May 21 2012

Stem Cells: Which Way to the Clinic? (Updated!)

Stem Cells

Image via www.radolojan.blogspot.com

For over two decades, the potential of stem cell therapy to cure some of our most devastating diseases has been touted by the media.  A Google search of “stem cell research” yields over 57 million results, and yet, in mid-2012, there is only one approved stem cell product on the market in the United States (Hemacord®) and only one approved stem cell drug in the world (Prochymal®, Canada).  Why aren’t there more?  In a word, it’s hard.  It’s hard to harvest stem cells, it’s hard to do research with stem cells, and it’s hard to ensure that stem cell treatments will be both safe and efficacious in patients.

Stem cells are defined as being both self-renewing (they can regenerate themselves) and pluri- or multipotent (they can make cell types other than themselves).  The multiple types of stem cells include:

  1. Embryonic stem cells (ESCs): derived from a blastocyst that can self-renew and differentiate into any adult cell type (pluripotent).
  2. Adult stem cells (ASCs): undifferentiated cells that are present in tissues after development that can self-renew and differentiate to produce some or all of the cells in that tissue (multipotent).  Includes hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs).
  3. Induced pluripotent stem cells (iPSCs): Adult cells that have been genetically reprogrammed to an embryonic stem cell-like state (pluripotent).

One important question to answer before jumping through the regulatory hoops to get a stem cell therapy on the market is to determine what exactly is a stem cell therapy?  Is it a drug?  Is it a tissue?  The FDA classifies stem cell therapies as human cells and tissue-based products (HCT/Ps).  As stated in 21 CFR Part 1271, a HCT/P is regulated solely under Section 361 of the Public Health Service (PHS) Act if it meets the following criteria:

  1. It is minimally manipulated, and
  2. Intended for homologous use, and
  3. Not combined with a drug or device, and
  4. Either:
    1. Does not have a systemic or metabolic effect, or
    2. Is for reproductive use, autologous use, or allogeneic use in a first- or second-degree relative.

Although the CFR defines minimal manipulation and homologous use, there is still significant legal debate over the scope of the wording.

An example of a “361 product” would be peripheral blood derived progenitor cells from a mother to be used as a progenitor cell transplant for her child.  If the HCT/P is a 361 product, then it must be registered and listed with the FDA to ensure there is no risk for transmission of disease from the donor to recipient and that good manufacturing practices are in place.

If the HCT/P is not a 361 product, then it is regulated under Section 351 of the PHS as well as under the CFR.  The clinical use of the 351 HCT/P can only proceed after an Investigational New Drug (IND) application has been filed.  An IND application includes a general investigational plan, clinical protocols, chemistry, manufacturing and control data, pharmacology data, and toxicology data.  The FDA recommends early communication between the sponsor, investigator, and the FDA to determine the proper route for nonclinical and clinical studies.

Recently, Osiris Pharmaceuticals obtained a landmark regulatory approval in Canada for Prochymal®, their off-the-shelf MSC treatment for pediatric Graft-vs-Host-Disease.  This marks the first approval in the world for an off-the-shelf drug in which the stem cells are the active ingredient.  The FDA has asked Osiris for more information on Prochymal® before it grants marketing approval but has allowed the use of Prochymal® in the US in an Expanded Access program, in which the drug is available to critically-ill patients without enrollment in a clinical trial.

The FDA announced the approval of the first stem cell product in the US, Hemacord®, manufactured by the New York Blood Center (NYBC), in November, 2011.  Hemacord® is an umbilical cord derived hematopoietic stem and progenitor cell product “intended for use in unrelated donor hematopoietic progenitor cell transplantation.”  The approval of Hemacord® awakened the debate on whether this type of hematopoietic stem cell product needs such strict regulatory oversight.  The NYBC undertook the $2 to 3 million dollar process of licensure to “create a higher quality and standardized product,” but many researchers and clinicians are concerned that this action will ultimately result in limiting patients’ access to umbilical cord progenitor cell transplantation.  Many small stem cell banks will not be able to afford the onerous process of licensure, raising concern that this could be the first step towards FDA regulation of the more broadly used peripheral blood progenitor cell transplant.

The FDA is also embroiled in a controversial court case with the Colorado company Regenerative Sciences.  Regenerative Sciences markets autologous and cultured MSCs derived from bone marrow for injection into an injured area to treat musculoskeletal and spinal injuries.  In 2008, the FDA sent a letter to Regenerative Sciences stating that because the MSCs were for nonhomologous use and were being cultured, they were regulated as a 351 HCT/P product and an IND or licensure was required.  Regenerative Sciences sued, and the potentially landmark case is currently proceeding through the courts.

Whatever the outcome of the Regenerative Sciences case, it is clear that the translation of stem cell biology through the clinic is leading to a new regulatory framework.  In CBER’s recent Strategic Plan for Regulatory Science and Research, it states that “CBER must learn how to assess the risks of these novel technologies and identify product characteristics that can predict safety and efficacy in quality-control tests.”

The current regulations are not adequate to address the identity, purity, potency, tumorigenecity, and immunogenicity, not to mention pharmacodynamics, pharmacokinetics, dose, and clinical efficacy of the broad range of stem cell therapies that seek market approval.  The FDA is addressing some of these issues in its seminar series, “Pluripotent Stem Cells in Translation,” for which the next meeting is scheduled in July, 2012, and has also released several guidances concerning cellular therapies.  The future for stem cell therapies is bright, but the regulatory path to the clinic is not yet fully defined.

UPDATE:  On 25 Jul 2012, the United State District Court of the District of Columbia ruled in favor of the FDA.  The court called it a “close question”, but agreed with the FDA that the Regenexx™ Procedure (the culture of autologous MSCs) is a drug, not a practice of medicine.