This presentation explores the progress that has been made and the challenges ahead as cellular therapeutics strive to mature in the marketplace.

1. Cellular Therapeutics:
Exploring Challenges
Within the Regulatory Framework

2. Presentation Contents
• Cell Therapy: Where Are We?
• Cell Therapies: A Drug or Not a Drug?
• Quicker Approval Pathways for Cell Therapies
• Cell Therapy CMC Requirement Challenges
• Applying a QbD Framework to Address Cell Therapy CMC Challenges
• Cell Therapies: CGMP Challenges
• Want to Read More?

3. Cell Therapy: Where Are We?
• The field of stem cell therapy truly launched with the first successful bone
marrow transplant in 1968
• Cellular therapeutics benefited greatly from embryonic stem cell work;
however, divisive ethical debates limited progress
• Advancement of somatic stem cell research, coupled with new technologies, is
fueling rapid cell therapy progress
• Much progress has been made, but the industry is now grappling with tailoring
the regulatory framework to allow cellular therapeutics to come to market
more quickly to treat patient populations in need

4. Cell Therapies: A Drug or Not a Drug?
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?

5. Cell Therapies: A Drug or Not a Drug?
• Mesenchymal stem cells (MSCs) are collected from a patient's own bone
marrow or fat tissue, or from donor tissue not altered or manipulated
• Hundreds of stem cell clinics now perform procedures using MSCs that are
regulated as human cells, tissues, and cellular and tissue-based products
(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

6. Cell Therapies: A Drug or Not a Drug?
• 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

7. Cell Therapies: 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 do arise – the mere act of separating stem cells from their
neighboring cells always entail some manipulation

8. Cell Therapies: A Drug or Not a Drug?
• A high-profile lawsuit settled in 2014 in the United States Court of Appeals for the District of Columbia
helped provide some clarity of position
• FDA contended that Regenerative Sciences’ autologous bone-marrow-derived MSCs to repair joint
injuries represented more than minimal manipulation
• Regenerative Sciences claimed the procedure qualified for regulation under section 361
• 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 during the procedure further suggesting more than minimal
manipulation

9. Cell Therapies: A Drug or Not a Drug?
• This case helped to establish FDA’s comprehensive regenerative medicine
policy framework released in November 2017
• The four guidance documents within the framework 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

10. Quicker Approval Pathways for Cell Therapies
• December 2016 The 21st Century Cures Act was signed into law
• The 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
• RMAT pathway is similar in spirit to the accelerated approval designations for
traditional small molecule and biotherapeutic drugs

11. Quicker Approval Pathways for Cell Therapies
IRONY??
• The 21st Century Cures Act allows companies to apply for RMAT designation based on “real-world
evidence,” rather than requiring data from a preclinical study
• The hundreds of stem cell clinics operating in the U.S. could be robust sources of this “real-world
evidence”
• In some cases this real-world evidence has been gathered by treating patients with therapeutics in
violation of FDA clarified regulations
• Will companies provide data (even very supportive data) derived from procedures and therapies
the FDA is making increasingly clear are illegal?

12. 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

13. Cell Therapy CMC Requirement Challenges
Cell therapy CMC work is challenging because:
• 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
• Starting materials will vary and often be in limited supply

14. Applying a QbD Framework to Address Cell
Therapy CMC Challenges
• Quality by Design (QbD), a product development and product lifecycle
management construct - 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
• 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

15. Cell Therapies: CGMP Challenges
• Section 351 autologous cell therapies are more than minimally
manipulated, thus fall under CGMP regulations like any drug
• How will the FDA, industry and healthcare providers manage hundreds
and thousands of new cell therapy CGMP manufacturing sites?
• These CGMP manufacturing sites will likely look a lot different than
traditional pharmaceutical manufacturing plants - hospital production
theaters and even bedside manufacturing

16. Want to Read More?
Article:
“Cell Therapies Come of
Age: Overcoming
Challenges Within the
Regulatory Framework”

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