Regulation of autologous adult stem cells – the case of regulatory regress

by Alexey Bersenev on October 18, 2012 · 3 comments

in regulation

Post was updated 18 October, 2012 at 5:50 pm. EST

The recent troubles with US company Celltex, clash between Regenexx and FDA and some other cases demonstrate the uncertainty in regulation of autologous adult stem cells (AASC) for regenerative medicine. Developers, who are trying to bring AASC-based therapies to the bed side usually confused about regulatory path. Some of them assume (or pretend to know), that AASC is a practice of medicine/ tissue (graft) and, therefore, is not a subject of federal regulation as a drug or biologic. But those, who chose to contact regulators (be compliant) to clarify the path to the market, still confused about agency’s recommendations. The most frequent questions are:

  • Should AASC product be regulated as a drug/ biologic or as a graft/ tissue? If yes, why?
  • What regulatory agencies regulate the steps of AASC product development cycle (raw material procurement and testing, manufacturing, facility authorization, clinical trials, market approval…)? How do they interconnected and what documents at what period of time should we submit?
  • Is GMP-grade manufacturing required?
  • Should we conduct all phases of clinical trials?

From the other side, regulators may not be entirely sure about the right and appropriate path. This uncertainty usually associated with new kinds of therapies, which just left a lab bench and haven’t been implemented in patients. This is a typical case for AASC. Regulators have limited time to catch up with rapidly progressing field and, usually, lack of expertise. Therefore, the law and guidance development could lag behind of scientific and clinical progress. The group of authors, proposed to call this situation regulatory regress:

Regulatory regress reflects the potential for uncertainty in scientists’ attempts to achieve regulatory compliance, and regulators’ uncertainty in recognising when such compliance has been attained.

The authors analyzed regulatory regress for the case of GMP accreditation of clinical stem cells labs/ facilities in UK. One of their showcases included UK Stem Cell Bank. Clinical-grade stem cell lines manufacturing is regulated by few agencies. The authors called them actors. In UK, actors include:
(HFEA) Human Fertilisation & Embryology Authority (use of embryos and derivation of ESC), (HTA) Human Tissue Authority (storage of human tissue – raw material), (MHRA) Medicines & Healthcare products Regulatory Agency (clinical device) and (EMA) European Medicines Agency (medicinal product = drug for therapeutic use). In UK two different agencies grant clinical trial authorization and marketing authorization.

Some observations from their showcase analysis:

The analysis is led by the observation that both laboratories are investing considerable labour in (1) interpreting regulatory texts and (2) identifying which regulatory texts were the relevant ones for interpretation.

The main problem of regulatory regress:

Regulatory regress means that a regulatory actor does not know the correct interpretation of a regulation until the wider networks shaping its meaning are settled, yet these wider networks cannot be settled until a correct interpretation is agreed.

Ok, let’s get back to our case (AASC) and look at situation in US. I was trying to draw the scheme, which suppose to demonstrate the actors in potential regulatory regress for the case of AASC regulation in US:

FDA – Food and Drug Administration (manufacturing, clinical trials, market authorization, license)
FACT – Foundation for the Accreditation of Cellular Therapy (facility accreditation)
ICMS – International Cellular Medicine Society (facility accreditation)
AABB – American Association of Blood Banks (facility accreditation – jointly with ICMS)
IRB – Institutional Review Board (independent ethics committee, clinical trials with or without FDA)

This is hypothetical scheme. All of these actors are playing some role or/ and intend to play in AASC regulation in US. Right now, pretty much everything “covered” by FDA. So, developers, which chose to be compliant, communicate almost exclusively with FDA. You can add trials approval through IRB and facility accreditation through FACT.

I think, regulatory regress for use of AASC in regenerative medicine is open. Variety of actors will add more complexity and significantly wide open regulatory regress. One of the issues here is communication between actors. For example, ICMS is aimed to “bypass” FDA* (*see comments) provide a framework for exclusive regulation of AASC for regenerative medicine. So, at the moment, developer may be confused about which way to go (ICMS or FDA). It may prolong the product development and may require consultants for interpritation of options and requirements.

{ 3 comments… read them below or add one }

Ricardo Luis Rodriguez October 18, 2012 at 8:28 am

As president of the ICMS, I would like to correct some assertions you make which would have been very easily avoided by just asking questions.
The ICMS/AABB do not aim to bypass the FDA. On the contrary, we plan to meet with the FDA.
Secondly, our aim is to provide a framework for operating adult autologous stem cell facilities based on existing Cellular Therapy Standards widely accepted, as well as existing surgical facility operating guidelines that are also widely accepted. It is not intended to substitute for or supplant regulatory guidelines.
Finally, as a scientist I’m sure you understand the importance of looking at the evidence before forming an opinion. With that in mind, please read the standards when they open for public comment in the spring. I’m looking forwards to your thoughts then.


Alexey Bersenev October 18, 2012 at 5:57 pm

Thank you for the comment! I didn’t know about ICMS plans to meet with FDA. So, to me, at the moment, it look like a disconnect and more complexity. Doesn’t FDA provide (or intend to do so) a framework for autologous stem cell facilities? I know that they don’t divide for type of cells. FACT provides a framework for cell therapy facilities also. Not just for hematopoietic tissue, for all cell therapies.
Well, thanks for letting us know about ICMS plans. Sounds like good plan. I hope your communication with FDA will be productive and useful. Looking forward to read proposed standards. I can post a link for my readers and it will be open for public comments.

Post was modified according your comment.


Linda Miller October 19, 2012 at 7:56 pm

Alexey –
I can understand how perhaps you would make the assumption that the intent of the ICMS was to “bypass the FDA” given the requirements of the ICMS advisory board on their website which state: “Advisory Board and Council Members must affirm that minimally culture expanded stem cells are 1). Part of the practice of medicine and used as part of a physician practice in one state and through the state practice of medicine, 2). Do not constitute the creation of a new biologic drug or product that would fall under any part of FDA regulation on new drugs or biologics and 3). Exempt from any US Food and Drug Administration regulations.”
In an effort to curtail the angst associated with your notion of “regulatory regress”, please be reassured that there are significant efforts being made by several leading cellular therapy organizations, including FACT, to work with the FDA and discuss issues related to the use of AASC including the practice of medicine vs. manufacturing of therapeutic agents as well as what constitutes more than minimal manipulation of human cells. And while it may take the FDA a longer timeline to establish appropriate regulations, the cellular therapy professional societies are committed to developing needed standards to protect patient safety while encouraging advancements in regenerative medicine.
Given the recent ruling against Regenerative Sciences, I believe the ICMS is going to discover that many of their participating clinics are indeed engaged in activities outside what has been shrouded as practice of medicine. Interestingly, there still is no information on the ICMS website identifying either their member clinics or the roster of their recently announced standards committee. It would be helpful to know exactly what cellular therapy experts they have developing their guidelines. I too, look forward to reading the draft ICMS standards.


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