While the field of stem cell therapy has been in development for decades, most notably with the first successful bone marrow transplant in 1968, regenerative medicine is now experiencing rapid progress fueled by scientific and technology advancements. Although cellular therapeutics benefits greatly from embryonic stem cells, debates over the ethics of this type of research has led to the discovery of a more sustainable alternative, somatic stem cell research.
This said, many of the emerging cell therapies are scientifically and medically complex with many learnings and understandings still to come. As if core scientific and medical complexities were not enough, the industry, medical community and regulators are grappling with the challenge of conforming the regulatory framework to support the commercialization of cellular therapies, for instance cellular therapy classification, quicker approval pathways, and CMC challenges.
Cell Therapies: A Drug or not a Drug?
Within the cell therapy arena, regulators, the medical community and industry alike are often confronted with an unsettling question. What is this, really? Should a given cell therapy be regulated as human cells, tissues, and cellular and tissue-based products (HCT/Ps), or should the cell therapy be regulated as a drug with the FDA oversight and regulatory approval process that accompanies that designation?
As cell therapies have become more common and indications have expanded, it’s becoming increasingly common to be trapped in “no man’s land” trying to answer this question, creating tension and confusion for the range of stakeholders involved in the decision-making process. Today, the dispute primarily centers around somatic stem cells that are harvested and prepared for transplantation through minor surgical procedures at stem cell clinics and other medical service providers.
Mesenchymal stem cells (MSCs) are collected from a patient's own bone marrow or fat tissue, or from donor tissue not altered or manipulated and can form fat, bone or cartilage, making them useful for repairing bones and joints, minimizing inflammation caused by conditions such as rheumatoid arthritis, and promote the repair of a range of tissues. Hundreds of stem cell clinics now perform procedures with MSCs that are regulated as HCT/Ps under Public Health Service Act (PHSA) section 361. Procedures falling under section 361 classification are subject to regulations similar to that of other surgical procedures that are primarily aimed at avoiding contamination, infection and the spread of infectious disease.
HCT/Ps that require “manipulation” or alteration are governed by PHSA section 351. These products/procedures are considered to be indistinguishable from drugs and must undergo a rigorous regulatory approval process before being administered to patients. Some of the lines that separate section 351 products from those of section 361 are clearly drawn. For example, cells and tissues used homologously, meaning they perform the same function in the recipient as they do in the donor — such as the transplantation of bone marrow to restore healthy blood-cell production, are regulated under section 361. And therapies that employ a patient's own stem cells (autologous) are more likely to fall under section 361 than those that use allogeneic cells (from a donor).
So back to the question at hand: A drug or not a drug? Broadly, the FDA considers a product to be a drug if “more than minimal manipulation” is required for its effectiveness. Ambiguities can arise, however, because merely separating stem cells from their neighboring cells always entails some degree of manipulation.
The question of minimal manipulation was at the core of the high-profile lawsuit settled in 2014 in the United States Court of Appeals for the District of Columbia. Regenerative Sciences in Broomfield, Colorado filed suit against the FDA after the FDA contended that their autologous bone-marrow-derived MSCs to repair joint injuries represented more than minimal manipulation; and therefore, it did not qualify for regulation under section 361 as Regenerative Sciences claimed that it did.
The procedure involved extracting MSCs from the patient's bone marrow or synovial fluid. The cells were then cultured in the patient's autologous platelet lysate, allowed to multiply, and mixed with an antibiotic before being re-injected into the same patient at the site of orthopedic injury.
In the end, it was determined that even though the cells were cultured in the patients’ own platelet lysate, cell division in culture is not the same as cells dividing in the body. The acceleration of the culturing process could lead to increased risks of undesirable genetic alterations that could promote tumor growth and other negative consequences. Additionally, an antibiotic was introduced further suggesting more than minimal manipulation.
It was this case that gave a better pathway to thinking about the meaning of the phase minimal manipulation and led to the FDA’s comprehensive regenerative medicine policy framework released in November 2017. The framework, comprised of four guidance documents and designed to build on the FDA’s existing risk-based regulatory approach, more clearly describes which products are to be regulated as drugs, devices, and/or biological products and outlines how the FDA intends to focus its enforcement actions against products that raise significant safety concerns.
Quicker Approval Pathways for Cell Therapies
One of the significant challenges cell therapies have experienced as the industry strives to make these products commercially viable is a timely approval process. In December 2016, President Obama signed into law The 21st Century Cures Act. This act included the Regenerative Medicine Advanced Therapy Designation (RMAT), a provision to speed up the development and approval of cell- and tissue-based therapies, tissue engineering products, and combination treatments.