Good Science Digest

The Physicians Committee
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testing road map

Image Credit: FDA.

A growing number of scientists are realizing that biological and physiological differences between—and even among—species are leading to failures in the development of safe and effective medicines.

Scientists from a variety of backgrounds are working to develop better methods to evaluate safety. And they have been successful in elevating our abilities to investigate how investigational new medicines interact with human cells, tissues, and biological and physiological processes.

As is often the case, law and policy did not keep pace with science. Now, we are at a standstill, where many of these so called “human-based” scientific approaches already exist for evaluating medicinal safety, such as organ chips and computational methods, but they have not been fully utilized for multiple reasons.

One main hindrance is Food and Drug Administration (FDA) regulations.

Before the regulated industry can be expected to implement a new approach to answering a regulatory question for the FDA, industry must be confident that the FDA will accept the new approach.

One step towards implementation is regulators clearly communicating that human-based approaches, such as advanced in vitro and in silico approaches, are accepted if sufficiently evaluated. FDA may start this communication by broadening the regulations that currently require animal data.

FDA staff have stated informally at meetings, that the agency retains discretion to accept modern approaches to assessing safety that do not use animals. Certainly, the law of the land allows it.

The Federal Food, Drug, and Cosmetic Act (FFDCA) is the United States law that gives FDA the authority to regulate drugs. The FFDCA does not mandate animal data for pharmaceutical development. Rather, this mandate arises from FDA promulgated regulations.

In September 2017, an FDA blog announced that a Regulatory Reform Task Force would review agency regulations and requested input on regulations that need to be modified or repealed because they place an burden on the regulated community. This was the opportunity we needed, as we had already been recommending that FDA broaden regulations that currently require animal data to also allow for the use of modern approaches that are based in human biology and physiology.

We combed through the Code of Federal Regulations and ultimately identified 235 regulations that should be changed because they place a burden on industry to use animals, even if a more predictive or cost-effective approach is available.

Our suggestions should be adopted because they remove this burden, help ensure the longevity of the regulation in the face of rapidly advancing science, and will help FDA improve product safety and meet its goal of replacing and reducing animal testing.

Making the proposed regulation changes would be consistent with FDA’s own participation in the National Institutes of Health (NIH) and Defense Advanced Research Projects Agency (DARPA) tissue chip collaborations and the vision for advancing the methods available to drug sponsors through FDA’s own Predictive Toxicology Roadmap.

Bookmark our Good Science Digest to stay updated on how the Regulatory Reform Task Force and FDA responds to our input.

We are seeking a student or recent graduate interested in promoting alternatives to the use of animals in medical research and education for our summer 2018 Replacing Animals in Research Internship. Apply today!

February 23, 2018   animals in education

 

In February 2018, science fiction became science fact, as scientists in Shanghai reported the successful cloning of cynomolgus monkeys (long-tailed macaques) using a process called somatic cell nuclear transfer (SCNT). This is the same process used in 1996 to clone Dolly the sheep, and it was subsequently used to produce live births in more than 20 other species.

But SCNT uniformly failed in primates until the Shanghai group discovered how to promote the growth of the created embryo in a surrogate mother macaque. Although nearly all the implanted embryos did not survive, two live births resulted—genetically identical sisters Zhong Zhong and Hua Hua.

SCNT operates by obtaining a donor oocyte (egg cell), then removing the nucleus and inserting a cultured fetal fibroblast (connective tissue cell) from an aborted fetus. Techniques developed by the Shanghai researchers promote the development of the created embryo after transfer to a surrogate mother (Figure).

Cloning of macaque monkeys by  somatic cell nuclear transfer.

Source: Liu, et al. Cloning of macaque monkeys by somatic cell nuclear transfer. Cell 2018;172:1-7

The purpose of this research is to create populations of genetically identical monkeys to facilitate research into human diseases, and particularly neurological disorders such as dementia and Parkinson disease that have escaped elucidation and treatments based on animal research. The presumption is that by eliminating genetic variation as a complicating factor, fewer monkeys can be used while obtaining more reliable information from (for example) monkey brain research.

Concerns and objections to this research are based on the claimed usefulness of the cloned monkeys for human-relevant science and on several ethical issues, raised even by the researchers themselves. The cloning of genetically identical monkeys does not address the fundamental reasons that nonhuman animal research is unreliable for human applications. These reasons include extensive and immutable genetic differences between humans and nonhuman primates (here, here, and here), including very different brain genetics (here, here, and here).

Since human monozygotic (identical) twins differ in gene expression, disease risks, and responses to treatments (here and here), even for brain disorders, claims that the cloned monkeys can translate to human benefit are unscientific.

Regarding the ethical concerns, where do we start? The SCNT process begins by aborting a fetus from a mother impregnated for that purpose. Another monkey has an egg cell removed from her ovary. Then after the egg cell and fetal fibroblast are fused to create the embryo, it is transplanted into a third monkey (the surrogate mother). If the embryo produces a live birth, the newborn is taken from the mother and maintained in a captive environment, only to be used and killed in cruel and futile experiments.

Finally, this achievement by Chinese scientists moves us one huge step closer to the possibility of cloning humans, a process these researchers state they will not pursue. But there is a reliable dogma in medical science: If it can be done, someone will do it. Only legislation and science ethics prevent this, and does anyone want to rely on those shaky deterrents? 

Legendary World War II general Omar Bradley stated regarding the advent of the atomic bomb: "The world has achieved brilliance without wisdom, power without conscience." As China awaits the birth of as many as six more cloned monkeys, here we are again.

We are seeking a student or recent graduate interested in promoting alternatives to the use of animals in medical research and education for our summer 2018 Replacing Animals in Research Internship. Apply today!

February 22, 2018   animal testing, animals in education

 

Five Top Challenges for Animals in 2018

1. Animals Are Killed in Military and Medical Training

For years, the Physicians Committee and others have been pushing the Department of Defense to stop using goats and pigs to train medics and corpsmen (the Navy’s equivalent to medics). In these courses, animals are shot with firearms, stabbed, and dismembered. But jaw-droppingly realistic devices are available that replicate human anatomy, and some parts of the military are getting the message that these devices are better than nonhuman animals. We have already started the year strong, bringing to light the unauthorized use of animals by the Marine Corps and highlighting efforts within that branch of the military to replace animals. We also partnered with former M*A*S*H actors Jamie Farr and Mike Farrell and placed three billboards in San Antonio, Texas, to bring this issue to the attention of the Army Surgeon General. We have plenty more planned in the months ahead.

2. FDA Regulations Still Mandate Animal Testing

While we have succeeded in changing law and policy in the chemical sector, and now U.S. law states the Environmental Protection Agency (EPA) and the chemical industry must use and develop alternatives to animal testing, the Food and Drug Administration (FDA) lags behind. Current FDA regulations were established decades ago and do not provide flexibility to support modern science. Many regulations mandate that animal tests must be conducted prior to clinical trials in humans. However, drug development stakeholders—including the FDA itself, other federal agencies and private industry—now acknowledge that animal tests fail to predict human outcomes 95 percent of the time. Through the Preclinical Innovation and Patient Safety (PIPS) initiative, we have recommended the FDA update the regulations to allow for use of any scientifically evaluated preclinical approach, whether or not it involves animals. As part of regulatory reform at FDA, we combed through agency-wide regulations to identify specific regulations that need to be changed and provided proposed language and justification. We will continue to provide input to FDA on this issue and push for updated regulations. We are hopeful that 2018 is the year of regulation change, as our recommended changes complement roadmaps recently unveiled by the FDA and the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) that aim to improve testing by moving away from animal tests.

3. Animal Research Interests Seek to Decrease Protections for Animals in Labs

A troubling new effort led by organizations that represent animal experimenters and their institutions aims to drastically cut protections for animals in laboratories. Essentially, they would like to create an oversight system that allows laboratories to self-regulate—when federal laws and government enforcement are already extremely lax. One of their recommendations is to drastically reduce how often most research facilities are inspected by the U.S. Department of Agriculture (USDA), which would significantly impair the public’s ability to monitor those facilities’ compliance with the law. In addition, USDA is proposing recognizing third-party inspections of research facilities, which would ask animal experimenters to help monitor themselves. The Physicians Committee is working with a large coalition of organizations to lobby Congress, the USDA, and the National Institutes of Health (NIH) to maintain or even strengthen current laws and regulations—not weaken them. In the months ahead, we'll be asking our supporters to contact these agencies and likely their members of Congress.

4. Government Budget Jeopardizes Funding For Human-Based Research

Last year, the Administration proposed major budget cuts for the EPA - nearly half of current levels. EPA funding cuts put the future of human-based research at stake because a lack of funds would inhibit EPA's ability to continue developing modern safety assessment methods that do not use animals. We lobbied to maintain the research budget for alternatives – and won! But the work continues. The Trump Administration’s recently-released budget cuts this funding from EPA again. The National Institutes of Health (NIH) has begun funding some really excellent human-focused research such as the National Center for Advancing Translational Sciences (NCATS) and small business grants to companies developing alternatives. However, the research funds directed towards human-based testing are a drop in the bucket compared to research dollars invested in animal testing. In order to quickly and responsibly develop and integrate modern, predictive testing approaches, we must call on our government to increase funding of research that can be expected to be more predictive for humans because it is based on human cells, tissues and biological processes.

5. High-Quality Human Cells and Tissues For Research Are Not Easy To Obtain

While many people understand the reasons for human-based research, using human cells and tissues, fewer people understand how these tissues are obtained for research. One way human cells and tissues are obtained are as byproducts of surgery.  Many of us have the option to donate tissue to research that would otherwise be discarded. However, this option is not always presented to patients. We must increase the availability of human cells and tissues used for research, by educating the public and beginning a discussion on best practices for tissue procurement. We will bring together stakeholders to surmount some of these practical problems.

We are seeking a student or recent graduate interested in promoting alternatives to the use of animals in medical research and education for our summer 2018 Replacing Animals in Research Internship. Apply today!

January 26, 2018   animal testing

 

Great Science: 2017’s Top 10

This past year was full of advances in science and policy that demonstrate exciting progress in making science more humane and human-relevant. Here are our favorites:

1. USDA database mostly restored

The removal of USDA inspection reports from their online database earlier this year left the public with no way of readily accessing these reports, preventing public knowledge of which facilities using animals had violations of the Animal Welfare Act. After great pressure from the Physicians Committee and other animal advocacy organizations, the database was partially restored. While inspection reports can now be readily accessed again, identifying information of certain violators, specifically breeders, has been blacked out. 

2. Bioprinting of human tissues 

Bioprinting of three-dimensional (3-D) human tissue allows researchers to create more accurate models of human tissues and organs to study and eliminate the use of animals. There are often differences between individuals in the effectiveness or toxicity of a given drug, mostly because we all absorb and metabolize—or break down—drugs at different rates. The differences between animals like rats or mice and people are even greater. With 3-D bioprinting, models can be made from the patient’s own cells, allowing researchers to tailor treatments to the specific person. We have reported on two different studies authored by scientists who created tissues to help assess how drugs are absorbed into or metabolized in the body. We also reported on a 3-D-printed brain model. In fact, there were 199 studies in the scientific literature this year reporting advances in creating human tissues models using bio-printing techniques, and we expect this to keep growing in the coming years. 

3. Surgical simulation advances

This year saw the rise of a new way to teach medical procedures without animals. Maximum Fidelity Surgical Simulations has pioneered a groundbreaking method for perfusing the blood vessels of human cadavers. Using artificial blood, the cadavers can be used in scenarios ranging from operating rooms to outdoor exercises for military medics.

4. Organs-on-chips

Miniature versions of human organs make up microphysiological systems, or organs-on-chips. These tiny devices, which are about the size of a USB flash drive, are designed to mimic human tissues and allow scientists to see how human cells and tissues behave. Organs-on-chips are capable of replacing animals for drug testing and the development of new treatments, as well as studying a variety of disease processes and responses. The National Institutes of Health doubled down on previous investments in 2017, providing $15 million a year for two years to scientists around the country to develop models for human diseases. They even debuted a “tissue chips in space” project. Major progress on developing these breakthrough systems was made in 2017, in studying lung cancer, cardiotoxicity, asthma and infection, vascular biology, and the blood brain barrier

5. FDA Releases Predictive Toxicology Roadmap

In December, the Food and Drug Administration released a groundbreaking Predictive Toxicology Roadmap aiming to transform the safety testing conducted for FDA-regulated products. The six-part Roadmap reflects a shift at FDA from animal-based testing toward cutting-edge human-based approaches, such as organs-on-chips, computational toxicology and read-across methodologies. Human-based approaches are expected to provide more predictive information than animal testing because they enable scientists to directly investigate how drugs interact with human cells, tissues and processes. 

6. Adverse Outcome Pathway for Respiratory Sensitization  

This fall, scientists led by the Physicians Committee’s Kristie Sullivan, M.P.H., published a paper outlining an Adverse Outcome Pathway for chemicals which cause sensitization of the respiratory tract. This dangerous condition develops often in health care, cleaning, and chemical industry workers, and causes them to experience severe coughing, wheezing, constriction of the airways, and other asthma-like symptoms that worsen upon repeated exposure to smaller and smaller amounts of specific chemicals, making work dangerous or impossible. Our team of toxicologists, immunologists, and chemists combed the scientific literature for all studies related to this endpoint, and constructed a pathway for how we think this condition develops, from exposure to chemicals at the molecular level to priming of immune cells to over-react and cause these symptoms.  

AOPs outline the state of the science for a particular toxicological endpoint (or effect, such as carcinogenicity) and make it easier for scientists to develop nonanimal approaches to test chemicals for effects of interest. Now that the AOP has been published in the scientific literature, the team is evaluating the human cell-and computer-based methods they identified to build evidence for regulatory agencies to use these methods instead of animals to identify chemicals that may cause this devastating disease. 

7. State and county officials speak out against UW’s use of animals

Live pigs are used and then killed in the University of Washington’s paramedic training program. But in January 2017, after outreach from Physicians Committee staff and members, eight members of the Washington House of representatives wrote to UW to raise their concern about the practice. A few months later, two elected officials in King County, home to UW, followed suit. The university is feeling the pressure and has agreed to pursue the development of a method to replace animals. While several human-based methods are already available for surgical airway training, UW’s decision is progress.  

8. Stem cell resource established

Human induced pluripotent stem (iPS) cells provide a human-based approach to model diseases. This year, significant advancements were made in modeling several diseases with stem cells, giving us better insight into the effects of those disease in humans. Some breakthroughs include the use of stem cells to model diabetes, prion disease, and anorexia nervosa. To continue to facilitate breakthroughs, researchers from the Human Induced Pluripotent Stem Cell Initiative created the most comprehensively characterized bank of human stem cell lines complied to date. These normal human-derived stem cells will benefit scientists by allowing them to better understand the natural variations of stem cell lines, and thus natural variations among the human population.

9. Funding for EPA research to develop alternatives supported by Congress

Research at the EPA’s National Center for Computational Toxicology is essential for spurring progress to replace animal testing with human-relevant methods, especially under a mandate from the Lautenberg Chemical Safety Act for the 21st Century that requires EPA to replace and reduce animal tests for assessing chemical safety. However, the Trump administration’s 2018 budget proposal would have slashed funding for the chemical research by 31 percent. After lobbying by the Physicians Committee and other organizations, these proposed cuts to EPA budget did not become a reality and computational toxicology funding levels were maintained, allowing the EPA to continue developing studies that protect public health and countless animal lives. 

10. Plants Found to Model Anesthetic Drug Efficacy

A very unique study published in December found that plants exhibiting touch-induced movements (such as the Venus fly-trap) respond to anesthetic drugs in similar ways to humans. The drugs apparently block the same molecular mechanisms and electrical signals at work in humans and other animals, and could represent an alternative to testing the safety and effectiveness of new drugs in animals.

We are seeking a student or recent graduate interested in promoting alternatives to the use of animals in medical research and education for our summer 2018 Replacing Animals in Research Internship. Apply today!

January 17, 2018   dementia

 

Microsoft founder Bill Gates recently announced a personal investment of $50 million in the Dementia Discovery Fund (DDF), a public-private fund supported by charities, industry, and government to diversify the search for a drug to treat dementia. Gates wants the scientific community to look beyond amyloid and tau proteins in the brain, two key hallmarks of the disease, for the causes of dementia with the ultimate goal of creating an effective treatment. He is correct that so narrowly focusing research into the role of these proteins has diverted our attention from more productive research. But his laser focus on treating rather than preventing dementia is not the only strategy to overcome this disease. The search for a drug to treat Alzheimer’s disease and related dementias has met with little success. And given the rapid rise in the incidence of these diseases, the scientific community and those who fund their work would better serve the public by shifting their focus to prevention—or, at the very least, making prevention a high priority.

We have some suggestions:

First, as we have learned in other major research pursuits, the use of animal models of disease typically fails to provide us with meaningful insights into how a disease originates and progresses in humans. Therefore, all research should take full advantage of the many innovative methods that are human relevant. We applaud DDF for its support of in vitro human-based approaches in their search for therapeutics. These include using cell-biology based approaches to find targets in human brain tissues (Cerevance), human neurons derived from induced pluripotent stem cells (Gen2), in vitro platforms to restore immune cell function (TIAKI therapeutics), and an in silico program to screen a library of more than 500,000 compounds virtually for drug candidates (DDF ChemCo).

Second, investments should be made in these underfunded areas:

  • Human brain tissue banks and resources like the Allen Cell Types Database. To better understand the causes of dementia at the population level, we need more research into the lifestyle factors that play a critical role in driving the disease, which can help explain racial-ethnic disparities.
  • A better clinical test to diagnose the disease earlier and track its progression. This will help identify patients for earlier intervention studies. If we had a disease specific biomarker like cholesterol for heart disease or hemoglobin A1C for diabetes, the development of Alzheimer’s may become easier to control. The key to finding such a biomarker will require a better understanding of the external factor(s) driving the disease in humans and strictly focusing the search in human specimens. More clinical trials assessing the efficacy of nonpharmacological interventions such as changing dietary habits, so that we can give people evidence-based advice to take control of their health.
  • Design clinical trials to include patients with multiple chronic conditions so that interventions can be broadly applicable to patients with many chronic conditions. Many drug trials exclude these individuals in order to demonstrate the specificity of a treatment for the disease. However, Alzheimer’s often occurs with other chronic medical conditions. Testing lifestyle interventions would fill this research gap and encourage patients to participate in trials before they develop any signs of the disease.
  • Use the common database for which Gates advocates to catalog links between modifiable lifestyle patterns and dementia prevalence or incidence over time in different parts of the world. Moving away from focusing on data derived from animal models and failed drug trials will help us better understand what is really driving dementia that we can change in a short period of time.

Despite billions of dollars spent, pharmaceutical companies have not been able to find a drug to even delay the onset or progression of dementia. Pfizer’s recent announcement to end its research program on developing new drugs for Alzheimer’s disease is indicative of how fruitless and disappointing these efforts have been (hyperlink to: https://www.usnews.com/news/top-news/articles/2018-01-07/pfizer-ends-res...). With the high financial burden the disease implies and the devastating impact on the patient and families, we must invest more in human studies that will help us understand how to treat and prevent this disease. If Gates devoted a mere 10 percent of his $100 million planned investment in these areas, we might spare millions of people from the crippling effects of dementia.

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