While the FDA has a critical role in market oversight, individual market participants are also responsible for understanding the regulatory framework affecting the sale, distribution, and utilization of cell therapy, gene therapy, and tissue engineering products. This interview is aimed to help you understand the FDA framework affecting HCT/Ps within the U.S, as well as the framework and recommendations implemented by Health Canada.
Interview with Dr. Riam Shammaa, Medical Director at CCRT
Cade Hildreth: What is your background and how did you become involved with stem cell policy and regulation?
Dr. Riam Shammaa: I am a pain physician by training. I am also a faculty member at Mount Sinai Hospital and a lecturer on Musculoskeletal Medicine at the University of Toronto. In 2015, I became the medical director of The Canadian Centre for Regenerative Therapy (CCRT). The Centre works with the industry, start-ups and Health Canada on bringing Translational research from the bench to the clinic in a safe and regulated way.
We have successfully conducted and approved multiple studies and clinical trials in the field of regenerative medicine and stem cell therapy. Through our research arm we started working with (California Institute for Regenerative Medicine) CIRM on advancing qualified regenerative medicine platforms and stem cell therapy into INDs and clinical trials.
What struck me the most through our work was how open and helpful Health Canada, the FDA and CIRM were during our talks. They are looking to collaborate with physicians, organizations and the industry to advance this field. They provide advice, consulting meetings, and pre-submission meetings to make sure that your applications and projects are successful.
Cade Hildreth: When does the FDA regulate HCT/Ps and how does it define them?
Dr. Riam Shammaa: HCT/Ps fall under CBERs jurisdiction. They regulate any Blood products, Gene, Cellular and Tissue Therapy. I have included a link to the page that includes all the types of Tissue and cells in the definition.1 The regulation of HCT/Ps falls mainly under 2 sections in the 21 Code of Federal Regulation, section 361 and 351.
There are some exceptions under section 1271. The main aim of the regulations is to allow a safe development and implementation of such products at the clinical level.
Cade Hildreth: What major policy guidelines have been introduced by the FDA since that time and when were they released?
Dr. Riam Shammaa: Over the last 3 years, the FDA updated their guidelines to elaborate on their definitions and criteria for each product to qualify under a section or code. The last major update was in November 2017, where the FDA simplified and consolidated the definitions and the criteria to qualify as a 361, a 351 product or if the product is exempt.2
Cade Hildreth: How would you describe the key differences between 351 and 361 products?
Dr. Riam Shammaa: 361 was developed mainly for certain HCT/Ps autologous use or in a 1st degree relative allografts, such as IVF, Bone marrow and cord blood products. It describes how if a product is only for autologous use or in a 1st degree relative allograft, and not manipulated to a degree where it changes the characteristics or the use of that product, then that product can be used directly without the need of drug application.
351 is basically a drug application, meaning if the product doesn’t meet the criteria, then it should demonstrate data of safety, purity and potency and apply for an IND for clinical trials.
The major changes and clarifications from this document are:
- What is minimal manipulation of a tissue (example: Using tumescent fluid for adipose harvesting is considered more than minimal manipulation!), and what is homologous use (example: injecting adipose in a joint is non homologous use).
- If for homologous use, bone marrow aspirate (and not) concentrate may fall under the same surgical procedure exception 1271.15(b) .
- If for homologous use, bone marrow concentrate may or may not qualify under the same surgical procedure exception based on intention! Which needs to be clarified.
- Adipose derived allografts are not under 361 and are under 351.
- All allograft products (amniotic, umbilical, exosomes, proteins..etc) are under 351, and are seen as drugs that need to apply for IND to prove safety, purity and potency. They should not be used in the market before that.
Page 5 of the new guidelines simplifies the definition of those differences.
Cade Hildreth: What trends are you seeing with 361 stem cell products?
Dr. Riam Shammaa: Many companies that produce any type of allografts are exploiting 361 to market their products and sell them doctors claiming that they are under 361 and that they can be used. They are clearly not under 361 and they are unapproved products.
Cade Hildreth: What concerns you with stem cell industry’s interpretation of 361 products?
Dr. Riam Shammaa: The use of unstudied, unproven or unapproved allografts under 361, is dangerous on many levels:
- These products did not demonstrate any safety or efficacy data.
- Many of these products have not been characterized, meaning the doctor does not know what is inside of them, and because they are not complying with the FDA regulations, there is no way of knowing what they contain. The doctor is basically relying on claims provided by the sales representatives.
- Doctors that inject a patient under such a claim are solemnly responsible for the side effects or the toxicity and risk losing their licenses.
Cade Hildreth: How are Canadian regulators similar to and how are they different from the FDA in terms of their approach to stem cell regulation?
Dr. Riam Shammaa: In 2012, Health Canada was the first regulatory body to approve a cell therapy product (Prochymal) for GvHD. In Canada there is no similar sections such as 361 and 351. All HCT/Ps fall under Health Canada regulations and require approval.
However, because the field is advancing in a very fast pace, Health Canada decided to implement frameworks and recommendations rather than regulations, to keep an agile decision making process. This allows a very fast approval pathway.
Cade Hildreth: Over the next 5-10 years, what do you think we will see with regard to FDA oversight of stem cell therapeutics?
Dr. Riam Shammaa: Now as the pathways are becoming clear, many companies have legitimate products and are conducting clinical trials to prove their safety and efficacy. The regenerative medicine field is becoming a multi-billion dollar field with many products within reach of patients. This raises concerns over safety, accountability and intellectual property (IP) protection of those products.
We will see the FDA cracking down on any unregulated tissue products that are making false claims or jeopardizing the safety of patients.
Cade Hildreth: How can people get in touch with you or learn more about the Canadian Centres for Regenerative Therapy?
Dr. Riam Shammaa: People can reach me by email at riam.shammaa@utoronto.ca or our website at https://ccrttoronto.ca/ I would be happy to hear from them to discuss these matters further.
Footnotes
1.https://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm150485.htm
2.https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585403.pdf.
Do you have questions for Dr. Shammaa about FDA or Health Canada regulation of HCT/Ps? If so, ask them in the comments below.