A Closer Look At Oversight Of Cellular And Tissue-Based Products

At any wound care or podiatry meeting that I have attended in the past five years, I have been hearing the terms “stem cells” and “regenerative medicine” from speakers, sales reps and company managers. What do these terms really mean?

In our offices, we have been inundated with sales reps from many companies, including companies I have never heard of in my 27 years of practice in podiatry and in the wound care arena, each gushing over their latest and greatest amniotic tissue. The reps say the products’ processing is what sets them apart and their fresh products are what we should want for our patient. 

I just wanted to give a review of how these products get approval for use, and what it means when a product rep comes in and says the products are approved by the Food and Drug Administration (FDA).

The FDA regulates products commonly known to us in podiatry and in wound care as cellular and tissue-based products (formerly skin substitutes) under one of the four categories or regulatory approvals described below. The category depends on the origin and composition of the product.

1. Human cells, tissues and cellular and tissue-based products. The Center for Biologics Evaluation and Research (CBER) regulates cellular and tissue-based products, and is responsible for regulating biological and related products including blood, vaccines, allergenics, tissues, and cellular and gene therapies. Companies producing cellular and tissue-based products must register their products with the FDA. Companies that have cellular and tissue-based products are not required to demonstrate the safety or effectiveness of their products, and the FDA does not evaluate the safety or effectiveness of these products. These products would be derived from harvested tissues and organs like heart, kidney and cadaveric skin and amniotic tissues, which we are more familiar with in podiatry.

2. Premarket approval. The FDA’s premarket approval (PMA) is the required process of scientific review to ensure the safety and effectiveness of Class III devices. Such wound care products regulated under the PMA process will require evidence that they promote wound healing before they are approved for marketing. Often, researchers perform a randomized clinical trial in order to support the claim of safety and efficacy of the given product. The products in this category that we are familiar with are Apligraf (Organogenesis) and Dermagraft (Organogenesis).

3. 510(k) submissions. According to FDA documents, a 510(k) is a premarket submission demonstrating that the device to be marketed is at least as safe and effective to a legally marketed device that is not subject to PMA. In other words, the submitted product should be substantially equivalent to a product on the market before 1976, often called the “me too” product. Companies compare their device to one or more similar legally marketed devices and make and support their substantial equivalency claims. Since a clinical trial is not required, wound care products regulated under the 510(k) process will not typically require clinical evidence to establish effectiveness in wound healing in comparison with products regulated under the PMA process, which always require substantial clinical evidence.

4. Humanitarian Use Device (HUD). Similar to a PMA application, a Humanitarian Use Device (HUD) is exempt from the effectiveness requirements of a PMA. As the FDA notes, a HUD application “is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose." The company must show that no comparable devices are available to treat or diagnose the disease or condition, and that the company could not otherwise bring the device to market. Humanitarian device exemption approval is based on evidence of probable benefit in a population with the disease occurring at a frequency of less than 4,000 patients per year in the United States. Scientists used a HUD to develop the treatment for the outbreak of Ebola in the U.S. in order to provide treatment quickly as clinical trials in this case would not have been ethical or feasible in a short period of time.

Assessing The Marketing, Efficacy And Potential Reimbursement Challenges With Cellular And Tissue-Based Products

As you can see, the cellular and tissue-based product category allows for the marketing of products for wound care without the need for randomized clinical trials for both safety and efficacy support. There is a growing trend in calling these products “stem cells” as we often associate embryonic maturation with stem cell activities and naturally assign this action to small tissues in a bag that have been processed in some fashion or “minimally manipulated” the same action that occurs naturally in the womb.      

There is a potential concern in the near future with reimbursement from the Centers for Medicare and Medicaid Services (CMS) and other private insurers for payment of these products at the current level. What CMS has done in the last year with reimbursement for ocular tissue repair with amniotic extracellular matrix membrane allograft may be a warning to us that CMS may be looking to model the reimbursement in wound care in the same fashion. In 2018, the Medicare Physician Fee Schedule allowed amounts are: $1,448 for physicians in office and $58 for physicians in facility.

Could we potentially see this scenario in wound care? This is likely in the era of cost containment and outcomes measures. Many of these stem cell products have not shown superiority, efficacy and or even safety, and the intent of the human tissue use rules were meant for products to replace “like products” (i.e., kidneys replace kidneys, hearts replace hearts, etc.). Accordingly, the FDA and CMS are looking at this with amniotic tissues that really never were for “homologous use,” and thus rethinking whether these products should have clinical trials or premarket assessment. We will continue to monitor this over the next few years.

I have not jumped headlong into using amniotic tissue as many people have. From my perspective, I don’t believe there is enough evidence that amniotic tissue will heal chronic wounds better or faster, or is superior to existing treatments, such as good old- fashioned sharp debridement, offloading, compression dressing, removing infected bone, ensuring vascular competency and all of the normal common sense approaches to wound healing. There are very few companies with amniotic tissue products that can scientifically show that their product upregulates the production of growth factors, cytokines and regulates the matrix metalloproteinases above the level of the patient’s own wound. Accordingly, I am studying and weighing the need for these costly products.    

As for cadaveric tissues, I am using them more and have found that they often deliver to what is needed to allow the wound to fill in and continue to epithelialize on its own. The cost is less as a tissue bank harvests the skin from a donated organ. My patients also truly appreciate the gift of the donor’s skin.