April 30, 2015

Germline Genetic Engineering of Embryos Reported; Policy Debates Intensify on Prohibitions

Following on the recent post, the rush to develop some initial policy statements on the use of genome editing techniques for germline engineering is now understood following the first publication of an attempt to perform germline engineering on embryos using the CRISPR/Cas 9 (CRISPR) system, as reported by Chinese scientists. Several weeks ago, two separate policy statements were issued by experts in genome editing who called for either a moratorium or an ethics-initiated slowdown on any use of the technique on embryos. At the time, there were rumors of an imminent publication, and this was true. The new publication reports that the use of CRISPR to alter the germline of about 86 non-viable embryos had mixed results; some of the embryos accepted the genetic changes, but some did not and “off-target” events were reported, indicating that unintended genomic alterations occurred. These experiments have been widely reported, and have alerted the general public to an issue that they were generally unaware of. Public reaction has followed as well as some official commentary. The journal that published the paper has now issued a statement on its decision to publish: 
Protein & Cell has fully realized that this study can provide direct evidences to address some of safety concerns of the CRISPR/Cas9 technique. It may also raise a series of questions and bring further controversies to the field of gene-editing research. In this unusual situation, the editorial decision to publish this study should not be viewed as an endorsement of this practice nor an encouragement of similar attempts, but rather the sounding of an alarm to draw immediate attention to the urgent need to rein in applications of gene-editing technologies, especially in the human germ cells or embryos.
Official responses have also followed the publication of the CRISPR embryo studies. The NIH has issued a policy declaration making it clear that no federal funding is available for research that uses genome modification to the germline of a fertilized egg or embryo. The statement anchors the policy in the already existing legal/regulatory climate: 
However, NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.
Practically, there are multiple existing legislative and regulatory prohibitions against this kind of work. The Dickey-Wicker amendment prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed (H.R. 2880, Sec. 128). Furthermore, the NIH Guidelines state that the Recombinant DNA Advisory Committee “will not at present entertain proposals for germ line alteration.” It is also important to note the role of the U.S. Food and Drug Administration (FDA) in this arena, which applies not only to federally funded research, but to any research in the U.S. The Public Health Service Act and the Federal Food, Drug, and Cosmetic Act give the FDA the authority to regulate cell and gene therapy products as biological products and/or drugs, which would include oversight of human germline modification. During development, biological products may be used in humans only if an investigational new drug application is in effect (21 CFR Part 312). 
The NIH reiterates the lack of federal funding for any CRISPR (or other technology) attempts at germline engineering. It notes that the combination of existing prohibitions on funding embryo research combined with the ongoing supervision of gene therapy by RAC, supplemented with FDA pronouncements on its jurisdiction over some biotechnology products, create a patchwork of constraints on research in the U.S. RAC considered fetal gene therapy in 1999; as the NIH statement summarizes, the committee was not receptive to this form of prenatal genetic intervention. This new debate, however, focuses on a much more radical genetic intervention. The Chinese experiments were generally not "successful" in the goal of altering the specific gene in the target embryos; this lack of success, while derived from controversial experiments, will only bolster the case for halting any such scientific work, as the recent work validates the safety concerns alone. But what is emerging - despite any enforceable international restrictions - is an urgency to codify resistance into regulation sooner rather than later.

April 20, 2015

The Prospect of CRISPR/Cas9 Human Reproductive Technologies Stirs Urgent Policy Discussions

In recent weeks, there has been growing attention to the possibility that recently developed technologies which allow precise editing of genomic DNA could be used for human reproductive purposes, possibly modifying the genomic DNA of a fertilized egg or embryo to create heritable genetic changes. The growing use of the genome editing technology known as CRISPR/Cas9 (CRISPR), first reported in 2012, is permeating much of current genetic research and is driving the policy discussions. A meeting on germline applications held in January of this year at Napa, California, and convened by some of the founders of the original Asilomar conference on recombinant DNA, took up the question of using CRISPR for germline genome engineering. This working group, which included Dr. Jennifer Doudna, an originator of this technology, has now published a call for caution as this technology could be employed to perform germ line editing that would manifest in human offspring. The CRISPR technology allows for more precise and efficient editing in genomic DNA than earlier editing techniques, and has a number of useful applications, both for research and clinical use. According to several reports, there might be attempts at CRISPR-mediated human germline modification that are already underway but unknown and that possibility has stirred the scientific community to action. The participants at the Napa meeting called for further research and more transparent discussions for all stakeholeders. Finally, they called for scientists to refrain from employing CRISPR in any attempts at human germline engineering. The scientists agreed to:
Strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations. (In countries with a highly developed bioscience capacity, germline genome modification in humans is currently illegal or tightly regulated.) This will enable pathways to responsible uses of this technology, if any, to be identified. 
In parallel with that statement, a second group of researchers in the field of gene editing called for a complete moratorium on the use of CRISPR for germline genetic engineering. They stated:
In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations. This makes it dangerous and ethically unacceptable. Such research could be exploited for non-therapeutic modifications. We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development, namely making genetic changes that cannot be inherited. At this early stage, scientists should agree not to modify the DNA of human reproductive cells. Should a truly compelling case ever arise for the therapeutic benefit of germline modification, we encourage an open discussion around the appropriate course of action. 
Already, there are published reports of germline modification in monkeys. As for human gene modifications writ large, in 2015, there is the established field of gene therapy, overseen by the Recombinant DNA Advisory Committee (RAC), and slowly embraced by the FDA. These therapies provide genetic alteration to living persons through their somatic cells, so there is no heritability of the changes. RAC was asked to consider fetal gene therapy protocols in the late 1990's, but concluded that the risk/benefit ratio did not justify approval. Current reproductive medicine offers preimplantation genetic diagnosis to prospective parents seeking to avoid transmitting known genetic diseases, but that technique does not involve genome editing. The speed at which CRISPR-based technologies are entering genetic science guarantees that the debate over controversial applications will continue. Not surprisingly, any proposed CRISPR-based reproductive technologies are likely to encounter much more resistance that many other assisted reproductive technologies (ARTs) have encountered to date. Will CRISPR-based reproduction elicit the kind of furious legislative responses to the possibility of human cloning that followed the creation of the cloned sheep Dolly in 1997? Since there are no credible reports of use, the public is not confronted with the issue, but the scientific and bioethical communities can see ahead, and are trying a proactive rather than reactive approach to getting a public debate started.

April 15, 2015

NSABB to Resume Deliberations Over Risks and Benefits of Gain-of-Function Virus Research

The National Science Advisory Board for Biosecurity (NSABB) will hold a public meeting on May 5, 2015 in which it will resume deliberation over the risks and benefits of “gain-of-function” (GOF) research. This is the first meeting of the group since last fall. GOF virus research is research which alters the genetic properties of viruses in order to study how genetic mutations affect transmission and pathogenicity; in the process, a new potential pandemic pathogen (PPP) may be created. In October, 2014, the  White House Office of Science and Technology Policy (OSTP) declared a pause on the federal funding of GOF research for H5N1 influenza, Mddle East Respiratory Syndrome coronavirus (MERS) and Severe Acute Respiratory Syndrome coronavirus (SARS) and outlined the beginning of a formal deliberative process to occur over the next year: 
The deliberative process will offer recommendations for risk mitigation, potential courses of action in light of this assessment, and propose methodologies for the objective and rigorous assessment of risks and potential benefits that might be applied to the approval and conduct of individual experiments or classes of experiment. 
The OSTP called for a two-track process
The deliberative process is envisioned to be time-limited, to involve two distinct, but collaborating, entities, and to be structured to enable robust engagement with the life sciences community. As a first step, the National Science Advisory Board for Biosecurity (NSABB) will be asked to conduct the deliberative process described above and to draft a set of resulting recommendations for gain-of-function research that will be reviewed by the broader life sciences community. The NSABB will serve as the official federal advisory body for providing advice on oversight of this area of dual use research, in keeping with federal rules and regulations. As a second step, coincident with NSABB recommendations, the National Research Council (NRC)of the National Academies then will be asked to convene a scientific conference focused on the issues associated with gain-of-function research and will include the review and discussion of the NSABB draft recommendations. This NRC conference will provide a mechanism both to engage the life sciences community as well as solicit feedback on optimal approaches to ensure effective federal oversight of gain-of-function research. The life sciences community will be encouraged to provide input through both the NRC and NSABB deliberative process. 
Although the federal decision to halt research funding has been interpreted as a reaction to the spate of biosecurity incidents last year at government laboratories, the general topic of GOF research has required more attention from deliberative bodies since the controversies of 2011-2012, and the NSABB thus began to pick  up that project last fall. In parallel, a meeting was organized by the National Research Council in December, 2014. Now, a working group of the NSABB has issued a preliminary draft for the May meeting, the Framework For Conducting Risk And Benefit Assessments Of Gain of Function Research. This draft outlines the deliberative schedule already underway as the NSABB is charged with identifying the parameters that would shape decision-making on the merits of the research going forward. It identifies specific categories and exemplars of risks and benefits, all of which will guide the third-party contractor hired to perform and analyze the risk/benefit ratio for this research and provide these inputs to the NSABB and NRC. This draft framework will be discussed at the May 5 meeting; public comments to the NSABB can be provided until April 28, 2015.

April 4, 2015

Proposed Federal Legislation on Labeling of Genetically Engineered Food Products

Federal legislation has been introduced to impose a national scheme on the labeling of genetically engineered (GE) foods. The Safe and Accurate Food Labeling Act of 2015 (H.R. 1599) was reintroduced following a recent hearing on the subject in the House Agriculture Committee. This proposed bill continues an ongoing oscillation between state and federal initiatives on the labeling of GE food. H.R. 1599 would amend Section 403 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 343) (FFDCA) to classify a food as misbranded if:
[I]t bears labeling (indicating that bioengineering was or was not used in the production of the food) in violation of section 425.
Misbranded foods are prohibited by the FFDCA. The proposed bill would preempt state labeling laws regarding GE food. To date, several states have passed mandatory GE labeling foods. The proposed anti-labeling law introduced in the House would preempt the food labeling laws passed by Vermont, Connecticut and Maine. Also at the federal level and in opposition, bills to mandate nationwide labeling of GE foods have been introduced for many years, none of them getting very far. However, the Genetically Engineered Food Right to Know Act (H.R. 913) has also been reintroduced in this session of Congress; this bill would amend Section 403 of the FFDCA to declare that a food is “misbranded” if:
[I]t is a food that has been genetically engineered or contains 1 or more genetically engineered ingredients, unless the ingredients label clearly states that the food has been genetically engineered or identifies any genetically engineered ingredients, as applicable. 
Legislators in Maine have proposed delinking that state’s labeling law from the need to wait for other regional neighbors to follow suit. As it stands, Maine’s law cannot take effect until 4 other Northeastern states pass labeling laws. As state laws go, Vermont is on track to be the first state to require labeling when its law goes into effect in 2016. Legislative activity over mandatory labeling of GE food has occurred in more than half the states. In another aspect of the labeling debate, Agriculture Secretary Tom Vilsack has proposed that labeling information could be delivered by a smartphone app, making it available to consumers on a discretionary basis, without imposing direct labels on food products. That proposal has not satisfied critics, who view do not view that approach as an equitable substitute for mandatory labeling. The upshot of all this activity is that both federal laws, in opposition to each other, are still very unlikely to pass. At the state level, Vermont is on track to an active law in 2016, and we are likely to see some state pro-labeling ballot initiatives again in the 2016 election, similar to what occurred in 2014.

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.