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Good Science

May 11, 2017   other

 

It happens more often than it should: Patients experience serious or even fatal complications during clinical trials for not-yet-approved medicines. But complications can also happen after the Food and Drug Administration (FDA) approves the drug and it is sold to patients.

Drugs should be tested using human biology-based methods such as tissue chips and modeling approaches to give us a better sense of how humans will react to the treatment. Animal tests simply can’t ensure safe medicines, but the FDA still requires animal tests for all new medicines.

A study published this week confirms the scope of the problem. Doctors found that 32 percent of FDA-approved medicines from 2000 to 2010 were “affected by a postmarket safety event.” This means they were either withdrawn, required black box warnings, or led to FDA safety communications after patients began taking them.

The study raises concern about how well medical products are tested, particularly given recent pressure on the FDA to speed up the approval process. One way to speed the approval of safer treatments is to accept modern tests that are based on human biology.

The Physicians Committee is working to make testing faster and more human-relevant. We support the development of new approaches and train regulators how to use them. Additionally, we are working with lawmakers and leading patient safety groups to change FDA regulations and National Institutes of Health funding practices. These science, policy, and educational advances will help safeguard patients by giving the FDA better information before approval decisions are made.

Want to learn more? Check out this episode of The Exam Room to hear our experts discuss medical safety:

 

 

Congress held confirmation hearings last week for Food and Drug Administration commissioner nominee Scott Gottlieb, M.D., who was asked about how to improve speed, safety, and costs in the drug development process. New technologies are often based on human cells and tissues instead of animals.

On Tissue Bioprinting

When asked about tools like tissue bioprinting, a human-relevant method that could help reduce or replace animal testing, Dr. Gottlieb responded that anything that can be done to make the drug development process more predictable—better tools to evaluate safety and effectiveness and bring down cost—should be considered. He says this is one place where we can “have our cake and eat it, too.”

 

On Regulatory Science

Dr. Gottlieb said that it is a challenge and opportunity to make sure that the FDA has the best training and tools, and is forward-leaning in adopting the best science into the principles used to govern the review process. He said that improving the quality of tools used by the FDA to test drugs, while still meeting FDA's high bar for safety and efficacy, would be a priority.

March 3, 2017   animal testing

 

Toxicologists study the effects of chemicals, drugs, and other products to assess potential harms to human health or the environment. The Physicians Committee promotes the use of nonanimal toxicological test methods, because they can be faster, more cost-effective, and human-relevant, and will allow us to collect much more information than we can currently using expensive, slow animal tests. 

The Society of Toxicology (SOT) annual meeting is the world’s largest gathering of toxicologists, and the Physicians Committee actively participates every year. Last year, we presented on Adverse Outcome Pathways as part of a continuing education session and held a hands-on training on the same topic. Adverse Outcome Pathways are a framework to collate information on how chemicals affect biological systems (like cells, tissues, and organs) and support the development of predictive nonanimal tests.

This year, the meeting will be held March 12-16 in Baltimore, Md, we are again hosting or co-sponsoring multiple events to engage and train toxicologists and regulatory scientists with scientific and policy initiatives to replace animal tests with more human-relevant methods. These include stakeholder discussions of progress in reducing or replacing pesticide lethal dose and skin irritation tests, regulatory reform of the pharmaceutical sector, and a four-hour training on the use of “read-across” to predict the toxicity of certain chemicals based on their chemical structures. 

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

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

Sunday, March 12
Read-Across: Case Studies, New Techniques, and Guidelines for Practical Application
1:15-5:00 PM
Baltimore Convention Center
Chairpersons: Kristie Sullivan, Physicians Committee for Responsible Medicine & Mark Cronin, Liverpool John Moores University

Abstract: The relationship between structure and activity has been exploited in the hazard characterization of chemicals for several decades, including specifically the practice of “reading across” or applying toxicity data from one or more chemicals to another with a similar structure to fill a data gap. Read-across is currently a useful strategy to increase our understanding of chemical hazard without de novo testing. However, expertise, application, and acceptance of the results of a particular read across vary within and among organizations and geographical regions. There are a number of reasons for this, including regulatory or legislative drivers, an increasing motivation to expand the use of non-testing strategies, and minimal consensus around how to weigh evidence and address and express uncertainty. Recently, multiple stakeholder organizations have contributed to active and robust discussions on read across in a variety of venues in an effort to build consensus around these issues. This course will update participants on those efforts and provide practical guidance for conducting read-across for regulatory use, including across different regulatory regions. Speakers will present experience-driven case studies to share best practices and communicate the state-of the-art for structure-based read-across, while looking ahead at how results from New Approach Methodologies including in vitro, “omics,” and high throughput/content methods may be incorporated into a read across to improve its outcome.

Tuesday, March 14
Hands-On Seminar: Creating an Adverse Outcome Pathway in the AOP Wiki
5:00-7:00 PM
Hyatt Regency Baltimore
Constellation Ballroom A

Deepen your understanding of the AOP Wiki and gain experience entering an Adverse Outcome Pathway in a structured, hands-on seminar Tuesday evening.

Version 2.0 of the AOP Wiki was released in November 2016, and 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.

See full agenda and please register in advance to ksullivan@pcrm.org.

Wednesday, March 15
Driving Innovation in Preclinical Pharma Testing: Takeaways and Opportunities Following the 2017 Preclinical Innovation and Patient Safety Roundtable
6:45-7:45 AM
Hilton Baltimore
Room Tubman A

DiscoverX and the Physicians Committee for Responsible Medicine invite you to join us for breakfast and discussion on improving preclinical testing through scientific innovation, regulatory updates and training. 

On January 11, 2017, stakeholders from federal agencies, the pharmaceutical industry, academia, health, research and patient organizations, and technology companies attended the Preclinical Innovation and Patient Safety Roundtable to discuss scientific, legal and training issues that stifle preclinical innovation and negatively affect patients. This meeting will highlight key takeaways and recommendations for next steps.

Please RSVP to ebaker@pcrm.org.

Alternative Approaches to Systemic and Topical Toxicity: Making Progress on the EPA OPP Six-Pack
5:00-6:30 PM
Sheraton Inner Harbor
Loch Raven room

This open stakeholder discussion will feature presentations and discussions highlighting work to reduce and replace in vivo testing for the “six-pack”, a set of six acute systemic and topical toxicity tests required by the EPA Office of Pesticide Programs for pesticide active ingredients and formulations. These tests include: acute oral, dermal, and inhalation toxicity, skin and eye irritation, and skin sensitization. 

The evening will focus on two specific elements of this ongoing work: 1) a pilot effort to reduce formulation testing using the GHS Additivity Equation for acute systemic toxicity, and 2) in vitro methods for skin and eye irritation. Ongoing work to provide predictive analysis of the in vitro methods and necessary next steps will be discussed.

The participation of all stakeholders wishing to learn more or get involved is highly encouraged.

February 24, 2017   animal testing

 

How do we know if we’re succeeding? It’s a question we are always trying to answer. If we want to improve research and testing by reducing animal experiments, we need to know how many animals are used in laboratories. But we don’t.

Rough estimates of how many animals are used in United States laboratories are as high as 100 million annually, but we have little idea whether that number is accurate. More importantly, we have no idea whether that number is going up or down. This lack of clarity can largely be blamed on a problem unique among industrialized nations – namely, our only federal law designed to regulate the use of animals in labs excludes from the definition of “animal” more than 90 percent of animals used in labs. Most rats and mice and all birds and cold-blooded vertebrates are not covered by the Animal Welfare Act.

For the small percentage of animals covered by the Animal Welfare Act, each research facility must send the U.S. Department of Agriculture (USDA) an annual report listing the number of animals used, categorized by species. Unfortunately, the use of these reports as a monitoring system hit a major snag earlier this month, when the USDA abruptly shut down its animal welfare database.

While the online database was very useful, even when research facilities’ annual reports were available, it’s not clear how much the numbers could be trusted. Under the Animal Welfare Act, every U.S. research facility must have an Institutional Animal Care and Use Committee, which is in charge of evaluating proposed requests for animal use and ensuring legal standards of animal care and husbandry. These committees are the primary entity in charge of compliance with federal law, but according to a USDA audit,over a three-year period ending in 2011, almost half of all them were found to be in violation of the law. One of the primary reasons for the committees’ 1,379 Animal Welfare Act violations over that time was that the groups “did not recognize the importance of submitting an accurate annual report.”

Compare the U.S. system to that of the European Union, where all vertebrates (including rats, mice, birds, and fish) and even octopuses and squid are covered by the region’s law on animal use for scientific purposes. That law also results in the collection of information on not only how many animals and what species are used in experimentation each year but also where the animals originate and for what purpose they are used (broadly speaking). This information, which has been published every three years by the EU in a public report, shows that between 2008 and 2011 the number of animals decreased by more than a half-million. Under a new law, the next report, including even more detail, will be published in 2019. If we had similar information in the U.S., we could know if efforts to reduce animal experimentation are succeeding or failing and which efforts are most successful.

On this side of the Atlantic, how do we get closer to a more transparent system? The best step might be to reverse the 2002 congressional action that changed the Animal Welfare Act’s definition of “animal” to exclude the species mentioned above. That’s unlikely given the current divisiveness on Capitol Hill. However, Republican Rep. Ken Calvert of California and others are trying at least to require that more information about the federal government’s use of animals in testing be made available to the public.

In addition, three scientists at Hannover Medical School in Germany think they might have one answer to this problem of transparency—registries of animal studies, which could include details of each experiment and animal numbers. As the journal Science reports, these registries would address the problem that half of all animal experiments are never published in scientific journals. In contrast to the dearth of publicly available numbers on animal studies, the U.S. Food and Drug Administration already mandates that researchers preregister human clinical trials online.

Ultimately, whatever the system of transparency, it’s clear more is needed. Unless the shutdown of USDA’s animal welfare database is either reversed by the agency or overturned by a court, organizations like ours will be forced to wait months or years to receive records via federal Freedom of Information Act requests, and  may have to bring separate lawsuits against the USDA to obtain the information. Meanwhile, numbers for most animals used in U.S. laboratories aren’t available from any central repository. The federal National Institutes of Health funds approximately $13 billion worth of animal experiments each year. The public deserves to know how that money is spent, and whether we are moving in the right direction—away from animal research.

 

February 17, 2017   Alzheimer's disease

 

A Need to Change Clinical Research Approaches in Studying Alzheimer's Disease

Alzheimer’s disease is the most common form of dementia, affecting more than 5 million Americans. This number is expected to triple in prevalence by 2050, which is estimated to quadruple health care costs to $1 trillion.

To prevent this oncoming public health crisis, in 2011 Congress passed the National Alzheimer’s Project Act (NAPA) to create a national strategic plan coordinating the federal government’s efforts to treat and prevent dementia. An Advisory Council on Alzheimer’s Research, Care, and Services, consisting of members from relevant federal agencies and nongovernmental organizations, meets quarterly to evaluate progress, update the strategic plan, and make recommendations to Congress.

At the Council’s Feb. 3 meeting, Physicians Committee scientist Feng-Yen Li, Ph.D., delivered a public commentary to outline impediments to progress to find an effective intervention to treat or prevent Alzheimer’s disease. For example:

  • Drug candidates are initially tested in animal models that do not recapitulate the human disease, unlike human-based models, which are derived from patients or patient data.
  • Patients with chronic health conditions (e.g., diabetes, cardiovascular disease) that often occur alongside the most common form of Alzheimer’s disease are often excluded from participating in clinical trials, which means important underlying factors may be overlooked and the drugs may fail to work in these patients.
  • Drug targets for clinical trials are often based on genetic defects or pathways characterized in the rare inherited form of Alzheimer’s but are tested in patients with the common form of Alzheimer's who may or may not have genetic risk factors.
  • Alzheimer's drug development is often focused on reducing the signs of pathology such as brain plaques. However, these may just be a consequence rather than a cause of the disease. Little focus is on the underlying lifestyle risk factors of the disease.

Dr. Li strongly recommended the Council direct future funding and research efforts in Alzheimer’s disease to clinical trials based on data derived from humans or human-based models and focused on modifying lifestyle risk factors such as diet. A copy of the full commentary is available here.

To further promote these concepts, the Physicians Committee’s Ann Lam, Ph.D., has organized a discussion panel on Shifting Perspectives on Dementia, Science, and Health Policy at the 2017 American Association for the Advancement of Science meeting, featuring three experts in Alzheimer’s prevention research: Drs. Rhonda Au, a professor at Boston University; Jessica Langbaum, an associate professor at the Banner Research Institute; and Neal Barnard, president of the Physicians Committee.

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