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"The existing preclinical system largely depends on animals to predict what will happen inhumans. This system often fails."

 

"Many human-relevant technologies that will improve safety and reduce preclinical animal tests already exist, and many more innovative methods are in development."

 

Download: Averting Drug Disasters (PDF)

Averting Drug Disasters

drug-disasters

How to Stop the Next Pharmaceutical Catastrophe

 

When Ryan Wilson enrolled in a phase 1 clinical trial for TGN1412—a drug for leukemia and arthritis that was tested on monkeys in preclinical experiments—he never imagined the consequences.

While in the hospital in London, England, where he received the drug intravenously, Mr. Wilson, then a 22-year-old trainee plumber, began experiencing adverse reactions. He would spend 147 days in the hospital with heart, liver, and kidney failure, leading to doctors amputating all of his toes and several fingertips.

Wilson was one of six men in the 2006 clinical trial who, after taking TGN1412, began experiencing serious adverse events, including organ failure. One of the men was said to look like “the elephant man” after suffering angioedema—which causes swelling under the skin—in his head. After the adverse reactions began, doctors told all six men that they would likely develop cancers or autoimmune diseases.

In the world of pharmaceutical clinical trials, this was not an isolated event. In January 2016, one man died and five others were hospitalized in France—three with possible brain damage—after taking part in a clinical trial for a painkiller that had been deemed safe enough to proceed to human trials after preclinical experiments in chimpanzees and other animals.

Rats, mice, dogs, and monkeys were all used in the preclinical toxicity tests of the drug, but “no ill-effects were noted in the animals, despite doses 400 times stronger than those given to the human volunteers,” according to a report France’s National Agency for Drug Safety released in March. In the affected human patients, the drug had “astonishing and unprecedented” reaction in the brain that was “unlike anything seen before.”

And this February, the Food and Drug Administration halted the phase 3 clinical trial of the cancer drug pacritinib after patients died from intracranial hemorrhage, cardiac failure, and cardiac arrest. Preclinical safety tests of the drug were conducted on mice and dogs.

The drug development process is largely the same in the United States as other countries. Preclinical research is critical to gathering safety information before a drug is tested in humans. However, the existing preclinical system largely depends on animals to predict what will happen in humans. As evidenced by the unfortunate events described above, this system often fails. In fact, today, 95 percent of new drugs fail because they are unsafe or do not work in humans, despite previously appearing safe in preclinical animal tests.

According to a 2014 FDA presentation, adverse drug reactions cause about 100,000 human deaths annually, making adverse drug reactions the 4th leading cause of death in the United States.

Pharmaceutical Research Reform


After years of work by the Physicians Committee and others, the Institute of Medicine determined in 2011 that the use of chimpanzees is not essential for any area of disease research, prompting the National Institutes of Health to end federally supported chimpanzee experimentation.

Given that our closest living relatives are not required for research and testing, what does this say for research and testing using animals even less similar to humans? Each year, hundreds of thousands of animals—primates, dogs, cats, mice, rats, pigs, guinea pigs, and others—are still used and killed for preclinical drug research.

drug-testing-on-a-chip

Wyss Institute's Lung on a Chip

A recent commentary in BMC Medical Ethics highlights major issues related to animal experiments, including profit-driven motivations and a general denial of the limitations of animal models by scientists. To address the “serious issue stemming from flawed animal research, which needs to be addressed in the interests of human health and safety,” the author recommends strategies including “systematic reviews of existing animal studies” and “a full scale inquiry into why unreliable animal data are accepted by regulatory authorities while at the same time non-animal models and technologies with predictive value are less likely to be adopted.”

The FDA has the discretion to accept nonanimal methods for preclinical drug testing. But in practice, FDA provides little guidance or encouragement to drug developers regarding the use modern methods that could improve drug safety. According to a recent commentary in the Food and Drug Law Institute’s Food and Drug Policy Forum, co-authored by Elizabeth Baker, Esq., currently a senior science policy specialist for the Physicians Committee, the FDA should:

  • Amend existing regulations that currently mandate preclinical animal data to reflect stated FDA policy that drug sponsors have the option to submit data from nonhuman and/or human-based test methods.
  • Accept modern test methods that are demonstrated to be more predictive of human response than currently mandated test methods.
  • Issue FDA Guidance for Industry that clearly communicates when modern test methods are accepted.

The Physicians Committee is addressing this crucial problem by taking a collaborative and comprehensive approach that includes:

  • Working with Congress to make legislative change.
  • Working with the FDA to establish an optimal approach to acceptance of new methods.
  • Assisting the FDA in communicating through updated regulations and drafting FDA guidance documents.
  • Developing training programs for FDA reviewers and industry scientists.
  • Advising companies on FDA policies and use of human-focused methods.

Better Technology


Many human-relevant technologies that will improve safety and reduce preclinical animal tests already exist, and many more innovative methods are in development. Earlier this year, the Johns Hopkins Bloomberg School of Public Health announced that researchers have developed “mini-brains” made up of human brain neurons and cells. The “mini-brains” may be superior to animal experiments and could dramatically improve preclinical drug testing for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and even autism.

At the University of California at San Diego, researchers used 3-D printing technology to create a model to that could be used for patient-specific drug screening and disease modeling for conditions such as hepatitis, cirrhosis, and cancer. The team organized stem cells derived from patient skin cells into a structure that accurately mimics the human liver.

Physicians Committee scientists and staff are developing and promoting innovative modern technologies and influencing the laws and policies that govern their use. Ultimately, the Physicians Committee’s work in this area will lead to better outcomes for patients and a shift away from animal testing for human drugs.