Barbara A. Binzak Blumenfeld, PhD, is a shareholder at Buchanan Ingersoll & Rooney. She focuses her practice on the regulation of biologic research, and recently spoke with Becker’s Spine Review about where regenerative medicine is headed.
Question: What is the FDA’s current regulatory framework for regenerative medicine products?
Dr. Barbara A. Binzak Blumenfeld: First, it is important to clarify the use of the term “regenerative medicine” as it can mean a variety of things. In some cases, it describes cell therapies generally or stem cell therapies in particular. Other times it can also include gene therapies or ex vivo genetically modified cell therapies. I am using “regenerative medicine” here to refer to cell and stem cell therapies.
The FDA’s current regulatory approach for regenerative medicine was only formalized about 20 years ago. The roots of this regulation are based in the Public Health Service Act, which addresses the transmission of communicable diseases. As a result, the FDA regulates cellular therapies based upon the level of risk they pose for transmitting a communicable disease when removed from a donor and implanted into a recipient. The FDA has essentially created a three-tiered regulatory system for these cellular products, more formally referred to in FDA regulations as “human cells, tissues, and cellular and tissue-based products,” or “HCT/Ps.”
First, in several narrow instances, the transplantation of HCT/Ps is not subject to FDA oversight. One such case is the “same surgical procedure” exemption. In this situation, if HCT/Ps are removed from an individual and “such HCT/Ps” are re-implanted into the same individual during the same surgical procedure, then the FDA does not regulate the HCT/Ps. The FDA has clarified that this is a narrow exemption and has given a very specific meaning to the phrase “such HCT/Ps.” The applicability of this exemption has historically caused confusion for practitioners.
Second, HCT/Ps that pose a moderate level of risk and are subject to some regulation — but not FDA pre-approval — are known as “361 HCT/Ps” (based upon Section 361 of the PHSA). HCT/Ps must meet a number of criteria to fall within this category. Among other things, they must only be minimally manipulated, and they must be intended for homologous use. By limiting what happens to the cells when they are outside of the body, for example, the cells are not considered to have been manufactured into a brand-new product. Twenty years ago, these terms lacked a fully developed and clear meaning. Since that time, FDA has issued guidance documents to better explain its interpretation of these regulatory provisions.
Finally, HCT/Ps that pose a relatively high level of risk — that are more than minimally manipulated or that are not for homologous use, for example — require FDA pre-approval before they may be marketed. These are known as 351 HCT/Ps (based upon Section 351 of the PHSA). If cells are grown in culture and the growth media contains drugs or other growth factors, then these cells are almost certainly going to require FDA approval, usually in the form of an approved biologics license application. In this case, the cells are considered a new product that requires FDA regulation.
These regulatory subtleties have led to confusion among regenerative medicine stakeholders. Unless these stakeholders are aware of and understand these distinctions, they may find that they have inadvertently subjected their HCT/Ps to FDA’s regulatory authorities.
Q: What does the FDA's promise to crack down on unregulated stem cell treatments mean for the regenerative medicine industry?
BBB: The FDA’s renewed focus on regenerative medicine enforcement means that all impacted stakeholders will need to become more aware of how their activities or practices could be impacted. This includes physicians, medical institutions and clinics, universities and companies. Each entity should understand what steps they can and cannot take without HCT/P pre-approval.
In November 2017, the FDA announced its regenerative medicine comprehensive policy framework. This framework was comprised of two final guidance documents that discussed the scope of the same surgical procedure exemption, as well as the meaning of minimal manipulation and homologous use. The framework also included two draft guidance documents regarding devices used in conjunction with regenerative medicine products, as well as the implementation of the Regenerative Medicine Advanced Therapy designation for certain therapies that was established by the 21st Century Cures Act.
Significantly, the FDA’s framework included an announcement that it will exercise enforcement discretion for 36 months following the November 2017 announcement. This means that the FDA will generally allow time for stakeholders whose products require FDA pre-approval to seek that approval and come into legal compliance. However, the FDA can still take enforcement action against products posing a higher level of patient risk, such as those used for serious or life-threatening diseases. The FDA has recently reminded stakeholders about this 36 month period, encouraging them to begin discussions with the FDA well in advance of the end of that period.
Importantly, in May 2018 FDA filed two lawsuits (one in California and one in Florida) seeking permanent injunctions against individuals and companies that FDA asserted had ongoing compliance problems — more specifically, that their cell products did not have the required FDA pre-approval. The outcomes of these cases will provide additional legal guideposts for the regenerative medicine industry to follow.
In October 2018, the Federal Trade Commission announced that it had settled an action brought against a California physician and two related medical groups for deceptive advertising of “amniotic stem cell therapy.” The FTC Act prohibits the dissemination of false advertisements for the purpose of inducing a consumer to purchase a particular drug or service. Here, the FTC called out website statements and videos, having determined that the physician and clinics were making unsubstantiated claims about the benefits of their therapies.
Clearly, the FDA has become much more attuned to the state of the regenerative medicine industry than it had been in the past. I believe that the FDA’s and FTC’s actions should resonate with stakeholders and serve as examples of what can happen if they do not comply with the regenerative medicine legal and regulatory frameworks. However, I also think that the agencies will face challenges to keep up with the proliferation of new clinics that are advertising cell therapies.
I do not believe that the FDA is out to quash this industry. To the contrary, I believe that the FDA recognizes its importance and wants to apply its regulatory framework in a way that may have been missing for some years. Industry and practitioners should not abandon the field but should realize and appreciate the need to work within a legal framework. The goal for all stakeholders should be patient safety.
Significantly, the impending departure of FDA Commissioner Dr. Scott Gottlieb raises some questions about how the FDA will continue to regulate regenerative medicine therapies. A new FDA commissioner may have different priorities, though I find it difficult to believe that the FDA would revert to its pre-November 2017 framework or would abandon its enforcement efforts in this area. However, only time will tell how a new FDA Commissioner may impact this initiative.
Q: How do you think the regulatory landscape for orthobiologics will shape up in the near future? For spinal biologics?
BBB: I do not see any unique regulatory issues that the orthobiologics or spinal biologics communities will face. To date, FDA’s enforcement actions have been agnostic to the specific medical disease or condition targeted by a particular regenerative medicine therapy.
However, to the extent that FDA will focus its actions during the 36 month enforcement discretion period on cases where there is a higher risk to patient health, then I think that practitioners and companies focusing on treatments in these medical areas should be especially prepared to understand and comply with the HCT/P framework. A regenerative medicine therapy that is intended for bone or spinal uses is likely to be viewed as a more risky treatment overall than other less-invasive conditions, for example.
Q: What should surgeons who use biologic products know about the FDA's regulatory process?
BBB: Surgeons, as well as their medical groups or university medical centers, should understand several things. First, FDA has stated that the “same surgical procedure” provision that exempts an HCT/P from regulation is intended to be narrow. Therefore, if a surgeon removes cells from a patient and then mixes them with a drug before reimplanting them (even into the same patient), the resulting mixture will likely be considered an unapproved product subject to FDA regulation. Such actions are not within the physician’s practice of medicine.
Second, the “practice of medicine” argument has not, so far, been a successful defense in regenerative medicine enforcement actions. FDA (and at least one court) has rejected arguments that the specific actions and products involved constituted the practice of medicine. It is true that FDA does not regulate the practice of medicine. However, FDA does regulate the drugs, biologics, and medical devices that practitioners use in their practices. This is an important distinction. If a physician or surgeon takes steps that FDA considers to be manufacturing, then the cells have become an unapproved product that is now subject to FDA’s oversight.
All of this does not mean that patients have no access to regenerative medicine therapies. However, physicians and surgeons must be aware of the legal means to do so. For example, in certain cases a practitioner’s actions may meet the requirements for the same surgical procedure exemption, and the HCT/Ps would not be regulated by FDA. Alternatively, a practitioner can use a 361 HCT/P if the practitioner complies with the appropriate regulations, or they can use an approved therapy. Individuals can enroll in a clinical trial that is studying an experimental therapy. There are also options through FDA’s regulations on expanded access to investigational new drugs when the patient has a serious or immediately life-threatening disease or condition. Finally, the new “Right to Try” legislation may offer an opportunity for access to an investigational new drug in particular circumstances as well. The key is that physicians and surgeons must be aware of the various opportunities for legal patient access to regenerative medicine therapies.
Q: How will biologics companies respond to stricter regulations?
BBB: First, it is important to note that FDA’s HCT/P regulations themselves have not recently changed and therefore are not “stricter” than they have been in the recent past. Rather, FDA has issued more guidance documents to explain its regulations and how they are applied. FDA is also taking more enforcement actions against regenerative medicine products and entities than it historically has done.
I think that different segments of the regenerative medicine industry — not only biologics companies — have different levels of awareness and understanding of FDA’s requirements. For example, biologics companies are highly likely to understand that there are FDA requirements and regulations pertaining to regenerative medicine products with which they must comply. Even within that industry segment, however, larger companies are more likely to have the resources necessary to be aware of and to keep up with changes in this field. Similarly, large academic medical centers and universities are likely to have the appropriate infrastructure, such as technology transfer and legal departments, to be able to comply with these evolving requirements. My sense is that the larger entities across each of these segments are generally going to be the most risk-averse.
In my opinion, small or solo physician practices may not be aware of the existing FDA regenerative medicine regulatory structure, much less with how FDA has been increasing its enforcement efforts. I think that small or solo practices need to understand that this regulatory infrastructure exists, as well as how FDA interprets its regulations. This knowledge will help these stakeholders to understand which regenerative medicine practices and therapies may fall outside of the practice of medicine and within the sphere of unapproved product manufacturing.
Q: What are the long-term legal implications for making dubious claims about stem cell treatments?
BBB: Dubious claims and the resulting enforcement actions of some entities may provide a taint to the entire industry. Negative stories get more press coverage, and this could result in a chilling effect for research and innovation in the regenerative medicine industry.
We have already seen that FTC, which regulates truth in consumer advertising, is willing to take action in cases involving claims for regenerative medicine therapies. FTC focuses on consumer protection and requires claim substantiation. In the case of regenerative medicine, some patients may be particularly vulnerable depending upon their illness or condition. So all segments of this industry, including physicians and surgeons, should beware of making claims about the success of a treatment without supporting data.
From a non-FDA and non-FTC perspective, all regenerative medicine stakeholders should be working towards the achievement of the best possible outcomes for patients. For the medical community in particular, that means helping patients make informed choices about their treatment options. Regenerative medicine therapies should not be taken off of the table, but they should be appropriately presented and should follow the legal frameworks that have been put in place.