The need for discussions regarding guidelines for the development of therapeutics made from human cells, tissues, and cell- and tissue-based products has been building for a long time.
That need was evidenced by introduction of the REGROW Act (S. 2689/HR 4762) in Congress last spring, which tries to streamline commercialization of cell therapeutics, and by two days of public FDA hearings this past fall to clarify guidelines for cell-based therapeutics. “There’s a huge wave of interest from patients, patient advocates, and the drug development industry,” says Karine Kleinhaus, M.D., divisional VP for North America at Pluristem Therapeutics.
Opinion is divided between those who see expedited approval as a way to access potentially life-saving medications earlier and those who warn of the consequences of allowing safe, but possibly ineffective, therapeutics on the market.
“The current paradigm for cell therapy products was put in place nearly 20 years ago,” notes Jay Siegel, M.D., chief biotech officer and head of scientific strategy and policy at J&J. “It’s a fundamentally sound structure that tries to anticipate, classify, and regulate products for today and for the future.”
But just as the science and the business of cell therapy have evolved, so have the questions. “The diversity of cell therapy products today is enormous, ranging from classic tissue banking and reproductive medicine to genetic modification and stem cells development,” says Siegel. Regulatory nuances affect each of these therapies differently and have led to a complex, sometimes arbitrary, regulatory process.
THE FDA NEEDS GREATER CLARITY
“Companies need a clear, defined pathway to approval,” Kleinhaus stresses. “Regenerative medicine developers currently lack regulatory clarity and the confidence that the development path they embark on will be deemed correct by regulators at the end of a program.”
The Alliance for Regenerative Medicine (ARM) is among industry leaders calling on the FDA to list more examples of the extent to which a tissue’s structure must be preserved to qualify as “minimally manipulated.” It also recommends specifically listing centrifugation as a minimal manipulation technique except when it changes the character of the cells.
The term “homologous use” also lacks clarity. ARM suggests additional language distinguishing between structural and nonstructural cells, standardizing the meaning of “same basic function” within the guidance, and defining how the homologous-use provision should be applied to wound healing.
Each of those changes is intended to decrease confusion and enhance predictability. “Ensuring regulatory predictability is the most important aspect for updated guidelines,” Siegel says. At the FDA hearings, J&J advocated for companies to receive a product designation from the FDA’s Tissue Reference Group without disclosing confidential information on a public website. “We want the process more interactive so nuances can be discussed between agency and sponsor,” he explains. Additional points include making more of the information public so companies with similar products can see a decision, know why it was made, and apply that information to their own regulatory submissions. Ultimately, such information could be formalized and incorporated into an FDA guidance.
JAPANESE LAW LAUNCHED DISCUSSIONS
Japan’s Regenerative Medicine Law, passed in 2014, often is used as a model for expedited commercialization in this debate. That law triggered the development of the REGROW Act, which in turn helped catalyze the FDA hearings on cell therapy guidances.
After the REGROW Act was introduced, FDA hearings were scheduled, but public interest was so great that the time allotted for the hearing was doubled and the date rescheduled months later. More than 90 individuals presented statements at the hearing. That overwhelming response provides regulators a broad look at the real-world issues complicating the development of cellular therapies today.
Japan’s Regenerative Medicine Law was aimed to bring regenerative therapies to patients quickly. “It’s inappropriate to characterize Japan’s law as a shortcut, though,” says Gil Van Bokkelen, Ph.D., chairman and CEO of Athersys. “I have first-hand experience with the Japanese Regenerative Medicine Law, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has very high standards and rigorous requirements.”
Recalling meetings with the PMDA, Van Bokkelen says they discussed every ingredient used in the studies and later in manufacturing, trial designs, endpoints, and what evidence means in terms of product characterization, safety, and efficacy. “That meticulousness and the ability to incorporate data from international studies enables Phase 1, 2, and 3 trials to be compressed,” he explains.
CSO, U.S. Stem Cell
REGROW COMES UP SHORT
The REGROW Act does not mimic Japan’s Regenerative Medicine Law, and industry leaders have been outspoken. “Its intentions are good, but the details are lacking,” notes Miguel Forte, chief commercialization officer for the International Society for Cellular Therapy (ISCT). He explains the REGROW Act contradicts existing FDA guidelines, ignores some of the more advanced forms of cellular therapy, and generally is less focused than agency guidances. “It creates confusion.”
“The REGROW Act suggests that FDA review and approval processes need a complete overhaul, and that special pathways need to be created for cellular therapies,” says Michael Werner, executive director of ARM. “We disagree.” Instead, he advises evaluating the existing approval pathways to make them more effective by considering the needs and issues of each type of cell therapy. “There’s no need to start over.”
The most damning charge, however, is that the REGROW Act unintentionally creates a pathway for conditional approval without providing an efficacy standard. “There’s a real concern from the cell therapy industry, investors, and academics that bad outcomes caused by underregulation will undermine the development of effective therapies and erode public confidence in regenerative medicine,” Siegel says.
The REGROW Act almost certainly will die in committee, but it may be a stepping-stone to more informed regulations. As Siegel says, “Several changes have been discussed [but not formalized] that soften its rough edges by excluding gene therapy or nonhomologous uses, but it remains objectionable to many parties.”
EXPEDITED COMMERCIALIZATION BENEFITS SOME
Some organizations do favor an expedited commercialization process. For example, because U.S. Stem Cell, Inc. develops a culture-expanded product rather than a minimally manipulated one, “the REGROW Act would be beneficial for us, allowing faster commercialization,” says Kristin Comella, CSO for U.S. Stem Cell. “A patient’s own tissue, used to promote healing, should not be regulated as a drug,” she continues. Doing so would place unrealistic burdens on physicians. For instance, the double-blind placebo trials common in drug development would be cost-prohibitive and virtually impossible for physicians pursuing autologous cell therapies. Even most biotech companies wouldn’t have the funding for such trials.
Without a product to justify the expense, there’s little incentive for any organization, except perhaps the NIH, to conduct the research. Instead, autologous therapies evolve similar to other medical procedures, with details being disseminated through medical journals and with pioneering physicians gradually adopting them. Eventually, those therapies may become sufficiently mainstream to be reimbursed by thirdparty payers. Given that, Comella says, “Medical boards should provide oversight for autologous cell therapies like they do for skin grafts and other procedures. An attempt by the FDA to regulate the use of autologous tissue may be overreaching.”
Final guidances for therapies made from human cells, tissues, and cell- and tissue-based products may not be issued until late 2017. Werner predicts these discussions will also feature in the 2017 Prescription Drug User Fee Act (PDUFA) hearings.
Although there is an overwhelming call for greater clarity, other details involving the regulation of cell therapy products remain to be resolved. Even the need for a new, expedited approval pathway via the REGROW Act is questioned. Instead, the prevailing sentiment within the industry is that the FDA already has the tools to facilitate expedited development of appropriate therapies. The next step is for the FDA to incorporate the key points from the hearings into guidelines that reflect the current knowledge and technology, so they remain relevant for at least a few years. The issues under discussion are complex, and changes in FDA guidelines, therefore, will likley not be swift.