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Following the news that the National Institutes of Health (NIH) budget has increased by $3 billion for fiscal year 2018, the Physicians Committee wrote to NIH director Frances Collins, urging Collins to use the additional funds to prioritize human-relevant research. Read the letter below:


Physicians Committee Letterhead

March 23, 2018 

Dr. Francis Collins
Director, National Institutes of Health 9000 Rockville Pike
Bethesda, Maryland 20892 

Dear Dr. Collins, 

I am writing on behalf of the Physicians Committee for Responsible Medicine and our membership of more than 12,000 physicians and more than 175,000 other medical professionals, scientists, educators, and supportive lay members about increased funds provided to you in the recent fiscal year 2018 (FY18) Labor, Health and Human Services, and Education funding bill. We recommend that you invest this additional $3 billion in human-relevant research, not animal research. 

The National Institutes of Health (NIH) is the nation’s leader in biomedical research and has the potential to fund groundbreaking discoveries to improve health and save lives. As you are aware, animal studies are costly, time-consuming, and often poorly predictive of human health. With a continuously growing population in the United States and new and emerging health issues always on the horizon, changes in our approach to research funding are urgently needed. 

Currently, thousands of diseases affect humans that do not have effective treatments. Yet, new drugs take over 10 years to develop, typically cost more than $2 billion, and have a 95 percent failure rate in human clinical trials. Animals will always have physiological, anatomical, and genetic differences from humans that will impede the translation of research findings derived from animal biology. It is time to invest more in the development and application of human-based methods. We recognize that NIH is beginning to invest more in human-relevant models via the National Center for Advancing Translational Sciences and other initiatives; however this investment pales in comparison to the amount put towards animal research. We must shift this balance. 

This bill allocates $1.8 billion for Alzheimer’s disease research, which is the only top-ten chronic disease without an effective intervention for treatment or prevention. Today, 5.3 million Americans suffer from Alzheimer’s, and this number is expected to triple by 2050. At present, Alzheimer’s research relies on animal models, despite the fact that 99.6 percent of Alzheimer’s drugs that appear successful in animals fail in human trials, and it is known to scientists that animals do not develop the disease to the same capacity as humans. Rather than misusing the supplementary $414 million that is being allocated to Alzheimer’s research for FY18 on ineffective animal research, it should be devoted to efficient, human- relevant research. 

There are many humane and reliable human-relevant methods that are already being used to conduct scientific research and regulatory testing. Organs-on-chips and the multi-organ body-on-a-chip are cutting edge platforms that can significantly advance drug and toxicology screening and open the door for personalized medicine. Human-derived stem cells are redefining research by improving scientists’ understanding of how diseases progress and allowing the development of therapies for regenerative medicine. Three-dimensional bioprinting has made enormous advances, allowing the expansion of new therapies and diagnostics. This technology has the potential to one day manufacture custom-made organs. 

Adequate funding and support is severely needed to increase the development and application of these technologies. Investment in human-relevant methods should be prioritized over unhelpful and ethically questionable “humanized” mice and animal-human chimeras. In addition to funding extramural investigative research using human-relevant models, we suggest NIH consider other strategies to support a transition away from animal research. For example, increased resources and incentives could be provided to allow easier access to human tissues for research, grant applications featuring human- relevant models could be “fast-tracked” for approval, and specific calls for proposals could specify human-relevant models. 

We urge NIH to take this opportunity to increase its funding of groundbreaking human-relevant research, making research more ethical and effective and improving public health. Thank you for your attention to this urgent and important matter. 

Sincerely, 

Janine McCarthy, MPH Research Policy Specialist 

Kristie Sullivan, MPH Vice President for Research Policy

March 1, 2018   animal testing

 

It’s that time of year again! The Society of Toxicology (SOT) annual meeting—the world’s largest gathering of toxicologists—is taking place March 11-15 in San Antonio, Texas. Just like last year, Physicians Committee scientists are actively participating in sessions throughout the conference to advance their work in promoting more effective, nonanimal toxicological test methods. 

We are again sponsoring events to engage and train toxicologists and regulatory scientists with scientific and policy initiatives to replace animal tests with more human-relevant methods, including our Adverse Outcome Pathway seminar. We are also participating in multiple poster sessions to inform attendees of current topics in predictive toxicology and alternative test methods. 

Here is a select list of Physicians Committee-sponsored sessions or events. If you are attending SOT, we invite you to attend these sessions. Please contact Kristie Sullivan (ksullivan@pcrm.org) for more information. 

You can also download a curated list of other SOT scientific sessions and events of interest to scientists working with in vitro and computational methods. 

Monday, March 12

Poster Session:  Regulatory Policy and Policy Evaluation

The Preclinical Innovation and Patient Safety Initiative: Recommendations for Modernizing Preclinical Testing

Presenting Author: Elizabeth Baker

9:15 a.m. – 4:30 p.m. (Author Attended: 10:45 a.m. – 12:15 p.m.)

Convention Center Exhibit Hall

Abstract: Preclinical drug testing is critical to understanding the toxicity, pharmacology, and pharmacokinetics of candidate drugs. The Preclinical Innovation and Patient Safety (PIPS) Initiative fosters collaboration among drug development stakeholders—including federal agencies, patient, research and health organizations, academia, technology companies, and the pharmaceutical industry—to implement modern human-focused preclinical approaches. Participants recognize that more predictive approaches are fundamental to the timelier delivery of safe and effective medicines. This presentation highlights the scientific, regulatory, policy, training and educational recommendations made by a group of stakeholders during the kick-off roundtable in January 2017, and explores three projects identified by PIPS participants as likely to provide high impact on the field of toxicology. First, modern approaches to validation should incorporate human data. This is the only way to overcome the challenge of comparing human in vitro approaches to currently available animal safety data. The legislation 21st Century Cures and the Prescription Drug User Fee Act mandate that FDA make real world human data/evidence more accessible. PIPS identified that implementation of the mandates should include making real world evidence available to method developers for validation purposes in order to better understand a method’s predictive ability. Second, researchers must have access to human cells and high-quality tissues in order to use human-focused approaches. Currently, there are no guidelines for collection and care of human cells and tissues intended to be used for research. PIPS is coordinating efforts to develop guidelines to ensure the increasing demand is met. Third, despite significant private and public investment in the development of human-focused approaches, many FDA regulations require animal data. While industry may use modern approaches for internal decision-making, the regulatory requirements prioritize animal data and dis-incentivize use of modern approaches. PIPS has identified the regulations and coordinated multiple projects to push the agency to update the regulations to reflect flexibility that allows for evolving science. 

Tuesday, March 13

Hands-On Seminar: Creating an Adverse Outcome Pathway in the AOP Wiki

5 – 7 p.m.

Grand Hyatt Rooms Bowie A – B 

The Human Toxicology Project Consortium and the Physicians Committee for Responsible Medicine invite you to deepen your understanding of the AOP Wiki and gain experience entering an Adverse Outcome Pathway in a structured, hands-on seminar Tuesday evening. 

Version 2.2 of the AOP Wiki was released in January 2018.  This seminar will be ideal for those wishing to gain some hands-on experience with the new version as well as those who are new to the AOP concept. We will also present an available online course on AOPs, and course attendees will work through a case example in small groups

See full agenda and please register in advance to ksullivan@pcrm.org. Registration is appreciated, but not required. Please indicate whether you will bring a laptop.

Thursday, March 15

Poster Session:  Late-Breaking 01: Model Systems

Title: Towards an IATA for Chemical Respiratory Sensitization: Establishment of Reference Chemicals to Evaluate In Vitro and In Silico Approaches

Presenting Author: Kristie Sullivan

8:30 – 11:30 a.m.

Convention Center Hall 1

Abstract: Public health and regulatory needs require approaches to detect and discriminate respiratory sensitizers from dermal sensitizers; however no single method or strategy is generally accepted. An Adverse Outcome Pathway (AOP) for respiratory tract sensitization by low molecular weight organic chemicals identifies several promising in vitro methods. Most of these methods have only been assessed with a few well-known respiratory sensitizers (e.g., toluene diisocyanate or trimellitic anhydride). To further evaluate the utility of these in vitro methods, we have set out to build a more comprehensive list of reference chemicals, including known respiratory irritants, non-sensitizers, and dermal sensitizers. The ideal list of respiratory sensitizers should cover a range of chemical classes and include “challenging” chemicals, such as respiratory sensitizers thought to elicit effects through dermal exposure and those for which specific-IgE has not been detected in humans. To build the list, we are conducting a review of established structure-based profilers, recent literature, and human clinical reports, focusing on data verified in humans for translatability to human health outcomes. We are also making use of the Abstract Sifter literature review tool (Baker et al., (2007)) to identify additional potential respiratory sensitizers. Briefly, a set of PubMed MeSH terms describing adverse effects (AEs) for 92 known sensitizers was used to query a large database of chemicals and AEs, yielding over 7000 chemicals of potential interest. The top 500 ranked chemicals (based on article counts) are currently undergoing manual review. This reference chemical list is an important step towards an assessment of potential test methods and creation of internationally-harmonized integrated approaches for the detection of chemical respiratory sensitizers. 

 

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!

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