Misunderstanding BMA and a Regulatory Framework for Thinking About Combination Cell-Based Therapies – Part One

Misunderstanding Bone Marrow Aspiration

On occasion I am asked what the FDA would think about a physician combining two therapies together. Examples of combinations might include PRP and BMC, PRP and SVF (Stromal Vascular Fraction of single cells obtained after enzymatic digestion of fat tissue), PRP and Fuzz Balls (i.e., mechanically processed lipoaspirate) or BMC and a small molecule drug. Regardless of the combination, the approach for using a combination therapy will depend on medical evidence to support the combination, as well as the sequence for creating the combination. For example, a physician can request a PRP preparation and at the moment of treatment, could request that the PRP be combined with another agent. In contrast, the combination of PRP and another agent can’t be offered or advertised by the manufacturer of the PRP kit, unless the combination of the materials was cleared through the FDA as a combination product.

As it happens, there was a paper published a couple of years ago by Gassman, et al., in which the authors commented on the combination of lipoaspirate and BMC in an article entitled “Discussion: Improvement of Fat Graft Survival with Autologous Bone Marrow Aspirate and Bone Marrow Concentrate: A One-Step Method” which was published in the same issue as a paper by Xing, et al. that I reviewed in a series of posts. Xing, et al. published a study in which they determined that bone marrow aspirate (BMA) and bone marrow concentrate (BMC) both contributed to the viability of fat grafts in a rabbit model, with some advantages demonstrated in BMC-laced grafts.

There are a number of points that I feel compelled to comment on in the Gassman, et al. discussion article. And I will start with a trivial one. In the third sentence of the article, the authors indicate that the Xing, et al. study is an “…in vitro study that combines fat aspirate with bone marrow cells in a rabbit model…”. Which left me scratching my head. Maybe it is just me, but when I read the term “in vitro” I assume that all of the experiments will be conducted in a petri dish or equivalent. A rabbit model study isn’t an “in vitro” study, but it could be called a “pre-clinical” animal study.

Okay, I feel better, so let’s explore the comments further. For example, consider the following:

“Any additional donor site introduces the potential for complications. Bone marrow biopsies and bone marrow aspirates are known to be painful. Patient-reported pain scales would have to be looked at to determine the extent and duration of donor-site discomfort with bone marrow harvest. I doubt whether this new technique would be found attractive to patients because of donor-site pain and increased morbidity.”

Usually, the phrase “bone marrow biopsies” is applied to procedures performed to check on the presence of potentially cancerous disease present in bone marrow. The Xing, et al. paper was dealing with the equivalent of bone marrow aspiration, so why bring up bone marrow biopsy? While I don’t practice medicine, I am somewhat familiar with what is involved in bone marrow aspiration and have heard comments from patients after undergoing an aspiration, whose comments don’t support the contention in Gassman, et al. that bone marrow aspiration is “known to be painful”. But since I am the other kind of doc, I will highlight the findings of a physician who has extensive expertise in bone marrow aspiration.

I refer, of course, to Dr. Philippe Hernigou (Chief of Orthopaedic Surgery, Henri Mondor Hospital, University of Paris (East) France), who has published clinical results from more than 30-years of experience with performing bone marrow aspirations. The assertion by the authors that bone marrow aspiration is painful simply doesn’t stand up to the results reported in Hernigou, et al. (2014). For example, he indicated that 2 patients out of 523 reported persistent (out to 1-yr) donor-site pain rated at 1 out of 10 on the visual analog scale (0 is no pain). Immediate post-aspirational pain was reported as an adverse event (3 out of 10 on the visual analog scale) for 1% of the patients (n=6). These painful conditions disappeared within one week for four of the six patients. So, is there no pain involved during or after a bone marrow aspiration procedure? Of course not, but a large majority of patients in Dr. Hernigou’s study reported feeling little or no pain and certainly didn’t experience chronic pain.

I will consider the other element of the authors’ statement about pain and “increased morbidity” in the next post, after which I will take up the ridiculous speculations of Gassman, et al. on the regulatory framework for the combination therapy studied in Xing, et al.

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