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December 12, 2017   organ on a chip

 

road map

Image Credit: FDA.

The Food and Drug Administration (FDA) has joined other drug development stakeholders in pushing for the development and implementation of more predictive preclinical testing approaches. Last week FDA unveiled its Predictive Toxicology Roadmap, which aims to transform the development, qualification, and integration of new toxicology methods across FDA centers.

Toxicology testing is crucial for the development of safe medical products that are regulated by FDA because it informs potential risk to humans. Traditionally, toxicity testing has used animals to make predictions about human outcomes. However, the quality of information gained from animal tests has been the subject of much debate.

For far too long animal-based toxicity tests have been accepted as the benchmark for testing despite a general failure to provide information that is sufficiently relevant to humans. For example, the FDA and drug development stakeholders have known for more than 13 years that approximately 92 percent of new medicines fail in humans after passing animal tests.

This Roadmap acknowledges the scientific advances made and establishes a plan for support and implementation.

In an article released on the subject, FDA’s acting chief scientist stated, “Today, novel methods such as organs on a chip or mathematical modeling are being developed for toxicity testing that are generating unique opportunities to improve our ability to quickly and more accurately predict potential toxicities and reduce associated risks.”

The six-part Roadmap seeks to improve toxicity testing and formalizes FDA’s position on replacing/reducing animal testing.

The Roadmap establishes a Toxicology Working Group to facilitate communication among FDA centers. FDA knowledge will no longer be siloed in separate centers, but will rather be shared to help determine which approaches may be used for which purposes.

The group will identify gaps in current test methods and determine where newer approaches—

such as organ chips and computer simulations—may be identified, further developed, scientifically evaluated, and implemented.

The group will also develop a Toxicology Seminar Series to facilitate agency-wide training on new testing approaches. We’ve pushed for this much-needed initiative through consistent input to FDA and ICCVAM, as agency scientists must build their knowledge-base, confidence and familiarity with modern approaches to toxicity testing.

The Roadmap encourages frequent and often communication with FDA regarding interest in using new methods. FDA should take this opportunity to update its regulations that mandate animal data, to ensure the Roadmap is properly implemented. Companies may not be willing to rely on the Roadmap in the face of inconsistent regulations.

The Roadmap solidifies FDA’s commitment to working with the stakeholder community, which has seemed to increase over the past year. In January 2017, FDA participated in a Preclinical Innovation and Patient Safety (PIPS) roundtable hosted by the Physicians Committee. The roundtable aimed to increase stakeholder collaboration to advance modern, predictive approaches. FDA has also collaborated with the National Center for Advancing Translational Sciences (NCATS) and the Microphysiological Systems Working Group of the IQ Consortium to provide input on tissue chip technology.

The Toxicology Working Group will track progress and provide annual reports to the chief scientist to increase oversight and accountability.

We applaud FDA for its transparency and vision set forth in the Roadmap, and look forward to continued collaboration to save human and animal lives.

Learn more from our The Hill op-ed and The Exam Room.

 

United States Department of Agriculture

In October, organizations that represent animal experimenters and their institutions released a troubling report. It proposes drastically cutting protections for animals in laboratories, including a significant change to the Animal Welfare Act.

The report, titled Reforming Animal Research Regulations, recommends weakening federal standards for animals in laboratories and also giving animal experimenters greater control over the creation of new rules. Essentially, it would help create an oversight system that allows laboratories to self-regulate.

A 2014 Pew Research Center survey of adults in the United States found that 50 percent of respondents "oppose" the "use of animals in scientific research” compared to 47 percent who "favor" the practice. Pair that level of concern with the federal government's poor enforcement of animal welfare in laboratories. In 2014, the U.S. Department of Agriculture’s (USDA) own Office of Inspector General (OIG) found:

  • USDA inspectors did not always review animal use protocols and annual reports (the documents that list how many of each species were used and in what pain category), as required.
  • USDA closed investigations involving grave Animal Welfare Act (AWA) violations, including animal deaths and serious repeat violations.
  • USDA failed to properly punish laboratories by reducing fines by an average of 86 percent – despite previous OIG recommendations to end this practice.
  • Some laboratories’ Institutional Animal Care and Use Committees (IACUCs) are not adequately monitoring their facilities.
  • USDA wasted resources by conducting more than 500 inspections at more than 100 facilities that hadn’t housed AWA-covered animals for more than two years.

All of this should be cause for greater protections for animals and improved openness about what happens inside laboratories. Yet the authors of the report suggest that the government actually pare back its requirements.

Some of the report’s recommendations include:

  • Drastically reducing how often most research facilities are inspected by the U.S. Department of Agriculture (USDA). This change would significantly impair the public’s ability to monitor those facilities’ compliance with the law.
  • Exempting many animal use requests (called protocols) from review by a laboratory’s full Institutional Animal Care and Use Committee when the protocols include "low-risk, noninvasive, or minimally invasive procedures." Instead, the report proposes allowing much animal use to be approved by only one or two members of the committee. But when Congress amended the Animal Welfare Act in 1985, it intended these committees to serve as groups of people, not simply individuals. In addition, even protocols that don’t involve invasive procedures are still harmful to animals, who will experience the stress of confinement, handling, and preparation for experiments. Also, there is no shortage of reported injuries and deaths to animals during routine laboratory practices, including animals who died of dehydration due to broken air conditioning or water feeders and animals who died when their cages were sent through industrial washers.
  • Giving animal experimenters greater control over the creation of regulations and stifling public input. The report’s authors suggest that "[n]ear-final documents should be reviewed by an external advisory committee of experts engaged in animal research from the regulated community before they are disseminated for public comment or final agency review." This suggests that the comments of animal experimenters and the facilities that employ them should be given more weight—or be the only comments considered—when making new rules.

At a time when there is more pressure than ever to reduce government regulation, it’s crucial that we stand up for the rules that give some modicum of protection to those who are most vulnerable. And that's what the Physicians Committee is doing. We’re working with other organizations to plan a strategic response to the recent report and the larger effort to weaken federal animal welfare regulations.

 

November 27, 2017   animal testing, cancer

 

Mice are telling cancer researchers to give it up

It is widely known that mouse research to study human cancers is fraught with unreliability. Scientists have for decades attempted to replicate human cancer growth and treatment responses in mice by disabling their immune systems and grafting human-cell-line-based cancers onto them, a model known as a xenograft. These studies have notoriously faulty outcomes. A new report has shown that recent “improvements” to this technique are just as faulty.

In general, cancer animal research (see here, here, and here) has a failure rate of at least 95 percent, as determined by the results of clinical trials based partly on mouse studies. The few "successes" are usually clinically irrelevant, providing minimal or no real-life value. A 2014 study from the National Cancer Institute revealed an average 2.1 month life prolongation (and often as little as a few days) for the 72 cancer drugs approved from 2002-2014, and even this minimal benefit is illusory in two-thirds of the drugs in clinical use.

Researchers characteristically address the very high attrition rate for drugs developed from animal research by postulating that “better” techniques with animals are needed. Various approaches to improve the predictability of these stand-ins for human cancers have been tried without success. In recent years, there has been much hope ascribed to an approach referred to as patient-derived xenografts (here, here, and here). The mice used in these studies are termed PDX mice and are often called human avatars. To produce these avatars, extracts from human cancers (obtained by biopsies or surgical excisions) are injected into mice, thereby creating mice purportedly expressing the injected cancer. These models can be created from a patient's own tumor, in which case the patient then has a “model” specific for his or her own cancer. It has been thought that such "precision oncology" models will remedy the problems with cell-line-derived cancer tissue, and will identify tumor markers, genetic targets, and effective treatments for a patient's specific cancer.

A recent report from Boston researchers reveals why the ballyhooed PDX approach fails to solve the age-old problem of translation from mice to humans—a problem researchers understandably call the Valley of Death. Using 1,110 tissue samples from 24 different cancer types, these researchers evaluated genetic changes occurring after transplantation of patient-derived cancer tissue into PDX mouse avatars.

Genetic changes in the transplanted tumors occurred rapidly, and these were markedly different from initial genetic characteristics and genetic changes observed during tumor evolution in patients. Genetic mutations noted in patient tumors sometimes disappeared after transplantation. The authors concluded: "Notably, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have major implications for PDX-based modeling of human cancer."

In other words, the human cancer in the PDX mouse's biological environment leads to mouse-specific changes that invalidate the mouse as a descriptor of the human tumor or as a method for identifying tumor targets and developing treatments. It is no wonder that this precision oncology approach displays no more precision than previous failed cancer research methods using mice. Similar genetic discrepancies would surely be expected for any species using PDX technology, and the conclusion remains that nonhuman research is immutably inadequate for the study and treatment of human cancers.

Where to from here? First, it's long past time that we take notice of the many ways that mice have shown us that they are not tiny humans. Despite decades of research model manipulation, mice are no better at recapitulating the course or treatment responses of human cancers. Second, the logical transition to human-relevant cancer research methods is overdue. Whether the barriers to this transition are researcher arrogance, career and funding considerations, or regulatory restrictions, these must be overcome if the abject failure of mouse research for cancer is to be reversed.

November 13, 2017   other

 

Physicians Committee Medical research program director Ann Lam, PhD, with award winners Dr. Francesca Pistollato and Dr. Lena Smirnova, and Green Neuroscience Laboratory director Elan Ohayon, PhD.

Physicians Committee Medical research program director Ann Lam, PhD, with award winners Dr. Francesca Pistollato and Dr. Lena Smirnova, and Green Neuroscience Laboratory director Elan Ohayon, PhD. 

For the second year in a row, the Physicians Committee is partnering with the Green Neuroscience Laboratory to present the Green and Open Neuroscience Hero Awards for outstanding contributions to human-relevant research. This round of awards will be given at the 3rd Annual Green and Open Neuroscience Symposium & Soiree Nov. 13, 2017 in Washington, D.C. The free and public event is held as a satellite to the annual Society for Neuroscience meeting, the world’s largest annual meeting of neuroscientists, and will inform scientists about the promise of neuroscience research conducted without animals.

This year, two awardees are being recognized for their contributions. Awardee Dr. Lena Smirnova, research associate at Johns Hopkins University Bloomberg School of Public Health and the Center for Alternatives to Animal Testing, works to develop human “mini-brain” 3-dimensional organoids and other cell models to study the impact of environmental chemicals on brain function. The second recipient, Dr. Francesca Pistollato, research scientist at the European Commission Joint Research Center, is acknowledged for her work on human-based science, particularly with human induced Pluripotent Stem Cells (iPSCs) in the area of Alzheimer’s disease.

The Green and Open Neuroscience Hero Award is given to scientists, educators, policymakers, or advocates who help improve our understanding of the brain and health through research and perspectives that strengthen ethics, open science, the environment, education, arts and protection of neurodiversity (See also: greenneuro.org/principles). These heroes exemplify how science can be dramatically advanced while maintaining the highest standards of responsible science.

Through presentations, discussions, and music, the evening soiree is both a celebration and an opportunity to consider potential collaborations and the necessary steps that need to be taken in neuroscience in order to promote groundbreaking, humane research in the 21st century.

Last year’s winners include Dr. Jacopo Annese of the Brain Observatory, for his work to create a high-resolution human brain atlas to humanize the understanding of the brain, and Dr. Stacey Lopresti-Goodman of Marymount University, for her groundbreaking research on animal cognition and outstanding contributions to forwarding ethical science education.

The event is open to the public, with an optional registration here.

November 11, 2017   animal testing

 

Awardees are given a hand-made hare statue to signify the prize's emphasis on "fighting animal testing". Pictured are Kristie Sullivan, MPH, Physicians Committee's vice president for research policy, Sara Amundsen, Humane Society Legislative Fund, and Catherine Willett, PhD, Humane Society of the United States.

We are excited to announce that, together with our partners, the Physicians Committee has won the Lush Lobbying Prize, which is awarded each year to organizations or individuals “pushing for change, focusing on policy interventions promoting the use of alternatives.” This award acknowledges our work with the Humane Society of the United States and the Humane Society Legislative Fund on the Frank R. Lautenberg Chemical Safety Act for the 21st Century. This bill, which was enacted into law in June 2016, contains the first ever national United States requirement for the Environmental Protection Agency (EPA) and chemical companies to consider and use alternatives to animals in chemical testing. The EPA is also required to create a strategic plan to replace and reduce animal tests, provide incentives to use non-animal alternatives, and report regularly to Congress on its progress.

Eighteen winners from all over the world are being honored for their contributions to end animal testing in science, public awareness, training, and lobbying at an awards gala in London, the evening of Friday, Nov. 10. The lobbying award prize totals 50,000 British pounds and will be shared among the three organizations.

The Lautenberg Act signals a new direction in chemical assessment, in which human-relevant test methods and approaches are required to be used, developed, and promoted by the EPA and any entities providing chemical toxicity data to the EPA. By requiring the EPA to replace and reduce the use of animals in chemical testing, create a strategic plan to implement nonanimal methods into their chemical assessment practices, and report to congress on its progress every five years, it represents the beginning of the end of animals killed in toxicity testing.

Kristie Sullivan speaks at Friday's awards ceremony in London.

Thank you to the Lush Prize for recognizing this achievement.

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