Regulatory Guidelines in Regenerative Medicine_
The Center for Biologics Evaluation and Research (CBER) is the Center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act.
CBER protects and advances the public health by ensuring that biological products are safe and effective and available to those who need them. CBER also provides the public with information to promote the safe and appropriate use of biological products. Biological products are approved for marketing under provisions of the Public Health Service Act (PHS Act).
However, because most biological products also meet the definition of "drugs" under the Federal Food, Drug, and Cosmetic Act (FD&C Act), they are also subject to regulation under FD&C Act provisions. Licensing of biologic products under the PHS Act is very similar to the new drug approval process for human drugs.
Following initial laboratory and animal testing, a biological product is studied in clinical trials in humans under an investigational new drug application (IND). If the data generated by the studies demonstrate that the product is safe and effective for its intended use, the data are submitted to CBER as part of a biologics license application for review and approval for marketing.
The Tissue Reference Group (TRG) was created as specified in the "Proposed Approach to the Regulation of Cellular and Tissue-based Products" published by FDA in February of 1997.
The purpose of the TRG is to provide a single reference point for product specific questions received by FDA (either through the Centers, or from the Office of Combination Products) concerning jurisdiction and applicable regulation of human cells, tissues and cellular and tissue-based products (HCT/Ps).
HCT/Ps are defined in 21 CFR 1271.3(d) as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. FDA has implemented a risk-based approach to the regulation of HCT/Ps.
Under the authority of section 361 of the PHS Act, FDA established regulations for all HCT/Ps to prevent the introduction, transmission, and spread of communicable diseases. These regulations can be found in 21 CFR Part 1271.
"STEM CELLS REGENERATE DAMAGE IN CORTICOSPINAL INJURY"
Published: Friday, April 01, 2016
For the first time, researchers show functional benefit in animal model of key motor control system. Researchers at University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System, with colleagues in Japan and Wisconsin, report that they have successfully directed stem cell-derived neurons to regenerate lost tissue in damaged corticospinal tracts of rats, resulting in functional benefit. “The corticospinal projection is the most important motor system in humans,” said senior study author Mark Tuszynski, MD, PhD, professor in the UC San Diego School of Medicine Department of Neurosciences and director of the UC San Diego Translational Neuroscience Institute. “It has not been successfully regenerated before. Many have tried, many have failed – including us, in previous efforts.” “The new thing here was that we used neural stem cells for the first time to determine whether they, unlike any other cell type tested, would support regeneration. And to our surprise, they did.”
Specifically, the researchers grafted multipotent neural progenitor cells into sites of spinal cord injury in rats. The stem cells were directed to specifically develop as a spinal cord, and they did so robustly, forming functional synapses that improved forelimb movements in the rats. The feat upends an existing belief that corticospinal neurons lacked internal mechanisms needed for regeneration.
Previous studies have reported functional recovery in rats following various therapies for spinal cord injury, but none had involved regeneration of corticospinal axons. In humans, the corticospinal tract extends from the cerebral cortex in the upper brain down into the spinal cord. “We humans use corticospinal axons for voluntary movement,” said Tuszynski. “In the absence of regeneration of this system in previous studies, I was doubtful that most therapies taken to humans would improve function. Now that we can regenerate the most important motor system for humans, I think that the potential for translation is more promising.” Nonetheless, the road to testing and treatment in people remains long and uncertain. “There is more work to do prior to moving to humans,” Tuszynski said. "We must establish long-term safety and long-term functional benefit in animals. We must devise methods for transferring this technology to humans in larger animal models. And we must identify the best type of human neural stem cell to bring to the clinic.”
Ken Kadoya, UC San Diego and Kokkaido University, Japan;
Paul Lu, UC San Diego and VA San Diego Healthcare System;
Kenny Nguyen, Corrine Lee-Kubli, Kumamaru Hiromi, Gunnar Poplawski, Jennifer Dulin, Yoshio Takashima, Jeremy Biane and James Conner, UC San Diego;
Lin Yao, Joshua Knackert and Su-Chun Zhang, University of Wisconsin.
Funding for this research came, in part, from the Veterans Administration, the National Institutes of Health (grant NS09881), the Craig H. Neilsen Foundation, the Bernard and Anne Spitzer Charitable Trust, the D. Miriam and Sheldon Adelson Medical Research Foundation and Kitami Kobayashi Hospital.
By Kevin Punsky
Mayo Clinic finds surprising results on first-ever test of stem cell therapy to treat arthritis
December 6, 2016
JACKSONVILLE, Fla. — Researchers at Mayo Clinic’s campus in Florida have conducted the world’s first prospective, blinded and placebo-controlled clinical study to test the benefit of using bone marrow stem cells, a regenerative medicine therapy, to reducearthritic pain and disability in knees.
The researchers say such testing is needed because there are at least 600 stem cell clinics in the U.S. offering one form of stem cell therapy or another to an estimated 100,000-plus patients, who pay thousands of dollars, out of pocket, for the treatment, which has not undergone demanding clinical study.
The findings in The American Journal of Sports Medicine include an anomalous finding — patients not only had a dramatic improvement in the knee that received stem cells, but also in their other knee, which also had painful arthritis but received only a saline control injection. Each of the 25 patients enrolled in the study had two bad knees, but did not know which knee received the stem cells.
Given that the stem cell-treated knee was no better than the control-treated knee — both were significantly better than before the study began — the researchers say the stem cells’ effectiveness remains somewhat uninterpretable. They are only able to conclude the procedure is safe to undergo as an option for knee pain, but they cannot yet recommend it for routine arthritis care.
“Our findings can be interpreted in ways that we now need to test — one of which is that bone marrow stem cell injection in one ailing knee can relieve pain in both affected knees in a systemic or whole-body fashion,” says the study’s lead author, Shane Shapiro, M.D., a Mayo Clinic orthopedic physician.
“One hypothesis is that the stem cells we tested can home to areas of injury where they are needed, which makes sense, given that stem cells injected intravenously in cancer treatments end up in the patients’ bone marrow where they need to go,” he says. “This is just a theory that can explain our results, so it needs further testing.”
Another explanation is that merely injecting any substance into a knee offered relief from pain.
“That could be, but both this idea and the notion that a placebo effect could be involved would be surprising, given that some patients are still doing very well years after their study treatment ended,” says Dr. Shapiro.
He adds that these findings are important because while use of a patient’s own stem cells for regenerative therapy is extraordinarily popular, the treatments may be untested and are often poorly regulated.
Stem cell clinics often offer expensive treatments for conditions that range from multiple sclerosis, lung and heart disease, to cosmetic treatments, such as facelifts. None of these techniques have been studied because clinics maintain that use of a patient’s own cells is not a drug.
But, depending on how they are processed and used, stem cells can, in fact, be regulated by the U.S. Food and Drug Administration as biological products or drugs requiring rigorous safety and efficacy approval processes. In early September, the FDA held scientific meetings to clarify how to regulate such practices.
Mayo Clinic researchers developed their study with FDA approval.
“We feel that if we are going to offer any stem cell procedures to our patients, the science needs to be worked out,” Dr. Shapiro says.
The study was conducted in Mayo’s Human Cell Therapy Lab. Researchers extracted 60 to 90 milliliters of bone marrow from each patient, then filtered it, removed all blood cells, and concentrated it down to 4 to 5 milliliters. The solution, which contained tens of thousands of stem cells, was injected into a patient’s knee using ultrasound-guided imagery.
“We actually counted all of the stem cells with markers that are accepted by the FDA, and we made sure they would be able to survive inside the patient,” Dr. Shapiro says. “Counting is expensive. Most clinics just draw the cells from bone marrow or fat and inject them back into the patient without checking for stem cells, hoping that patients get better,” he says.
Dr. Shapiro and his colleagues are currently designing new studies that will test whether the stem cells home to distant areas of injuries, as well as exploring other implications suggested in their findings.
Study investigators include Mayo Clinic in Florida senior author Mary L. O’Connor, M.D., Shari E. Kazmerchak, Michael G. Heckman, and Abba C. Zubair, M.D., Ph.D. Dr. O’Connor is now at Yale University.
Funding for this study was from Mayo Clinic’s Center for Regenerative Medicine.