FDA: Accept human-focused preclinical tests to improve drug safety

Patient deaths halted at least two pharmaceutical clinical trials in the last two months. The good news is, Robert Califf, M.D., who was confirmed by the Senate last week as commissioner of the Food and Drug Administration, has an opportunity to address this issue. In his new role, Dr. Califf is in a position to improve patient safety—from clinical trial participants to consumers—by modernizing preclinical tests.

Preclinical research is critical to gathering safety information before a drug is tested in humans. However, the existing paradigm largely depends on animals to predict what will happen in humans. As evidenced by recent unfortunate events, this system often fails.

In February, the FDA halted a Phase 3 clinical trial of the cancer drug pacritinib after patients died from intracranial hemorrhage, cardiac failure, and cardiac arrest. Details on preclinical tests are generally kept confidential, but the company confirmed tests were conducted on mice and dogs; rats, primates, and guinea pigs are also often used. Data from the animal tests did not stop the drug from entering a human trial that lead to multiple human deaths.

In January, one man died and five others were hospitalized in France—three with possible brain damage—after participating in a Phase 1 clinical trial for a painkiller. The company tested the drug in animals, including chimpanzees.

Today, 95 percent of new drugs fail because they do not work in humans or are unsafe, despite previously appearing safe in preclinical animal tests. According to a 2014 Food and Drug Administration 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.

The FDA may accept human biology-based tests for preclinical drug testing. But in practice, drug developers continue to use animal tests—even when a newer method may be more human-relevant, because FDA regulations and reviewers continue to require them.

In a commentary I co-authored in the Food and Drug Law Institute’s Food and Drug Policy Forum, we recommended that the FDA should:

·         Amend existing regulations to clearly state that drug sponsors can submit data from human-based test methods;

·         Issue FDA Guidance for Industry that clearly communicates when modern test methods are accepted; and

·         Facilitate the acceptance of modern test methods that are demonstrated to be more predictive of human responses to new drugs.

Many human-relevant technologies that will improve patient safety and reduce preclinical animal tests already exist, and many others are in development and continue to emerge.

Last month, the Johns Hopkins Bloomberg School of Public Health announced that researchers have developed “mini-brains” made up of human brain cells, which are likely to 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, bioengineers used 3-D printing technology to create a model from human cells that mimics the human liver and can be used for patient-specific drug screening and disease modeling for conditions such as hepatitis, cirrhosis, and cancer.

I look forward to Califf’s leadership at the FDA and encourage him to prioritize the modernization of preclinical testing methods. More than 100,000 drug or biologic clinical trials are registered with ClinicalTrials.gov and nearly 60 percent of Americans are taking prescription drugs. These patients need safer and more effective treatments—and 21st-Century human-focused test methods will ensure they get them.

Baker is a senior science policy specialist for toxicology and regulatory testing at the Physicians Committee for Responsible Medicine.