When is a Stem Cell a Drug?

About a decade ago, stem cell clinics began popping up offering unapproved treatments for all kinds of debilitating and incurable diseases using a patient’s own fat stem cells.

There are now at least 170 such clinics just in the US; many plastic surgeons doing liposuction have gotten on board. Stem cell clinics are even more popular outside the US, where they are part of the booming medical tourism industry. People travel all over the world for these treatments. In these cases the source of the cells and types of handling are not always clearly defined, making these treatments a safety concern.

The stem cell product generation involves collection of adipose tissue through liposuction, and isolation of the adipose stem cells with collagenase or other enzymes to create a stromal vascular fraction (SVF). This SVF is sometimes referred to as “The Soup” because of the lack of defined characteristics. The isolated product, which includes some stem cells, are then injected back into regions of the body from which the cells were not derived, which are referred to as non-homologous sites. The site of delivery depends on what condition is being treated but most of the potential administration sites (e.g., joints, muscles, circulatory system, central nervous system) are not homologous to the tissue of origin, the adipose tissue.

Fuzzy Guidelines

Some companies claim their treatments are approved by the US Food and Drug Administration (FDA), and tout cures for many incurable diseases and conditions, including Parkinson’s disease, multiple sclerosis, autism, inflammation, all types of cancers and aging. But news reports have characterized the treatments as the modern-day version of snake oil, and stem cell organizations such as the California Institute for Regenerative Medicine and the International Society for Stem Cell Research along with the US National Institutes of Health consider many of these clinics dubious and have issued safety warnings to educate the public. The FDA has cautioned consumers to make sure that “any stem cell treatment they are considering has been approved by FDA or is being studied under a clinical investigation that has been submitted to and allowed to proceed by FDA.”

How can the use of a patient’s own cells be potentially dangerous? Some of the safety concerns arise from the extent of the manipulation and possible expansion of the cells outside the body. There are also concerns about the quality controls incorporated in the process, the characterization of the mixture, and complications from the administration back to the patient and the administration site.

It is very possible that some of these SVF treatments, especially for tissue pain and minor inflammation, have some level of therapeutic effect by facilitating tissue repair through release of trophic factors and/or induction of repair/regeneration pathways. However, the exact mechanisms are unknown and it is hard to evaluate the record of success of these therapies because stem cell clinics rarely publish data or findings.

Moreover, the FDA guidelines, until recently, were considered ambiguous concerning the classification and use of these autologous therapies. In the US, cell therapies are, legally, considered both biologics and drugs. They fall under the purview of the Food, Drug and Cosmetic Act because they mitigate, treat and prevent disease, but they also fall under the Public Health Service Act, sections 351 and 361 specifically, because they convey infectious disease.

Category 361 products are self-derived (autologous), minimally manipulated and used in a homologous manner, and do not need an Investigational New Drug (IND) approval, just an Institutional Review Board (IRB), a site registration and local (not FDA) oversight. Category 351 products are those that are more than minimally manipulated or ones that are used in a non-homologous manner. Marketed drug products fall into this 351 category. They require the whole drug development package (an IND, preclinical safety studies, clinical trials and marketing approval) before they can be prescribed to patients.

Not surprisingly, there has been much confusion over the product classification and definitions of these adipose-derived therapies, particularly over the interpretation of the phrases “more than minimally manipulated” and “non-homologous use.”

Minimizing Confusion

A year ago, in an effort to minimize interpretations from previous guidance, the FDA released two draft guidance: Minimal Manipulation of Human Cells, Tissues, And Cellular and Tissue-Based Products and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations. Both further define minimal manipulation and homologous use and provide many clear examples, some specifically addressing SVF.

In order to consider a cell product minimally manipulated, the processing must be shown not to alter the relevant characteristics or physical state of the tissue. For example, if the original characteristic of adipose tissue is to provide cushioning and support to tissues and organs, insulation, and energy storage capacity, then isolating just the adipose stem cells and removing the extracellular matrix that contributes to the tissue’s function would be considered more than minimally manipulated.

In order to meet the requirements for homologous use the cell product must be used in a tissue that performs the same basic function as the tissue of origin. For example, adipose tissue does not function in bone and joints and use of adipose tissue to treat bone and joint disease would be generally considered non-homologous use. Ultimately, these guidance provide more description for more-than-minimally manipulated, adipose-derived products and clearly state their non-homologous use meets the definition of a marketed drug product.

The intent of the guidance is to educate and provide clinics and doctors with proposed rules to self-correct and reduce the need for enforcement action once these guidelines are approved.

The Preclinical Process

As a result of these clarifying guidance documents, there are now many stem cell companies working through the process of obtaining regulatory approval for their autologous adipose-derived stem cell therapies. This approval will require product characterization and preclinical safety assessments similar to the expectations of a small-molecule or a biologic drug, which may include in vitro and in vivo testing.

The process can be relatively straight-forward and short-term, but ultimately the extent of testing depends on the cell product source, ex vivo manipulations, and use with other products and therapeutic indication. Navigating this preclinical process requires scientists that are familiar with the intricacies of the regulatory expectations, implementation of the testing requirements and performance of the assessments within the regulatory framework.

Assessing Risks

In this budding field of stem cell therapies, there is a lot of promise and still a lot of unknowns. Even with the most stringent and detailed characterization of the cell product and understanding of mechanisms of action, adverse interactions could occur. That is why these products are assessed with a tiered, risk-based approach designed by the FDA to provide the appropriate level of oversight to protect public health.

One case detailed last year in Scientific American described the unintended consequences of not understanding altered cell characteristics of an isolated cell product and potential adverse interactions from chemical alterations. During a cosmetic treatment in 2009, a woman received some of her own adipose-derived stem cells along with some dermal filler to reduce the wrinkles around her eyes. The dermal filler compound—calcium hydroxylapatite—is the same compound that stem cell researchers use to drive the undifferentiated stem cells down the bone pathway. In this case, the dermal filler differentiated the stem cells to bone and the patient ended up with bone fragments in the tissues surrounding her eyes, which had to be removed surgically.

This treatment met the requirements of a Category 361 product in that it was minimally manipulated and for autologous homologous use UNTIL it was combined with another product. This (thankfully not life-threatening) example of how stem cell treatments can go awry without proper understanding of product and potential interactions support the need for more safety-based oversight of these novel products.

Despite clarifications to the regulatory guidance and reports of adverse reactions in patients with SVF products, the battle rages on with some stem cell clinics. Physicians and stakeholders involved with autologous stem cell clinics are continuing to challenge the non-homologous use issue, claiming they are not creating drugs and that they are using approved materials. And these clinics continue to practice what they term “transformative medicine.”

In the end, we must have a better understanding of the cells, their activity and interactions before they are administered to humans. Otherwise, we could be creating more health problems for patients already seeking therapies for untreated conditions.

How to cite:

Jackman, Shawna. Stem Cell Clinics. Eureka blog. Nov 16, 2015. Available: http://eureka.criver.com/stem-cell-clinics/