federal Labeling Requirement for Genetically Engineered Foods; State Labeling Laws Would Be Preempted

Vermont enacted the first state law that requires the manufacturers of food products with genetically engineered (GE) ingredients to label their food products accordingly. Its Act 120 became law on July 1, 2016. However, for decades, there has been an ongoing battle at the federal level over whether a national labeling scheme should be enacted (the term GMO/genetically modified organism is also used). (See earlier posts for more background). So, after the Vermont bill became effective, there was a flurry of activity in Congress again to address the issue of a federal labeling scheme for GE food products. (The FDA has not required labels on food products with GE ingredients, in a policy that dates back to 1992). The Senate recently passed a bill, S. 764, that would mandate a particular federal labeling scheme for GE ingredients, and would also preempt any state labeling laws. The federal bill uses the term "bioengineering" to describe the products covered by the law: 
[F]ood - (A) that contains genetic material that has been modified through in vitro recombinant [DNA] techniques; and (B) for which the modification could not otherwise be obtained through conventional breeding or found in nature. 
There is an explicit statement of the preemption achieved by this legislation: 
No State or a political subdivision of a State may directly or indirectly establish under any authority or continue in effect as to any food or seed in interstate commerce any requirement relating to the labeling of whether a food (including food served in a restaurant or similar establishment) or seed is genetically engineered (which  shall  include such other similar terms as determined by the Secretary of Agriculture) or was developed or produced using genetic engineering, including any requirement for claims that a food or seed is or contains an ingredient that was developed or produced using genetic engineering.
This last provision is aimed at the recent Vermont law, as well as other initiatives in Connecticut, Maine and Alaska. Since its enactment in 2014, the Vermont law had already impacted the food and restaurant industries, with some major players declaring that they would provide labels in anticipation of the law (see here). It was apparent that the Vermont law had immediate national impact, as food manufacturers faced compliance with the statute or avoidance of Vermont’s market (practically unworkable). Now, the House of Representatives has passed a version of the recent Senate bill, and it goes to President Obama for signing; it appears that he will sign it. The clear effect of the federal bill is to preempt the long-sought state labeling laws. However, does this bill actually require a label? The bill departs from other labeling proposals over the years (state and federal) in that it contains no explicit requirement to provide a “GMO” or other GE-related name on the main label of the product. The actual labeling scheme in the new federal law is quite elastic, describing the format of the labeling as follows: 
[T]he form of a food disclosure under this section be a text, symbol, or electronic or digital link. 
Thus, a consumer could use a smartphone to read a QR code, or utilize a provided link to access information, or read whatever disclosure material the manufacturer has chosen to provide. The forms of the notification could be arguably obscure, and indirect. In other words, at least so far, there will be no uniformity of disclosure. Already, there are allegations that the bill is discriminatory in that it will make it harder for some consumers to pursue the informational references; access to digitally formatted information is not universal. The USDA has two years to make the law operational, and may refine the labeling formats in that period, subject to public input.

June 22, 2016

RAC Approves First Use of CRISPR Gene-Editing Protocol in Humans

Yesterday, the Recombinant DNA Advisory Committee (RAC), a federal advisory committee to the NIH, held a public meeting to consider the first submission for approval to use a CRISPR/Cas9-based (CRISPR) study protocol with human patients. CRISPR is a technique that allows genes to be edited; it has swept through biomedical science in the last few years as a breakthrough technology. The RAC committee has provided oversight for the field of gene transfer therapies for decades (and supplements FDA and local institutional oversight by IRBs and IBCs). As an advisory committee to NIH, first constituted in 1974, RAC's regulatory portfolio for human experiments began with reviewing gene transfer studies pursuant to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. The field of "gene therapy" has largely been comprised of studies involving gene transfer into patients to correct, replace, or diminish gene activity relevant to various clinical conditions; to date, several thousand gene therapy clinical trials worldwide have been conducted. RAC's jurisdiction extends to the use of gene-editing protocols, as well as other gene-altering technologies such as RNA interference. Now, a collaborative effort from the University of Pennsylvania (Penn), M.D. Anderson Cancer Center, and the University of California, San Francisco produced a proposed study protocol involving CRISPR gene-editing that was discussed and evaluated by the RAC this week at its meeting. The protocol involves an ex vivo technology where T cells of cancer patients will be removed and subject to gene-editing to alter several cell receptors before the cells are infused back into the patient. The goal is to engineer the T cells of the immune system so that they target and destroy cancer cells; this initial study is to identify any safety issues that might emerge. The recruited patients have either myeloma, melanoma, or sarcomas and would be those for which conventional therapies are not available or effective. During the meeting, questions were raised about potential conflicts of interest due to financial interests of some investigators, as well as the involvement of Penn, as it was the site of the now well-known 1999 gene therapy trial that resulted in the death of Jesse Gelsinger; that trial had notable flaws involving the transparency of preclinical testing and of competing financial interests. After public review and discussion of the protocol, the committee voted to approve the protocol. Yesterday's approval marks the first RAC-sanctioned use of CRISPR technology in human patients.

This is the first study protocol submitted to RAC that uses CRISPR in humans, but it is not the first gene-editing human protocol that RAC has considered. Sangamo BioSciences received approval to use its zinc-finger gene-editing technology (ZFN) in two different human trials: an ex vivo protocol approved in 2007, and an in vivo protocol approved in 2015. In what appeared to be a coincidence, yesterday's meeting also considered the first proposed gene therapy trial to treat Ornithine Transcarbamylase (OTC) Deficiency since the 1999 Gelsinger trial. Several discussants referenced the Gelsinger incident in their comments. The committee held a discussion of whether preclinical trials for the gene transfer method in non-human primates were necessary before approval (only mice studies were provided); RAC then voted an approval with stipulated conditions


As gene transfer studies have become more routine over the last several decades, the scope and need for continued RAC oversight has been questioned. A recent study of RAC that was conducted by the Institute of Medicine examined whether gene transfer oversight by RAC continued to be necessary; the report concluded that only new protocols presenting novel vectors or technical approaches needed to be evaluated by RAC. However, the IOM committee explored whether the RAC model of a public advisory committee could be utilized more generically for other emerging biotechnologies. including, for example, protocols from the field of nanobiotechnology or synthetic biology, for example. The IOM report endorsed consideration of an expanded scope for RAC or an advisory committee with similar attributes to provide the kind of oversight for new technologies as RAC has provided for decades in the field of gene therapy.

June 15, 2016

National Academy of Sciences Report on Controversial Gene Drive Technology Endorses Further Research, Controlled Field Trials

The National Academies of Sciences, Engineering, and Medicine (NAS) has issued a report on gene drive technology, Gene Drive Research in Non-Human Organisms: Recommendations for Responsible Conduct. A gene drive is a method by which specific genetic mutations (or alleles) are preferentially inherited, and over time, the effect is to eliminate other competing alleles. This has population-wide consequences for an organism, and can permanently alter (or reduce) the genetic diversity of a species. The phenomenon of a gene drive occurs in nature, and has been observed in many organisms
In nature, certain genes ‘drive’ themselves through populations by increasing the odds that they will be inherited.
Now, however, advances in gene-editing technology have facilitated the development of deliberately engineered gene drives. From the report summary:
A wide variety of gene drives occur in nature. Researchers have been studying these natural mechanisms throughout the 20th century but, until the advent of CRISPR/Casfor gene editing, have not been able to develop a gene drive. Since early 2015, laboratory scientists have published four proofs-of-concept showing that a CRISPR/Cas9-based gene drive could spread a targeted gene through nearly 100% of a population of yeast, fruit flies, or mosquitos.
In other words, use of gene drive technology can impose a specific genetic allele (variant) on a population and eliminate all other forms of the gene. Effectively, the population is now homozygous for the preferred variant. That is both the attraction and the concern regarding the use of this technique. Genetic traits could be eliminated, and at its most extreme, whole populations could be "driven" out of existence. It is simple to imagine particular uses of the technology that would eliminate undesirable traits in a target population, such as the ability of mosquitos to spread malaria, or very currently, the ability of the Aedes aegypti mosquito to transmit the Zika virus. The report summarizes possible applications and the requirement for a deliberative approach to use of the technique:
Gene-drive modified organisms hold promise for addressing difficult-to-solve challenges, such as the eradication of insect-borne infectious diseases and the conservation of threatened and endangered species. However, proof-of-concept in a few laboratory studies to date is not sufficient to support a decision to release gene-drive modified organisms into the environment. The potential for gene drives to cause irreversible effects on organisms and ecosystems calls for a robust method to assess risks. A phased approach to testing, engagement of stakeholders and publics, and clarified regulatory over-sight can facilitate a precautionary, step-by-step approach to research on gene drives without hindering the development of new knowledge.
The report did not recommend a moratorium on research, despite noting the potential for adverse consequences. Instead, it endorsed continued research on the technology with some limited field evaluations:
Although there is insufficient evidence available at this time to support the release of gene-drive modified organisms into the environment, the likely benefits of gene drives for basic and applied research are significant and justify proceeding with laboratory research and highly-controlled field trials.
The current regulatory landscape for gene drive applications is summarized:
In the United States, regulation of gene-drive modified organisms will most likely fall under the Coordinated Framework for the Regulation of Biotechnology, which includes the U.S. Food and Drug Administration, the U.S. Department of Agriculture, and the U.S. Environmental Protection Agency. However, the diversity of potential gene-drive modified organisms and contexts in which they might be used reveals a number of regulatory overlaps and gaps. The U.S. government will need to clarify the assignment of regulatory responsibilities for field releases of gene-drive modified organisms, including the roles of relevant agencies.
At the present time, the patchwork structure for biotechnology regulation is currently under formal review by the Obama administration (see earlier post for more background). In general, as the new products of genetic engineering have been developed over the years, they encounter oversight from any one (or more) of three agencies: the FDA, EPA, or USDA. As the regulatory framework is redesigned, we could expect that various applications of gene drive technology will face an approval process customized to the particular goal and purpose of the technology. The report states:
It is important to note that a one-size-fits-all approach to governance is not likely to be appropriate. Each phase of research activity—from developing a research plan to post-release surveillance—raises different levels of concern depending on the organism being modified and the type of gene drive being developed.
The NAS report has received criticism from opponents of field testing, who noted that precise control of such experiments is not possible, and wider, possiblly uncontrolled spread of altered organisms could occur. Other criticisms suggest that the scope of the report is too limited, and does not adequately address possible dual-use concerns (malevolent uses of the technology). The report has some conceptual overlap with efforts of the World Health Organization (WHO) has previously released a guidance framework for how to introduce genetically engineered mosquitoes that are reproductively disabled, thus reducing the population of a malaria vector. In summary, the NAS panel has cautiously endorsed further gene drive research in the U.S., and contemplates eventual field trials of engineered organisms.

May 27, 2016

NSABB Finalizes Recommendations for Increased Oversight of Gain-of-Function Pathogen Research

This week, the National Science Advisory Board for Biosecurity (NSABB) returned to its ongoing deliberation over the scope and form of oversight of gain of function (GOF) research on viruses and other pathogens. Since a moratorium on federal funding was declared in 2014, the NSABB has been working on establishing guidelines both for funding and oversight of this specific research area. The concerns over GOF research are that experiments could produce particularly dangerous pathogens which pose public health risks (see earlier post for background). In this review, the NSABB actually focused its attention on a subset of GOF research, defined as Gain of Function Research of Concern (GOFROC):
[T]he working group identified the attributes of GOFROC, which is research that could generate a pathogen that is: 1) highly transmissible and likely capable of wide and uncontrollable spread in human populations; and 2) highly virulent and likely to cause significant morbidity and/or mortality in humans. 
In its public meeting this week, the NSABB adopted recommendations from a report by its own internal working group; they are as follows (underlined for emphasis): 
1: Research proposals involving GOF research of concern entail significant potential risks and should receive an additional, multidisciplinary review, prior to determining whether they are acceptable for funding. If funded, such projects should be subject to ongoing oversight at the Federal and institutional level. 
2: An external advisory body that is designed for transparency and public engagement should be utilized as part of the U.S. government’s ongoing evaluation of oversight policies for GOF research of concern. 
3: The U.S. government should pursue an adaptive policy approach to help ensure that oversight remains commensurate with the risks associated with the GOF research of concern. 
4: In general, oversight mechanisms for GOF research of concern should be incorporated into existing policy frameworks when possible. 
5: The U.S. government should consider ways to ensure that all GOF research of concern conducted within the U.S. or by U.S. companies be subject to oversight, regardless of funding source
6: The U.S. government should undertake broad efforts to strengthen laboratory biosafety and biosecurity and, as part of these efforts, seek to raise awareness about the specific issues associated with GOF research of concern. 
7: The U.S. government should engage the international community in a dialogue about the oversight and responsible conduct of GOF research of concern. 
This completes the current NSABB review of federal policies pertaining to GOF/GOFROC research. However, the report does recommend an ongoing institutional apparatus to review policies, not individual experiments. It also recommends that privately-funded experiments involving GOFROC receive additional oversight, although that could require Congressional action. Finally, against a backdrop of reported safety lapses at federal laboratories (see here and here), the NSABB locates improved biosafety and biosecurity measures as an equally important concern in establishing how GOFROC can be managed.