On September 12 and 13 of 2016, FDA conducted public hearing on clarification of regulatory guidances for cell therapy. In my view, it was historic event, because it was the first-of-its-kind public hearing for cell therapy field. The reason for the hearing was unexpectedly high number of controversial comments about 4 guidances that FDA released in 2014-2015. These guidances are aimed to clarify FDA’s current thinking on regulatory classification of Human Cell Tissue Products (HCT/P) and included definitions of “same surgical procedure“, “homologous use“, “minimal manipulation” and “adipose tissue-derived products“. The latest guidance was released almost a year ago, so it was long overdue to have this public hearing. Unusual public participation and controversial comments made FDA to reschedule this event from April to September and split it for 2 days. You can watch recorded webcast here and here.
FDA was criticized for waiting too long to have hearing to finalize these 4 guidances. It may take up to one year more to see final versions of these guidances. I completely agree with this criticism – up to 3 years from guidance release to final version is way too long. In a meantime, uncertainties, related to different statements in the guidances and some rooms for interpretation of current law make things even worse. It could contribute to proliferation of so-called domestic “stem cell clinics”, continuous unfounded marketing of 361 HCT/P with periodic warnings from FDA and undermine the public trust to FDA.
It is important to understand that hearing is not a favor from the Agency, it is a rule to comply with, in situations when FDA has a lot of comments from confused public. The mission of FDA is to serve public, therefore, they must to hear and learn from the public to amend regulation accordingly. This is a basis of democracy. Unfortunately, it is very hard sometimes to find a common ground between all stakeholders and FDA. And it was exact the case that we have been observing during the hearing. It will be impossible to find common ground here, because opinions of different stakeholders are so radical for some positions of regulation. One may appreciate how difficult it will be for FDA to decide and finalize these guidances.
It is also important to understand that FDA guidances are not enforceable laws, but a tool to explain current law in greater details and give recommendations “to improve stakeholders understanding”. Therefore, guidances must be in accordance with current law, but not depart from it. The current law, which defines HCT/P regulation is 21 CRF part 1271. FDA was criticized by some speakers that some positions in guidances are different from language, used in 21 CRF part 1271 (see examples below) or in letters to developers, therefore such deviations may look like an attempt to modify existent regulation or introduce new one. Guidance is not a right (read unlawful) tool to introduce new regulations. I agree with this criticism – FDA should be very very careful with language and introduction of new terms.
Because so many people wanted to speak, FDA allocated only 5-minute slots for each presenter. Some scheduled speakers were not able to make to the hearing (I assume, most of them are patients), but unfortunately, FDA did not use these empty slots for extended discussion, so a lot of time was wasted. Importantly, only FDA panel was allowed to ask questions during hearing, nobody else, so discussion was impossible. This rule seems very strange to me.
Patients were heavily present on a hearing and were the most passionate speakers. The most common appeals to FDA from patients were “do not regulate our own cells (bodies) as drugs”, “leave decision about auto- cell therapy on us and physician”. Almost all patients presented successful cases of their treatment by autologous adipose tissue -derived cells. Unfortunately, there were no patients, who got harmed by unapproved “stem cell interventions” (few such cases were presented by ophtalmologist right before hearing). Unfortunately for patients, FDA would not get emotional about these cases and tweak the regulation as requested by them. For FDA, patient cases is bunch of anecdotes, without solid scientific evidence. FDA needs studies, which will deliver this evidence. Still, I think, it was useful exercise and FDA learned something from patient testimonials.
Structural versus nonstructural tissues and homology of use
Many speakers expressed concerns, confusion and disagreement on regulatory classification of tissues as “structural” and “nonstructural”. I agree with these concerns. The problem is that FDA defines minimal manipulation and homology of use, based on this tissue classification. This classification was expanded with examples in the guidances. But, based on scientific evidence, such simplification is wrong. Several speakers brought up evidence for many “nonstructural” functions of adipose tissue and amniotic membrane. It was proposed to determine homology of use and degree of tissue manipulation based on either structural or nonstructural functions of one tissue, depending on manufacturer’s objective intent, but not FDA classification. Importantly, previously FDA described nonstructural functions of adipose tissue and amniotic membrane, but then ignored it in “minimal manipulation” guidance for determination of homology of use and degree of manipulation, claiming these tissues as purely structural. FDA should be consistent in their language.
A new key word (used in “minimal manipulation” guidance) for bifurcation to structural and nonstructural tissues is “main function”. This term was not used before and may significantly limit examples of homologous use. For this reason, some people (representing organizations) are proposed to eliminate term “main function” from the guidances. It was also proposed to eliminate “performs the same functions as in donor” from defining homology of use. For example, fetal tissues (plalcenta/ amnion) in wound coverage.
One of the most interesting “take home” messages from the hearing for me was proposal to extend definition of “homologous use” to mesenchymal stromal cells or other cells, which act through paracrine mechanisms. It was proposed by few academics (Arnold Caplan, Keith March and Joanne Kurtzberg), who said that there is scientific evidence for it. For example, March proposed to use term “functional homology” for MSCs from tissue as opposite to “structural homology”. March and Caplan said that irrespective of tissue of origin, after transplantation MSCs perform the same (= homologous) basic functions – paracrine, angiogenic- and anti-inflammatory. Ability of MSCs from any tissue, combined with endothelial cells from any tissue, to induce vasculogenesis in any tissue/organ was cited by March as example of “functional homology”.
Kurtzberg said that autologous cord blood transplantation cells in cerebral palsy should be considered as homologous use, because cord blood cells (e.g. monocytes) here are acting through signaling or paracrine mechanisms – which is their basic function in both donor and recipient. Unlike, hematological conditions, cord blood stem cells do not integrate/ differentiate in host brain. Engraftment and differentiation in other tissue would be considered as non-homologous.
I don’t think FDA will buy “functional homology” concept and paracrine mechanisms of MSCs as homologous. It sounds like “systemic metabolic” effects – a way no go for 361 pathway. But Kurzberg raised very good question about auto- cord blood transplant in cerebral palsy – since this type of therapy is not commercialized, who would hold the BLA – family, cord blood bank or hospital? FDA has to answer this question.
Pretty much all speakers expressed disagreement with FDA’s classification of adipose tissue as structural tissue exclusively. Such classification obliterates almost any use of adipose-derived cells outside of plastic/ cosmetic surgery (see more here). Also, everyone disagrees on classification of breast re-shaping by adipose tissue transfer as non-homologous use (because primary function is production of milk). Some commenters also disagreed on classification of adipose tissue decellularization as more than minimal manipulation, saying that this procedure does not alter structural function.
What concerning to me is FDA’s ignorance of scientific evidence for multiple functions of adipose tissue as connective tissue. Guidance says: “Because connective tissue provides structure and support to the body, FDA considers connective tissue, including adipose tissue, to be a structural tissue.” Common guys, what about blood or bone marrow? It is a connective tissue, why don’t you classify it as structural?
It is important to distinguish fat grafting (transfer) for cosmetic purposes and cell (usually refer as “stem cell”) isolation from adipose tissue for multiple (non-cosmetic) applications. Some speakers did not distinct these 2 ways of intended use in their talks. I don’t think FDA has any problem to leave fat grafting alone (with exception of breast – see above). But I don’t think FDA will change its position to anything related to SVF and other cells, isolated from adipose tissue, intended for other than cosmetic applications.
There were multiple appeals to FDA to create alternative pathway for autologous cells. Randal Mills of CIRM vaguely asked for some kind of “middle ground” regulation, but did not present any plan for what it could be potentially. Cord Blood Association (J. Kurtzberg) says that “current regulatory framework for drugs is not sufficient for cells”. If FDA decide to ease current regulation in favor of 361 products, the control and monitoring system could be achieved by (i) registration and inspection of surgical sites (proposed by ISCT) and other facilities, (ii) facility accreditation (by FACT or AABB) and (iii) creation of patient registries (example: GRAFT registry – recently created by plastic surgeons). Proposed REGROW Act was mentioned by few speakers, but was barely discussed as real alternative. FDA panel asked zero questions on alternative regulatory pathways for autologous cells, confirming their position (voiced somewhere before) that the current system is sufficient enough.
Cracking down on stem cell clinics
This hearing was portray in the media as a way to crack down on proliferation of “stem cell clinics” (see here and here), marketing unproven interventions. But I don’t know how exactly finalization of these guidances will affect these clinics. Let’s be realistic – final version of guidances will not magically shut down hundreds of clinics. The real problem of FDA is law enforcement. If they had a muscle, they would shut down some of clinics already, but it did not happen. Also, I’m not optimistic about “perfect language” in the final version of guidances, which will make everything crystal clear and close all loopholes.
I think, it was great and very useful hearing. Overall, I was able to count only 3 speakers, who fully agreed with existent regulation and guidances. Most of organizations (societies, foundations, associations…) provided very good constructive comments for each statement in each guidance and offer FDA their help. I don’t believe FDA will leave these guidances unchanged. Agency must respond to inconsistencies, confusions and some scientifically unfounded concepts, pointed out by multiple speakers during the hearing. I think, at least they will remove “breast re-shaping by adipose tissue is non-homologous use” example. FDA may respond by changing classification of adipose tissue as exclusively structural. I think, FDA will add examples to the guidances for homologous use (for example, umbilical cord tissue) and for minimal manipulation (for example, centrifugation in fat processing). It was asked by many organizations.
General public and some professionals believe that with these 4 guidances FDA is departing from its goal: “to improve protection of public health without imposing unnecessary restrictions on research, development, or availability of new products”. It will be very hard for Agency to convince general public that FDA does not impose unnecessary restrictions. Unfortunately, it will be impossible to convince patients. But I believe that such public hearing can change something and help to make educated scientifically founded decisions for improvement of regulation.
I’d highly encourage you to watch recorded webcasts (overall 9 hours) and learn! Of course, many speakers pushed their agenda and were biased, but, still it was very educational and useful.