The recent appropriations bill passed by Congress this week has some good news for NIH and the biomedical research community. The Trump administration had proposed cutting the NIH budget by about 18% for the upcoming year, and stripping $1.8 billion from the current year, compounding more than a decade of funding declines. Support for NIH in general has been bipartisan over the years, but that has not shielded the agency from funding volatility over the last decade or so. As reported previously here, the Trump proposal to slash NIH funding was a pillar of the emerging March for Science movement, and a motivator for participation in the April 22 march.
The Congress has now rejected the Trump proposal:
Lawmakers increased the budget for the National Institutes of Health (NIH) in its bipartisan deal to fund the government, effectively ignoring the Trump administration’s proposal.
Congress bolstered funding by $2 billion over the next five months, securing $34.1 billion for the NIH. It's the biggest boost the NIH has received in more than a decade, higher than at any point during the Obama administration.
The explanation for the Congressional resistance is multi-layered, and certainly the visibility of the NIH proposal was very high and the resistance was very public. In addition, Democratic strategizing in the budget process negotiations played a key role. The recent 21st Century Cures Act (see here) which focuses on breakthrough projects (but was not explicitly funded; see here) is now specifically funded in this new bill. More funding fights loom, however, as the 2017-2018 fiscal year is not far away, and the future proposed cuts to NIH are not resolved. But it's fair to say that the collective resistance to this year's NIH cuts (followed by its success) demonstrated significant political muscle, likely to be exercised in the next round of annual negotiations.
The March for Science on April 22, 2017 focused national attention on a number of science-impacting developments under the Trump administration. The march heralds more of developing movement than a single event. For the biomedical research community, the immediate concern is a proposed cut to the National Institutes of Health (NIH) budget of about 18% which is quite radical, and is a sharp departure from the recent Congressional efforts to restore the NIH funding decline over the last decade (see factsheet). A commentary by Harold Varmus, Nobel Prize winner and former director of NIH, notes the national effects of reductions to the NIH budget:
To understand just how devastating a cut of less than 20 percent of an agency’s budget would be requires some understanding of how the N.I.H. operates. Very little of its typical annual budget is spent on the agency’s administration: The industrious, underpaid government scientists who manage the funding of the N.I.H.’s research programs consume less than 5 percent of its budget. Only a bit more, about 10 percent, supports the work of government scientists. In sharp contrast, over 80 percent of its resources are devoted to competitively reviewed biomedical research projects, training programs and science centers, affecting nearly every district in the country.
Ironically, at the close of the Obama administration, Congress passed the 21st Century Cures Act, which would add a new $6 billion to medical research; it received widespread bipartisan support. It was particularly welcomed by the NIH leadership as promoting several new frontier initiatives: Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative and the Precision Medicine Initiative (PMI).
So the NIH funding climate remains turbulent, which is not optimal for a funding agency that makes multi-year grants to researchers. The NIH budget proposal was a motivating factor for many march participants, including research scientists. The disconnect between the vitality of American biomedical science and the political vulnerability of federal support is readily apparent. Decades of investment in life science research has had a cumulative effect of integrating molecular biology into medical practice, with many prospects for precise and targeted interventions in disease processes. But it's more than that at stake; the generation of scientific knowledge as a public good is an enterprise worth funding and protecting.
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.
It may not be widely known that the federal government retains a specific legal authority to expand the use of a patented invention that was developed using federal research grants, under a federal statute that was enacted in 1980 to remedy the underutilization of American inventive efforts. The Bayh-Dole Act accelerated the transfer of federally funded research into practical real world use; toward that end, the law allows federal grantees (such as universities) to pursue patent rights for any inventions developed in the course of the federally funded work. In addition, a little-known provision in the Bayh-Dole Act gave authority to any federal agency that funds research, such as the National Institutes of Health (NIH) (the major source of federal biomedical funding), to order a “march-in” of patent rights (35 U.S.C. 203) where the funding agency determines such action is necessary to achieve the goals of the statute. This authority is held by any federal granting agency/department (e.g., NASA, DOE, DOD). Effectively, then, NIH (or others) can compel a patent owner to allow third parties to make and use the patented invention. The patent owner is to be reasonably compensated for the use. According to the statute, march-in authority is justified when "action is necessary to alleviate health or safety needs which are not reasonably satisfied by the contractor, assignee, or their licensees" or "action is necessary to meet requirements for public use." To date, the NIH has refused to exercise this authority; five requests have been submitted since 1980. Most recently, in 2012, NIH was asked by Knowledge Ecology International (KEI) to use march-in rights for the AIDS drug Norvir due to excessive price raises (Abbott Pharmaceuticals held the patents); a previous KEI petition on Norvir had been filed in 2004. The NIH declined both requests (see earlier post). In its 2012 rejection, the NIH rejected the contention that price disparities between the price of drugs in the U.S. drugs compared to other high-income justified a march-in maneuver:
The NIH continues to agree with the public testimony in 2004 that the extraordinary remedy of march-in is not an appropriate means of controlling prices of drugs broadly available to physicians and patients.
In 2010, the NIH also declined to implement a march-in when a KEI petition was filed to remedy the manufacturing shortage of Fabryzyme by Genzyme, Inc. Now, KEI has filed a march-in petition with NIH over the high pricing of the prostate cancer drug Xtandi (patents granted to the University of California; now assigned to Astellas Pharma):
This letter is a request that the U.S. federal government use its rights in patents for the prostate cancer drug (enzalutamide), marketed under the brand name of Xtandi by Japan-based Astellas Pharma. This is a product that has an average wholesale price (AWP) of $129,269 per year, and which is far more expensive in the United States than in other countries. Specifically, we ask the Department of Health and Human Services (DHHS), National Institutes of Health (NIH), and/or the Department of Defense (DoD) to use its royalty free rights in the relevant patents, or to grant this request for march in rights. The relevant patents include, but are not limited to, the three patents listed in the FDA Orange Book for Xtandi (7,709,517, 8,183,274, and 9,126,941), all of which were granted to the Regents of the University of California, a public institution. All three inventions were made with the support of the United States government under National Institutes of Health SP ORE grant number 5P50CA092131 and Department of Defense (Army) grant number W81XWH0410129.
What can be expected with this most recent march-in petition to the NIH? In an environment where drug pricing is high on the radar screen for patients and for physicians (see earlier post on "financial toxicity"), and where the U.S. generally does not subscribe to price controls in health care, the high cost of drugs – especially new, targeted drugs – is causing politicians and bureaucrats to pay more attention. In January, prior to the filing of the new KEI petition, 50 members of Congress wrote a letter to NIH, asking that the agency set true guidelines for when the exercise of march-in rights would be reasonable. Then, in a hearing in the House Ways and Means Committee last week, Department of Health and Human Services (HHS) Secretary Burwell stated that HHS would consider the request for march-in guidance from the legislators. In the current campaign season, efforts to control drug prices are already part of political platforms and discourse (see here, for example). But with respect to the dormant march-in authority granted to the federal government, it may be that HHS and/or NIH are more willing to consider all measures and now actually welcome the existence of a statutory authority long ignored. At the least, NIH could begin to clarify how the march-in provisions are to be interpreted. However, that is not to say that march-in rights are a wholesale solution to drug pricing (see here for one study on the limits of such authority). For example, the ability of the federal government to negotiate drug prices for Medicare is often proposed as a leavening force; Congress has explicitly banned that option but it could be rescinded (or possibly by executive order?). Because some of the new “precision medicine” drugs are the most expensive (especially cancer drugs), the disconnect between the promise of genetically-informed medical care and actual access to biotech drugs is growing. That asymmetry will only add to the pressure on both legislative and executive branches to incorporate drug pricing realities into the overarching project of health care access as exemplified by the Affordable Care Act (Obamacare).
The rapid adoption of the CRISPR/Cas9 gene editing technology is evident in the explosion of papers describing the use of the technique for possible use in a variety of applications (e.g., retinitis pigmentosa, Duchenne's muscular dystrophy, HIV infection). As described in earlier posts here, the use of gene editing falls into two broad categories: altering genes in somatic cells (non-reproductive) to treat disease in individuals or altering the germline DNA in embryos to preemptively treat or minimize later-developing disease. It is the latter application that has led to many calls for an official moratorium, a ban on funding, and the convening of a wide public discussion on whether scientists should be able to edit germline DNA, which would create heritable genetic changes passed on to later generations. As reported here earlier, a development biologist in the U.K. applied to the Human Fertilisation and Embryology Authority (HFEA) for permission to use gene editing to study early embryonic development. That application has now been approved:
Our Licence Committee has approved an application from Dr Kathy Niakan of the Francis Crick Institute to renew her laboratory’s research licence to include gene editing of embryos. The committee has added a condition to the licence that no research using gene editing may take place until the research has received research ethics approval. As with all embryos used in research, it is illegal to transfer them to a woman for treatment.
The goal of Dr. Nakian's research is described:
To provide further fundamental insights into early human development we are proposing to test the function of genes using gene editing and transfection approaches that are currently permitted under the HFE Act 2008. We also propose to use new methods based on CRIPSR/Cas9, which allows very specific alterations to be made to the genome. By applying more precise and efficient methods in our research we hope to require fewer embryos and be more successful than the other methods currently used. Importantly, in line with HFEA regulations, any donated embryos would be used for research purposes only. These embryos would be donated by informed consent and surplus to IVF treatment.
The HFEA approval in the U.K. is without precedent and represents the first officially sanctioned use of gene editing on germline DNA. The 2015 publication of a gene editing experiments on non-viable embryos by Chinese scientists was widely condemned and it accelerated the urgency of considering ethical and regulatory aspects of this research as soon as possible. As described here earlier, a recent National Academy of Sciences (NAS) international summit on gene editing technologies had concluded with a consensus statement that it would be "irresponsible" to use gene editing for the purpose of altering germline DNA in the creation of embryos for reproduction. This research does not do that, explicitly. It will use gene editing to study how genetic changes affect embryonic development as its end goal. With regard to the U.S., there is already an NIH-imposed ban on any federal funding for gene editing on human embryos; in addition, the U.S. has no regulatory equivalent of the U.K. HFEA to consider any possible requests for the approval of non-reproductive embryonic developmental studies like the one approved here. The ongoing NAS study committee will convene another public meeting next week (February 11) to consider more impacts of gene editing technologies; details here.
The International Summit on Human Gene Editing, hosted by the National Academies of Science and Medicine (NAS, NAM) and international partners, has just concluded a 3-day meeting (archived webcast available here). This summit was called following the rapid dissemination of human gene editing research using the CRISPR/Cas 9 technology (see earlier posts here and here). The impact of this technology cannot be understated:
The rapid development and widespread adoption of easy-to-use, inexpensive and effective genome-editing methodologies has changed the landscape of biology. The simplicity of the CRISPR–Cas9 system allows researchers and students to make precise changes to genomes, thereby enabling many experiments that were previously difficult or impossible to conduct.
Widespread concern over possible attempts to engineer the human germline (perform gene editing on embryos or gametes for reproductive purposes) led to calls for caution or even a research moratorium (see here). At the conference this week, panels discussed the current technical state of human gene editing, existing and potential governance structures, international perspectives, and social consequences of the technology. The most controversial application of human gene editing – germline editing creating heritable genetic changes – was central to many of the discussions, and the conference oscillated between considering the legitimacy of germline editing and considering the arguably more mundane regulatory control of somatic gene editing. The conference coordinating committee has released a consensus statement that endorses further research on both somatic and germ-line gene editing, subject to existing regulations and oversight mechanisms. The full statement is here. I reproduce the portion of that statement that focuses on the hotly contested issue of germline gene editing:
3. Clinical Use: Germline. Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.
Germline editing poses many important issues, including: (i) the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism); (ii) the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment; (iii) the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations; (iv) the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country; (v) the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively; and (vi) the moral and ethical considerations in purposefully altering human evolution using this technology.
It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.
As reported by David Baltimore, chair of the conference committee, the members did not recommend either a ban or a moratorium on research into germline gene editing, but they state that any use of gene editing in reproduction at this time would be "irresponsible." In the U.S., the NIH has already ruled out federal funding for such research:
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.
The NAS contemplates ongoing public engagement with the controversies raised by human gene editing, in the form of an upcoming formal NAS study and the establishment of a publicly accessible forum to continue the discussion. More analysis of the conference and the effects on the current research climate will be posted here.
Over the last year, several ad hoc and professional organizations have continued to weigh in on whether the CRISPR/Cas9 gene-editing technology should be subject to any pauses in its adoption as a method of genome alteration or correction (see here). The advent of CRISPR/Cas9 technologies, beginning with the first publication in 2012, has accelerated scientific interest in gene editing because the technique has offered a more efficient approach than previous genome-altering methodologies. Here is an overview of the directions such research can take:
Genome editing has tremendous value as a tool to address fundamental questions of human and non-human animal biology and their similarities and differences. There are at least four categories of basic research involving genome editing technology that can be distinguished: 1) research to understand and improve the technique of genome editing itself; 2) genome editing used as a tool to address fundamental questions of human and nonhuman animal biology; 3) research to generate preliminary development of human somatic applications; and 4) research to inform the plausibility of developing safe human reproductive applications.
However, the CRISPR age is encountering fits and starts. Most controversially, the specter of CRISPR becoming a novel reproductive technology to perform gene editing on a human embryo has raised the most attention and concern. Earlier, this year, two groups of American scientists issued cautionary statements (see earlier post here); the NIH then reiterated its ban on any federal funding of research on gene-editing in embryos. More recently, other international bodies are weighing in. The U.K. Wellcome Trust has now issued a statement:
Research using genome editing tools holds the potential to significantly progress our understanding of many key processes in biology, health and disease and for this reason we believe that responsibly conducted research of this type, which is scientifically and ethically rigorous and in line with current legal and regulatory frameworks, should be allowed to proceed. We will continue to support the use of genome editing in preclinical biomedical research as well as studies that progress and refine these technologies. Within the UK, this research may involve the use of somatic (non-reproductive) or germ cells, including human embryos up to 14 days old - within the confines of the HFE Act 2008 - where appropriately justified and supported by rigorous scientific and ethical review.
Against that backdrop, a U.K. developmental biologist has applied to the Human Fertilisation and Embryology Authority (HFEA), for permission to edit the genome of a human embryo (there is no such agency in the U.S). The goal of the proposed research is to identify what genes in the developing embryo are active in the early post-fertilization stages; the research would use surplus embryos from IVF clinics where permission has been granted for such use. The license may be granted:
The Human Fertilisation and Embryology Authority (HFEA) has yet to review her application, but is expected to grant a licence under existing laws that permit experiments on embryos provided they are destroyed within 14 days. In Britain, research on embryos can only go ahead under a licence from an HFEA panel that deems the experiments to be justified.
In a separate development, The Hinxton Group, an international consortium centered on stem cell issues, published a statement calling for caution in possible reproductive applications, but not a moratorium:
Oversight structures must be in place prior to any attempts to use genome editing in human reproduction. Effective oversight requires the development of appropriate standards for preclinical data (e.g., What are acceptable thresholds for off-target events and mosaicism? What are appropriate methods for determining the impact of off-target events?). Initial attempts should be conducted only in the context of formal clinical research or trials. In addition, the health and well-being of participants, developing fetuses, and pregnancy outcomes should be monitored carefully. The health and well-being of those born should also be monitored in long-term follow-up and research, albeit with a mind toward the burdens this would impose.
Finally, in an event that will likely feature a spectrum of viewpoints, the Chinese Academy of Sciences (CAS) and the Royal Society (the science academy of the U.K.) are joining the U.S. National Academy of Sciences (NAS) to hold a highly anticipated international summit on human gene-editing on December 3, 2015 in Washington, D.C. A preliminary meeting (and webcast) to organize the summit will be held next week on October 5, 2015; details here.
In an unusual foray into advocacy involving the pharmaceutical marketplace, a coalition of oncologists has published a call to action in the Mayo Clinic Proceedings regarding the high price of cancer drugs; the physicians advocate for a number of regulatory and legislative measures to reduce the cost of cancer drugs, increase market competition, and ultimately improve patient access. It has been evident for a while that while molecular research has resulted in the development of new therapeutic approaches to cancer – especially targeted biotech drugs – the price of some of these drugs has well exceeded both patient and physician expectations; hence, the term "financial toxicity." In just one example, the Amgen drug Blincyto, an immunotherapy for leukemia, can cost about $178,000 for a course of treatment. The recent attention to funding research on "precision medicine" from the NIH and the White House focused on how cancer treatment (new drugs) is one of the chief beneficiaries of these efforts. In the published commentary, the oncologists make several points:
In 2014, all new US Food and Drug Administration (FDA) approved cancer drugs were priced above $120,000 per year of use.
For a patient with cancer who needs one cancer drug that costs $120,000 per year, the out-of-pocket expenses could be as high as $25,000 to $30,000—more than half the average household income and possibly more than the median take-home pay for a year. Patients with cancer then have to make difficult choices between spending their incomes (and liquidating assets) on potentially lifesaving therapies or foregoing treatment to provide for family necessities (food, housing, education).
The commentary specifically calls for the following measures:
(1) Creating a post-FDA drug approval review mechanism to propose a fair price for new treatments, based on the value to patients and heath care.
(2) Allowing Medicare to negotiate drug prices.
(3) Allowing the Patient-Centered Outcomes Research Institute, created through the Affordable Care Act initiatives to evaluate the benefits of new treatments, and similar organizations to include drug prices in their assessments of the treatment value.
(4) Allowing importation of cancer drugs across borders for personal use (e.g., prices in Canada are about half of prices in the United States).
(5) Passing legislation to prevent drug companies from delaying access to generic drugs (pay-for-delay).
(6) Reforming the patent system to make it more difficult to prolong product exclusivity unnecessarily (patent “evergreening”).
(7) Encouraging organizations that represent cancer specialists and patients (e.g., American Society of Clinical Oncology, American Society of Hematology, American Association for Cancer Research, American Cancer Society, National Comprehensive Cancer Network) to consider the overall value of drugs and treatments in formulating treatment guidelines.
A number of the suggested measures are familiar tactics, although not all in force. For example, the patent recommendations overlap with ongoing efforts to improve either patent quality or forestall dubious attempts to extend the term of lucrative patents (the “evergreening” phenomenon, for example, has been countered using patent law theories of double patenting). The phenomenon of “pay for delay” in which brand name companies pay would-be generic competitors to stay out of the market has encountered the Supreme Court’s Federal Trade Commission (FTC) v. Actavis decision in 2013 which endorsed antitrust inquiries into such arrangements; the Federal Trade Commission actively monitors such agreements. The call for the FDA to incorporate a pricing determinant in the drug approval process runs counter to any agency mandate to consider such questions in its regulatory work. Federal legislation to allow patients to import prescription drugs from Canada has been introduced, but not enacted. The call for the government to allow Medicare to negotiate bulk pricing with drug companies has been a political football for more than a decade since the enactment of Medicare Part D prohibited that option; the Obama administration has endorsed such negotiations, but the realities of Congress today make that unlikely. With respect for the calls to professional organization, the American Society for Clinical Oncology (ASCO) is actively pursuing methods for drug valuation that incorporate pricing. Despite these particulars, the Mayo commentary lines up with other public acts of priced-based resistance from the oncology community, such prescribing refusals based on cost (e.g., Sloan-Kettering oncologist practices) or cost-consciousness in prescribing practices. The article further endorses a consumer petition drive which seeks patient support for these efforts. A critical mass of attention is developing to the high pricing of new biotech cancer drugs; the British medical journal Lancet published a recent editorial:
It therefore seems depressingly clear that industry's inflated pricing of new cancer drugs is contributing to a failure of health systems to offer promising new therapies to the very people for whom the drugs are created—cancer patients worldwide.
It should be noted that despite the Lancet's pessimism, the U.K. did actually establish a Cancer Drugs Fund under the National Health Service to target assistance to those needing expensive cancer drugs; however, as just announced, the fund is over-budget and now restricting which drugs will be covered.
The rapid dissemination of the publication reporting the use of CRISPR/Cas9 gene-editing technology by Chinese scientists in an attempt at human germline modification has generated quick responses from several official quarters. The National Academy of Sciences (NAS) has announced its upcoming involvement in the scientific, ethical, and policy debate over the use of the CRISPR technology in germline applications:
The National Academy of Sciences and the National Academy of Medicine are launching a major initiative to guide decision making about controversial new research involving human gene editing. Human gene-editing technologies, such as CRISPR-Cas9, may lead to promising new treatments for disease. However, recent experiments to attempt to edit human genes also have raised important questions about the potential risks and ethical concerns of altering the human germline. Future advances are likely to raise new questions.
Our initiative will include an international summit this fall to convene researchers and other experts to explore the scientific, ethical, and policy issues associated with human gene-editing research. In addition, we will appoint a multidisciplinary, international committee to begin a comprehensive study of the scientific underpinnings and clinical, ethical, legal, and social implications of human gene editing. The committee will consider and recommend standards, guidelines, and practices governing the use of gene-editing technologies in biomedical research and medicine. An advisory group to steer the overall initiative will soon be announced.
The NAS initiative has now generated an official reaction from the Obama administration. It is evident that the administration would like to see the scientific community get out ahead of lawmakers in considering how to responsibly handle the potential of CRISPR in reproductive applications. In the White House statement:
The scientific community has a good record of establishing and adhering to ethical principles in genetic technology. In the 1970s, scientists called for a temporary moratorium on gene-splicing technology until the implications and policies could be sorted out. Similarly, this year scientists called for a moratorium on germline-editing research until the safety and ethical issues could be explored by the community.
The advances in health technology over the past century - vaccines, antibiotics, early disease diagnostics, and treatment for countless health conditions - have reduced infant mortality, extended life expectancy, and alleviated suffering for millions. But new technology also brings risks and ethical challenges that require careful consideration. For example, researchers in China recently conducted genome-editing experiments in human embryos of a kind not able to develop into a fetus or a person.
Research along these lines raises serious and urgent questions about the potential implications for clinical applications that could lead to genetically altered humans. The full implications of such a step could not be known until a number of generations had inherited the genetic changes made — and choices made in one country could affect all of us.
It is important that the NAS’ international summit fully explore the implications of germline editing for the current generation and generations to come across the globe, as well as the potential for alternative technologies that do not require germline alteration to deliver similar medical promise. The Administration looks forward to seeing the results of the scientific community’s discussion.
The quiet alarm that underlies these relatively rapid reponses highlights how the use of CRISPR technology application in human reproduction is not just another clinical application, but it goes right to the heart of human potential and scientific power, as well as not insignificantly raising fears of eugenic intent.
In the U.S., we lack a formal regulatory body devoted to oversight of reproductive technologies (unlike, e.g., the UK Human Fertilization and Embryology Authority) so we see a more ad hoc display of responses. The reminder by the National Institutes of Health that no federal funding would be available for gene-editing experiments on the human germline is a kind of de facto ban, since many U.S. scientists rely on federal support.
President Obama announced during the recent State of the Union address that his administration would initiate an enhanced funding and policy focus on the field of precision medicine. Precision medicine is informed by the collection of genetic, proteomic, microbial and other biological data of a patient – and the end result is to more sharply define disease states and allow for treatment that is more personalized, with a higher likelihood of success. In the specific case of cancer, for example, a patient’s tumor cells can be analyzed genetically to develop a precise molecular characterization – and treatments can be customized accordingly. According to the White House release:
Launched with a $215 million investment in the President’s 2016 Budget, the Precision Medicine Initiative will pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.
The proposed funding is directed to the National Institutes of Health (NIH), the NIH’s National Cancer Institute and the Food and Drug Administration (FDA), and the National Coordinator for Health Information Technology (ONC). The initiative will focus on oncology-related objectives as a starting point:
The cancer-focused component of this initiative will be designed to address some of the obstacles that have already been encountered in “precision oncology”: unexplained drug resistance, genomic heterogeneity of tumors, insufficient means for monitoring responses and tumor recurrence, and limited knowledge about the use of drug combinations. Precision medicine's more individualized, molecular approach to cancer will enrich and modify, but not replace, the successful staples of oncology - prevention, diagnostics, some screening methods, and effective treatments - while providing a strong framework for accelerating the adoption of precision medicine in other spheres. The most obvious of those spheres are inherited genetic disorders and infectious diseases, but there is promise for many other diseases and environmental responses.
The breakdown of this investment is as follows:
$130 million to NIH for development of a voluntary national research cohort of a million or more volunteers to propel our understanding of health and disease and set the foundation for a new way of doing research through engaged participants and open, responsible data sharing.
$70 million to the National Cancer Institute (NCI), part of NIH, to scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment.
$10 million to FDA to acquire additional expertise and advance the development of high quality, curated databases to support the regulatory structure needed to advance innovation in precision medicine and protect public health.
$5 million to ONC to support the development of interoperability standards and requirements that address privacy and enable secure exchange of data across systems.
The proposed investment of $215 million is actually quite small, when compared to an annual NIH budget of around $30 billion, and further still when it is divided among the target agencies. Congressional approval will also be needed, but that is probably likely, given ongoing bipartisan advocacy efforts in Congress to increase funding for “21st Century Cures.” However, apart from the financial aspects, the announcement does tie various policy architects together in the federal ecosystem of personalized medicine – imagining newly developed data from the NIH research cohort that is used to identify a new genetic marker for cancer diagnosis or susceptibility, leading to a new test devised by the NCI, which then enters the marketplace under a regulatory regime supervised by the FDA, and all emerging data points accountable in a more standardized electronic environment that the ONC has helped to develop. There are several regulatory sinkholes in this announcement, of course - what will it mean to launch a volunteer-sourced bio-database under government oversight, given a current minimalist privacy regime for genetic information (e.g., GINA). What regulatory scheme will prevail at the FDA with respect to LDTs and next-generation sequencing technologies (see recent post)?
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.
Recent developments regarding the biosafety practices in several government laboratories have raised concerns about the containment of potentially dangerous pathogens in scientific research. In the past month, a series of separate incidents exposed weaknesses in the oversight and management of dangerous pathogens. These included the accidental exposure of CDC scientists to anthrax in CDC labs, the discovery of forgotten vials of viable smallpox virus in an FDA lab housed at the NIH, and an unintentional cross-contamination of a benign influenza strain with a dangerous H5N1 influenza and its subsequent transfer. All of these events involve naturally occurring pathogens, but these events also occur at a time when public debate continues over the deliberate creation of potentially dangerous pathogens in the field of dual-use research of concern (DURC). With scientists reporting the creation of new pathogens in order to define what genetic changes correlate with pathogenicity or transmissibility, concerns emerged as to how such scientific detail should be publicly shared, and how such pathogens were to be safely contained in the laboratory environment. Most of the attention focused on the publication of genetic detail, evidencing concerns that the pathogens could be reconstructed for malicious intent. However, an equally serious concern related to the possibility that the newly designed pathogens could be released inadvertently, due to laboratory or personnel errors. This recent series of safety lapses now amplify the concerns over the general state of biosafety practices in laboratories handling the most dangerous pathogens, whether natural or engineered. Although the standards for the containment of dangerous pathogens in laboratories are well-known and generally followed, one untoward release of a high-risk infectious agent could be catastrophic. In general, there are established biosafety protocols which define the type of required facilities, procedures and personnel based on the level of risk that a particular pathogen poses to public health and/or the environment. The guidelines assign a biosafety level (BSL) based on that analysis; the high-containment BSL-3 and BSL-4 labs are required for work with the most dangerous pathogens. In addition, the transport of such pathogens is also managed with protocols that establish safe transfer. The CDC director, Dr. Thomas Frieden, conceded the pattern of biosafety lapses in a press conference and at a Congressional hearing yesterday. Dr. Frieden has shut down several labs and instituted a moratorium on some shipments of pathogens. The Government Accountability Office (GAO) has conducted several studies on laboratory safety in high-containment laboratories (private or public), specifically noting the absence of any overarching federal body to oversee these laboratories, particularly in view of their proliferation in the years since 9/11 (the anthrax incidents), as bioterror-related research has increased (note recent controversy over a BSL-4 lab established in Boston). The GAO was represented at yesterday’s hearing, and it reminded Congress of their previous investigations and recommendations on laboratory safety; the recent incidents may cause Congress to revisit this work and act accordingly.
In a move that signals the maturity of the gene therapy field, the National Institutes of Health (NIH) has announced that it will no longer subject all applications for gene therapy trials to automatic review by the Recombinant DNA Advisory Committee (RAC). Gene therapy is defined as:
the transfer of genetic material into humans with the goal of replacing or compensating for the function of abnormal genes, or to enhance the immune system’s ability to attack cancer cells.
RAC occupies a singular place in the history of government oversight of new technologies. The committee was established in 1974, following increasing concern by scientists in the then-emerging field of molecular biology as the techniques involving recombinant DNA were developed and disseminated. The Asilomar conference of 1975 originated with scientIsts, and led to the publication of physical and biological containment strategies to limit the risk of working with recombinant organisms (e.g., bacteria, viruses). RAC issued the first Recombinant DNA Research Guidelines in 1976, and these were the precursor to later guidelines for the gene therapy applications that were first submitted to RAC in the late 1980's. Now, following a study from the Institute of Medicine that called for streamlining the review process for gene therapy (removing redundancies in the review process), the NIH has acceded to their recommendation that RAC reviews of gene therapy be reserved for exceptional cases where both of these conditions exist:
1. The protocol review could not be adequately performed by other regulatory and oversight processes (for example, the institutional review boards, institutional biosafety committees, and the FDA).
2. One or more of the following criteria are satisfied:
Protocol uses a new vector, genetic material, or delivery method that represents a first-in-human experience, thus representing unknown risk.
Protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.
Proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for local and federal regulatory bodies to evaluate the protocol rigorously.
In reviewing the history of RAC oversight for the gene therapy field, the IOM stated:
When recombinant DNA technology was new, and the many risks concerning individual clinical trial protocols were uncertain, the public, scientists, and policy makers raised important questions about potential dangers—such as whether this technology could harm patients, create new infectious organisms, or make genetic alterations that could be passed down to future human generations. In its report, the IOM committee finds that the major concerns about recombinant DNA from 40 years ago do not raise the same level of concern today, as hundreds of gene therapy clinical trials have evaluated the technique’s safety and effectiveness.
The RAC committee stands as a model of a technology-specific review body set up to augment existing regulatory processes in the case where a novel technology has emerged with potential risks to health and safety. This recent move now becomes a model for partial deregulation of a maturing technology. Gene therapy protocols will continue to be reviewed by the FDA and institutional oversight panels. The IOM report recognizes that this model of regulatory layering still has relevance for current emerging technologies, and specifically cites the field of nanotechnology as a candidate for a future RAC-like review body to consider its specific applications in medicine.
A declaration of intent to conduct “gain-of function” experiments on the novel avian influenza A(H7N9) virus has been published by scientists who wish to alter the genetic composition of the viruses to determine what genetic changes/mutations correlate with altered function. Gain of function (GOF) experiments on pathogens alter existing properties and can result in the creation of more dangerous pathogens; the goal is to gain insights into the relationship between genetics (structure) and function. The H7N9 virus emerged earlier this year in China, and to date the World Health Organization reports 135 human cases, with 44 fatalities. This new effort to study H7N9 is proposed by a consortium of scientists, including Ron Fouchier and Yoshihiro Kawaoka, who were the principal investigators for the experiments on HPAI H5N1 viruses that produced viruses with potentially increased human to human transmissibility. Those earlier experiments raised such an alarm that publication of the research was halted in the U.S. while the NSABB federal advisory committee evaluated the risk of publication (both were eventually published). The proposed experiments fall into the category of DURC (dual research of concern), defined as such:
Dual use research of concern(DURC) is a subset of dual use research defined as life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.
The declaration of intent by the scientists is presumably an attempt to increase transparency and invite deliberation at the front end of the process and avoid the panicked reaction that followed the announcements of the earlier H5N1 experiments in 2011. The authors also include materials outlining the biosafety precautions that would accompany the experiments. Early official reaction from the CDC and NIH declares that such experiments will receive extra scrutiny before U.S. government funding will be made available, according to recently issued federal guidelines for DURC issued earlier this year. The CDC has also issued specific biosafety guidelines for working with the H7N9 virus. The following kinds of gain-of-function experiments were announced in the letter:
•Immunogenicity. To develop more effective vaccines and determine whether genetic changes that confer altered virulence, host range or transmissibility also change antigenicity.
•Adaptation. To assist with risk assessment of the pandemic potential of field strains and evaluate the potential of A(H7N9) viruses to become better adapted to mammals, including determining the ability of these viruses to reassort with other circulating influenza strains.
•Drug resistance. To assess the potential for drug resistance to emerge in circulating viruses, evaluate the genetic stability of mutations conferring drug resistance, and evaluate the efficacy of combination therapy with antiviral therapeutics. Also, to determine whether A(H7N9) viruses could become resistant to available antiviral drugs, and to identify potential resistance mutations that should be monitored during antiviral treatment.
•Transmission. To assess the pandemic potential of circulating strains and perform transmission studies to identify mutations and gene combinations that confer enhanced transmissibility in mammalian models (such as ferrets and guinea pigs).
•Pathogenicity. To aid risk assessment and identify mechanisms, including reassortment and changes to the haemagglutinin cleavage site, that would enable circulating A(H7N9) viruses to become more pathogenic.
These proposed experiments – altering the critical variables of spread and virulence for the viruses, changing drug resistance and vaccine susceptibility – will likely produce viruses that are potentially more dangerous than those we currently know about. The stated goal of such work is to learn which mutations alter the risk profile of a virus – confer pandemic potential – and use that knowledge to design vaccines or discover antivirals that can respond to these viruses. Further, it is argued that ongoing surveillance efforts can be focused on identifying virus isolates that display such mutations and pose an elevated public health risk, although this point is contested by other scientists. It’s not clear whether the NSABB will be involved at this early stage – to date, it has not advised on the merits of funding specific experiments which can be characterized as DURC. The recent tightening of federal review of such research will be put to the test with these proposed experiments as the investigators seek U.S. funds. With respect to the publication of results, the influenza researchers anticipate the possible fallout:
To advance A(H7N9) virus research, findings should be shared in refereed publications. Investigators agree to adhere to guidelines for responsible communication of results and every effort will be made to put the results in context and reduce sensationalism.
The questions that were raised by the H5N1 influenza controversy - what criteria are to be used when evaluating the funding for DURC or what conditions need to attach to such funding – will now surface with this H7N9 research declaration – and their resolution might establish a template for future research proposals.
Several developments have followed last month's Supreme Court decision that invalidated Myriad Genetics patent claims to isolated genes; (AMP v. Myriad opinion). Within hours of the Court’s decision, several competitors announced plans to offer BRCA1 and BRCA2 genetic tests. Myriad has recently filed patent infringement suits against Ambry Genetics (California) and Gene by Gene (Texas), based on the assertion of patent claims from ten patents it holds to BRCA1 and BRCA2 related genetic materials and methods (including some with contested claims in the Supreme Court). The complaint against Ambry is here; the complaint against Gene by Gene complaint is here. The suits, filed in Utah federal court, could be an opening play to fully litigate these other patents or a maneuver to create licensing structures for these patented materials and methods. A strategy by Myriad to obtain a preliminary injunction against these companies would have to contend with the more rigorous scrutiny for such requests after eBay v. MercExchange (2006), where the Supreme Court reaffirmed the need to consider "public interest" in the award of injunctions, and the current climate might lend support for such an argument against any injunction. Ambry has indicated that it will “vigorously defend” its right to offer testing services.The Court’s invalidation of some of Myriad’s patent portfolio related to BRCA1/2 testing has clearly led to altered expectations regarding the state of the genetic testing marketplace. Evidence of this is the response from Senator Patrick Leahy, Chair of the Senate Judiciary Committee, to Myriad’s lawsuit, calling for the National Institutes of Health (NIH) to exercise “march-in” rights that it holds pursuant to the Bayh-Dole Act of 1980. That option applies to patents for which NIH provided federal funding (or other federal agencies). Apart from the march-in authority, the U.S. government retains a default mechanism, a compulsory license that allows it to use any patented invention (or authorize 3rd parties to do so) under the statutory authority of 28 U.S.C. 1498, which requires “reasonable and entire compensation for such use and manufacture.” Since the march-in authority has never been exercised by the NIH (see here), it is unlikely to respond to Leahy’s call. Nor is it likely that the government would regard the BRCA1/2 genetic testing controversies as critical enough to trigger the compulsory license mechanism. These disputes are likely to be settled more informally, and more quickly, as the high visibility of these tests will retain public attention and maintain pressure on Myriad to support the expansion of genetic testing options.
