Cell Therapies Come of Age: Overcoming Challenges Within the Regulatory Framework

Feb. 7, 2018
While the field of stem cell therapy has been in development for decades, regenerative medicine is now experiencing rapid progress fueled by scientific and technology advancements.

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.

The RMAT pathway is similar in spirit to the accelerated approval designations established for traditional small molecule and biotherapeutic drugs. Like previously established accelerated approval programs, RMAT will facilitate companies developing regenerative medicine therapies for serious and life-threatening diseases among patient populations with unmet medical needs—opening up the opportunity to interact with the FDA early and often in the clinical testing process. And while not guaranteed as part of the designation, products with a RMAT designation may be eligible for priority review and accelerated approval.

An interesting and potentially problematic part of The 21st Century Cures Act is that it allows companies to apply for RMAT designation based on “real-world evidence,” rather than requiring data from a preclinical study. There are currently hundreds of stem cell clinics operating in the U.S. that could be robust sources of this “real-world evidence.” However, in some cases this real-world evidence has been gathered by treating patients with therapeutics in violation of FDA regulations. In short, will companies provide data (even very supportive data) derived from procedures and therapies the FDA is making increasingly clear are illegal? Nearly certainly not.

Cell Therapy CMC Requirement Challenges

The broad CMC requirements for cell therapies are like other classifications of therapeutics. CMC information provided must ensure quality of:

  • Starting material and reagents
  • Product manufacturing
  • Product testing and characterization
  • Product stability

While cell therapies present challenges in every aspect of development, arguably the most challenging is the product testing and characterization that leads to safe and robust manufacturing processes. Why is product characterization so challenging? Cell therapies must contend with the complexity of live cell products, incomplete understanding of mechanisms of action, difficulties in product characterization, often very limited availability of test product, and by their very nature, starting materials that will vary and often be in limited supply.

Interesting work is being done to learn how to better characterize cell therapy products. One strategy being embraced includes developing tests that reliably quantify the amount of various biological activities present in different MSC populations. To achieve this quantification, test methods are being developed to identify the molecules that exert critical influence on the growth and differentiation of SCs. Such molecules can be used in tests that evaluate and characterize cells during the manufacturing process and as lot-release measurements for cell-therapy products.

Then, informative molecular markers must be identified—molecules whose presence reflects specific states of activity, disease, response to drugs, potency, and other characteristics of cells and tissues. Once specific activities in MSC preparations can be quantified, molecular signatures that correlate with the quantities measured in biological assays can be sought and very useful patterns can be identified.

In short, a promising path to characterizing cell therapy products is to quantify biological activities in various MSC populations, identify the molecules exerting critical influence over these activities, and identify and quantify the effect of informative molecular markers.

Applying a QbD Framework to Address Cell Therapy CMC Challenges

As previously alluded to, linking measurable molecular and cellular characteristics of a cell population to final product quality and performance in a highly predictable manner is necessary for cellular therapeutics to truly advance.

Quality by Design (QbD), a product development and product lifecycle management construct, presents a great opportunity to help manage the complexities of cell therapy development and manufacturing.  The International Conference on Harmonization released the QbD framework in 2006 to help the life sciences industry manage process and product management based on scientific knowledge and risk assessment over the course of a product's development and lifespan.

A QbD construct begins by defining and describing a quality target product profile (QTPP), then identifying the product characteristics that directly influence the safety and efficacy of the product (critical quality attributes), then identifying the parameters that influence these attributes (critical process parameters) and finally creating a design space that quantifies how parameter variability will affect quality and performance of the final product.

QTPP describes the desired characteristic of the end product—characteristics such as identity, potency and purity. On the other hand, a critical process parameter (CPP) is a process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.

Within the QbD framework, the intersection of QTPP and CPP is described within the design space and specifically the design space describes the interaction of the CPPs and material attributes on QTPPs, and the range of product and process variability that is compatible with maintaining product quality. Variability in CPPs is particularly important within cell therapy manufacturing due to the variability of the input cells and the complex interactions between critical process parameters.

Another important QbD concept is the design of experiments (DOE) which is simply the organized and structured collection of approaches for overtime learning the relationship between input, process characteristics and product outcomes.

While QbD approaches and filings are encouraged by the FDA within the small molecule and more established biotherapeutics spaces, it will likely take some time for QbD to be formally applied to the cell therapy space. However, the QbD framework and overall philosophy is quite useful as cell therapies and their development processes mature within the market.

CGMP Challenges                                                                                                                      

As stated above, HCT/Ps that undergo more than minimal manipulation are governed by section 351 of the Public Health Service Act (PHSA) and are considered indistinguishable from drugs requiring a rigorous regulatory process before being administered within patient populations. Included within the regulatory construct is the application of current good manufacturing processes (CGMP), which provide guidelines for manufacturing, testing, and quality assurance to ensure that a product is safe for use.

Allogenic-derived cells are arguably more similar to traditional pharmaceuticals or biologics from a business model perspective. These products exist within a fairly traditional logistical construct and are scaled to profitably serve numerous patients with the same batch. On the other hand, section 351 autologous cell therapies represent an interesting dilemma. They are more than minimally manipulated, thus fall under FDA regulations as any drug does including CGMP manufacturing regulations. But, how will the FDA, industry and healthcare providers manage hundreds and thousands of new cell therapy CGMP manufacturing sites that will be required as autologous cell therapies gain traction?

Additionally, these CGMP manufacturing sites will likely look a lot different than a traditional pharmaceutical manufacturing plant as stem cell clinics (there are already hundreds around the country) and hospital production theaters continue to emerge and the possibility of bedside manufacturing advances.


As is often the case with emerging therapies, there seem to be more questions than answers. However, cell therapies are unquestionably moving toward fulfilling their tremendous promise within the world of regenerative medicine. Given the promise of these products, industry and regulators alike are working in an increasingly focused manner to determine how the needed regulatory constructs can be practically applied to cell therapies. Product characterization technologies and better understanding of mechanics of action are at the heart of the matter and much progress is being made.

As we better learn and predict the characteristics and conditions (along with how to create and control those characteristics and conditions) that allow cell therapeutics to achieve their desired outcomes, we will be able to treat disease states in a manner never before possible. Frameworks that are well established within the pharmaceutical industry, like QbD and CGMP, are highly useful constructs if applied with scientifically sound creativity to the new cell therapy paradigm.

While there are plenty of challenges ahead, all indications are that technology, biological understanding, regulatory frameworks and market need have aligned to propel cell therapies to the next level.


  1. "Development of Strategies to Improve Cell Therapy Product Characterization," Steven R. Bauer, Ph.D., FDA Office of Tissues and Advanced Therapies, Division of Cellular and Gene Therapies Cellular, Tissue Therapy Branch
  2. "HCT/P Regulation - 351 vs 361 Products," Paul Gadiock, Arent Fox LLP, Pharmaconference presentation, February 2017
  3. "New FDA Pathway to Accelerate Development of Cell Therapies," Jef Akst, The Scientist, May 22, 2017
  4. "FDA Announces Comprehensive Regenerative Medicine Policy Framework," November 16, 2017, www.fda.gov
  5. "FDA Cracks Down on Stem Cell Clinics," Susan Scutti, CNN, August 29, 2017
  6. "Regulatory Challenges for the Manufacture and Scale-out of Autologous Cell Therapies," Paul Hourd, Amit Chandra1, Nick Medcalf, David J. Williams, 1EPSRC Centre for Innovative Manufacturing in Regenerative Medicine, Centre for Biological Engineering, Loughborough University, Leicestershire, Wolfson School of Mechanical and Manufacturing Engineering, Loughborough University, Leicestershir
  7. "Quality Cell Therapy Manufacturing by Design," Yonatan Y Lipsitz, Nicholas E Timmins & Peter W Zandstra, Nature Biotechnology, January 14, 2016
  8. "From Bench to FDA to Bedside: US Regulatory Trends for New Stem Cell Therapies," Paul S. Knoepfler, US National Library of Medicine National Institutes of Health, December 7, 2014
  9. "CMC Requirements for Early Phase Gene and Cell Therapy Clinical Trials," Ramjay Vatsan, PhD, FDA Office of Cellular Tissue and Gene Therapies, ASGCT Clinical Trials Training Course, May 2010
  10. "US FDA Regulatory Framework for Cellular Therapy Products," Kimberly Benton, Ph.D., FDA Deputy Director, Division of Cellular and Gene Therapies Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research, Global Regulatory Perspectives Workshop, April 2013
  11. "Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)," FDA Guidance, April 2008
  12. "Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)," FDA Guidance, August 2007

BioTechLogic, Inc. provides regulatory and manufacturing consulting services with strategic and hands-on experience to assist clients in bringing their products to market quickly and successfully by augmenting and optimizing their organization’s resources.

About the Author

Tracy TreDenick | Head of Regulatory and Quality Assurance