FDA Commissioner Scott Gottlieb and CBER Director, Peter Marks, have just published a new piece on stem cells and regenerative medicine in the New England Journal of Medicine (NEJM).
What are the core points here and what can we learn from reading between the lines a bit?
There are some expected things and then some surprises.
The title of the article is “Balancing Safety and Innovation for Cell-Based Regenerative Medicine,” which really gets to the heart of what I think the FDA is trying to achieve with oversight of stem cells in 2018 and beyond: a balancing act whereby they both are preventing major negative outcomes and promoting innovation.
First, the elephant in the room (in the article)
The elephant in the room when one reads a piece like this and more generally in this arena is the mushrooming stem cell clinic industry with probably upwards of 700 clinics operating without FDA approval today. The FDA has talked tough about the clinics in the past 12 months. The FDA also issued a warning letter to US Stem Cell/US Stem Cell Clinic in 2017 and now already issued another warning letter in 2018 to American Cryostem.
While this clinic industry is not mentioned specifically in the new NEJM article, it’s there looming large between the lines. The authors do indirectly refer to harms associated with clinics in the US and abroad in this one passage as well as the problem with selling stem cells that have no proven efficacy:
“At the same time, the administration of such stem cells may be associated with serious adverse events.5,6 Even in the absence of serious adverse events, the use of therapies that are of unproven efficacy is a disservice to patients and to public health.”
Homologous Use and Minimal Manipulation
Homologous Use and Minimal Manipulation are two of the important elements of how the FDA determines whether a product is a drug or not. In many or even most cases, one might think that stem cell products would have to meet both of these criteria to be a 361 HCT/P not subject to full pre-market drug approval and the new FDA article suggests that too:
“In brief, products that are regulated solely under Section 361 generally are those that do not undergo substantial processing (minimal manipulation), are used in a manner in the recipient that is similar to that in the donor (homologous use), are not combined with another drug or biologic product, and do not have a systemic effect, unless they are designed for autologous transplantation, first- or second-degree–related allogeneic transplantation, or reproductive use (Table 1).”
There are qualifiers here such as “generally”, but this seems like a fairly concrete statement on the requirements. However, one potential loophole or area of uncertainty even now after the new FDA final guidances issuance is whether bone marrow stem cells that are minimally manipulated but that are unambiguously used in a non-homologous way (say bone marrow stem cells for say COPD, a brain disorder, etc.) can qualify for same surgical exception or not and can be a 361 product. I hope this statement in the NEJM article is an indication that there is no loophole here, but we’ll see.
In contrast, clinical use of adipose stem cells (a.k.a. “stromal vascular fraction”) is clearer. It appears to nearly always be a use of a drug product requiring pre-market approval since this product is not eligible for same-surgical exception and are by definition more than minimally manipulated according to FDA guidance. Many for-profit stem cell clinics also use fat stem cells in non-homologous fashions too so there are multiple reasons to view this product as a drug.
RMATs, Good Citizens
The data presented by FDA in this article on Regenerative Medicine Advanced Therapy (RMAT) designations is interesting. I already have a list of the 13 RMAT approvals on this blog, and will keep updating that, but the context of how many applications FDA receives is interesting:
“As of December 29, 2017, the FDA had received 43 requests for RMAT designation, had acted on 35 of these requests, and had granted 13 of them.”
So it seems that most RMAT applications are not approved. In fact, about 2/3 are not going to be granted, which is interesting. I still think approval of 13 RMATs in just a year is surprisingly fast.
The FDA will help clinics become compliant & run trials?
I read the following passage in the NEJM article as possibly a suggestion to stem cell clinics and/or individual health care providers using stem cells clinically to become compliant and that perhaps FDA will help them if they do:
“For example, the FDA will provide tools to encourage individual or small groups of physicians to collaborate in support of the development of a stem-cell or other regenerative medicine product, which will ultimately lead to the receipt of a biologics license by each of the physicians or groups (Figure 1). How might this work? The investigators who manufacture the product will need to agree on and follow a common manufacturing protocol and develop a common clinical trial protocol. Each site will then produce the product to treat the patients who are enrolled in the clinical trial at its own site. Subsequently, the pooled safety and efficacy data from the various sites that are participating in the trial will be submitted as part of a biologics license application for each.
If the clinical data that are submitted in conjunction with the manufacturing information show a favorable benefit–risk profile, the FDA could rely on that pooled data in determining whether the product is safe and effective. The agency would then issue a stand-alone biologics license to each of the physicians or groups so that each could proceed to produce the product independently. This approach, with appropriate planning and statistical analysis, would provide an alternative to how development generally has been conducted in the past to support approval. Such a pathway toward licensure may be well suited to groups of investigators or small firms that are able to consistently follow a common manufacturing and clinical protocol but that may not have access to the patient populations or infrastructure needed to conduct separate development programs. The approach may be particularly well suited to the development of products that involve manufacturing that is not highly complex yet is more than minimal manipulation and to clinical applications amenable to trials of relatively simple design.”
If I’m reading between the lines on the above passage correctly, it’s a surprising proposed kind of opening for clinics or would-be clinics, but clearly depends on high-quality data and communication with the agency. This maybe could be summarized as, “Do the right thing and we’ll help even if you are a ‘little guy’.” Of course, I don’t speak for the FDA and this is just my sense of what this section may mean.
The 36-Month Grace Period with Some Exceptions for the Riskiest Situations?
With the clock ticking starting in November 2017, FDA has said before and now says again in this new NEJM piece that entities have 36 months to figure out where they stand and get clarity on the guidances. Some of us are concerned that the hundreds of clinics may view that as a 3-year free pass of a sort, which could be a really bad thing for patients and the stem cell field.
I’m hoping the FDA will use its discretionary powers to take actions even during this 36-month period in cases where there are acute, highly risky situations involving stem cells and this bit from the NEJM piece suggests that’s the case:
“The FDA intends to take additional enforcement actions in cases in which it believes unproven products may put patients at risk.”
I believe there are at least a handful of such extremely risky situations right now that require basically immediate FDA action to prevent further patient harms. So far, the FDA under Dr. Gottlieb as much as things look more encouraging, still has only issued 2 warning letters within the realm of a huge clinic industry that is generally lacking both FDA approvals and rigorous science behind it. More action is needed as soon as possible.