The Ethical and Regulatory-Compliant Training and Practice of Regenerative Surgery in the United States and Abroad

Background

Although there are many evolving definitions for regenerative surgery (RS), this nascent field at present may be functionally defined as the application of regenerative material and techniques such as live cells or cell-derived material with surgical methods to affect clinical therapy for disease or restore normal human function. To date, there is no officially recognized allopathic medical training or board certification process specifically for RS. This becomes problematic in that patients are customarily familiar with “pairing” the appropriate specialty to the services or treatment they require. From a patient advocacy standpoint, this void or lack of any official “stem cell” surgeon makes it difficult for the discerning patient to find legitimate practitioners and may instead fall victim to those who might not even be surgeons or organ- or specialty-specific doctors relevant to their needs.

The key questions remain: To what extent does the current system of surgical education adequately address regenerative medicine issues, and is further certification or subspecialty qualification necessary for patient safety and professional standards here in the United States and abroad?

Status of surgical training in relation to RS

The standard process of surgical education in the United States is through residency training programs that are approved by the Accreditation Council for Graduate Medical Education (ACGME). (It is important to note that the osteopathic pathway to residency and fellowship surgery training is through a different professional organization; however, the American Osteopathic Association pathway will eventually be incorporated into the ACGME system of education and validation by 2015.) At present there are eight specialties of surgical residency programs officially recognized by the ACGME and American Board of Medical Specialties (ABMS): general surgery, otolaryngology, ophthalmology, neurosurgery, orthopedics, obstetrics/gynecology, urology, and plastic surgery. Transplantation, pediatric, vascular, colorectal, cardiothoracic, thoracic, and surgical oncology surgery requires further subspecialization fellowships after primary surgery residency. Upon satisfactory completion of residency and/or subspecialty fellowship training, both a written and oral board exam must be successfully completed to become fully certified, though it is still possible for surgeons to actively practice during pending completion of qualifying exams.

In review of ACGME medical competency requirements (section IV) across all surgical specialties, there is no precise or direct use of the words “regenerative” or “stem cell” [101 –108]. More broadly inclusive terms such as “basic sciences” or “wound healing” are used in addition to generalized statements such as the ability to “appraise and assimilate scientific evidence, and to continuously improve patient care based on constant self-evaluation and life long learning.”

The closest and most relevant statements made with respect to RS are noted under general surgery competency requirements listed in Section IV. (A.5.a.).(3).(d), which states:

A formal transplant experience is required. It must include patient management and cover knowledge of the principles of immunology, immunosupression, and the management of general surgical conditions arising in transplant patients. … [101]

This is in stark contrast to the nonsurgical specialty hematology–oncology, which overtly states that their doctors

Current postgraduate surgical education and RS

At present in the United States, there are no formal postgraduate “added certificates of qualification” in RS available for surgeons through ACGME or their ABMS-sanctioned specialty boards. RS education for the current generation of practicing surgeons occurs largely through postgraduate medical education programs such as medical conferences and uniquely focused conferences that bridge the bench-to-bedside gap with sessions aimed at translating basic and clinical science research. Annual clinical meetings within each surgical specialty do include some preliminary sessions on regenerative medicine relevant to their field. However, the more uniquely focused conferences aimed specifically toward the regenerative medicine and stem cell community have provided the greatest amount of translational science education for clinicians at this juncture. Conferences such as the World Stem Cell Summit have worked toward developing a collaborative dialog between surgeons and scientists in the regenerative field and have provided an early framework for ethical practice and regulatory compliance. Some of these conferences have begun to offer combined clinical practicums to offer hands-on intraoperative and procedural experience as well.

To the lay public this may appear to be ill-credible or medical science that is on the “fringe.” However, many advanced technologies in surgery did not incubate or develop within universities and/or formal ACGME programs of education. For example, the field of laparoscopic surgery started within the realm of private practice, and initial training courses were provided by inventors of the technology in a private setting. Eventually, laparoscopic surgery became part of standard surgical residency training. Furthermore, new fields of medicine usually start as loose coalitions of medical interests and primordial ideals that lead to a plurality of nubile postgraduate medical profession organizations. These early organizations go through a maturation and consolidation process that sometimes eventually become legitimately recognized by the American Medical Association and ABMS. In many ways this is how some of the ABMS-recognized specialties actually began. Whether this happens with RS remains to be seen, but the formal process for becoming an ABMS specialty (and to be recognized by State Medical Boards as a legitimate medical organization) moves at a glacial pace relative to technology, and the demand for innovative therapy for presently incurable disease will never wane. There will always be the risk of unscrupulous doctors and clinics whether official specialty recognition is ever obtained. The presence of RS postgraduate medical education, however, should not be taken as a sign of disingenuous or nefarious professional behavior, and during this time of transition should be viewed as a necessity for patient safety.

Status of RS practice

Within the United States the active practice of RS can only legally occur either through FDA-approved materials or under an institutional review board (IRB) or investigational new drug (IND) application. There are several organizations, both private and public, that have formed IRBs to clinically evaluate the merits of various stem cell therapies. Adipose-derived stem cells and stromal vascular fraction, both of which are components obtained from liposuction waste, have been the source of a vibrant community of research. Initial attempts at forming valid IRBs and regulatory-compliant clinical studies had started off with some difficulty and challenges, perhaps unwittingly as the surgical community is not as versant in technicalities as other research-intensive fields of medicine. Nevertheless, the ethical practice of RS even with an IRB or IND requires that the surgeon not charge full retail cost for the act of transplanting regenerative material, nor is the surgeon allowed to advertise that he/she is treating or “curing” a specific disease. (It is interesting to note that, in a preliminary web survey of regenerative surgeons, the surgical fees appear to be commensurate with standard liposuction costs, well under the typical $30,000 per procedure fee, which has almost become the unspoken industry standard for international clinics offering similar services at the time of this publication.)

Beyond the FDA, surgeons offering regenerative procedures must still abide by standards of care within their professional board organization in addition to that of the state medical boards. Although these are experimental protocols under a valid IRB, by virtue of being “experimental,” does not preclude the simultaneously occurring elements of surgical standard of care. In other words, if a liposuction procurement of adipose stem cells left an individual grossly disfigured, or upon deployment of the stem cells a surgical technique was less than standard of care, the surgeon would still be liable from a malpractice standpoint. Both the risk of potential lawsuit and professional sanctions at the local or state level offer an additional and often unspoken layer of public safety and scrutiny for RS in the United States.

RS abroad

Obviously, medical tourism has not only survived the recent downturn in world economy, but also actually grown quite dramatically with stem cell procedures still remaining a highly sought-after service. What has changed is the growing number of foreign countries that understand first-hand the negative impacts of stem cell catastrophes taking place on their soil at a detriment to bottom-line tourism dollars and overall negative press. A serious consequence of having the appearance of lawlessness also creates a systemic problem, whereby these new forms of medical business and industry are potentially built upon a foundation of less scrupulous interests. This ultimately creates a false and fragile “bubble” economy that carries no long-term benefit for any country and can have lasting repercussions on the credibility of their countries' medical science and exportable technologies.

Moreso than the United States, surgeons abroad are constantly confronted with greater risks and complications regarding operative materials regardless of regulatory approval status. Surgeons abroad are quickly becoming aware that stringency and disciplined conservatism toward any surgical material, even if autologous in nature, can never be excused, as even autologous mesenchymal stem cells may differentiate into donor-site incompatible tissues [110]. Furthermore, the untimely and close succession deaths of three prominent Filipino politicians allegedly receiving animal stem cells and two deaths in the United States within the Regenocyte clinic (possibly from ill-prepared marrow or adipose-derived stem cells) underscore the necessity for IRB-approved studies and adherence to high standards of surgical care [111,112]. In simple words, the extreme novelty of regenerative-based surgeries excuses no one from surgical standard of care.

Wary and skeptical as some countries might be, some have bravely ventured forward with very aggressive plans to rapidly translate ideas to the bedside, but not without rational consideration of additional regulation. A diverse mixture of regulations specifically aimed at monitoring stem cell- and RS-related services has taken on either an American or European influence. For pedagogical purposes, and though tremendously simplified, regulatory differences can be distilled as follows: the FDA perceives the use of regenerative cells as “drugs” and therefore requires federal oversight as stated previously, whereas its European counterpart, the EMEA, defines cell therapy products as clinical products but stipulates specific regulations associated with their use (Directive 2003/63/EC—amending Directive 2001/83/EC). Obviously, there is a difference in opinion as to whether or not use of regenerative material and techniques falls under the purview of medical practice. This philosophic difference of opinion plays out as a recurring theme throughout other countries in similar fashion.

Similarly, surgical training across the world follows a predominantly American, German, or British tradition of education process. Although it is impossible to review all surgical training requirements for each country, the British system, which has served as a model for many other countries, is well developed and documented. Review of the U.K. Foundation Programme Curriculum did not reveal any specific use of the terms “regenerative” or “stem cell” in the F1 and F2 levels of training [113]. However, specialty surgical training does not initiate until ST3 levels and above. The summary on key syllabus modules for ST3 and higher specialty training does carry somewhat generic but relevant language pertinent to RS in that fellows are required to have knowledge and training in “Pathological principles underlying system specific pathology” [114]. The concept of life-long learning to accommodate advances in technology is also embraced in their model of surgical education. However, again there is no precise wording or reference to regenerative medicine/surgery similar to American surgical training documents. The training of regenerative surgical techniques in Europe and most of the world has in large part become the domain of postgraduate medical education conferences and newly formed professional organizations.

Theoretical implications and future developments

To claim that the current generation of surgeons in training is receiving an education completely devoid of regenerative medicine concepts would be erroneous. Although the lack of specific language detailed in residency training documents is concerning and in some ways even distressing, there are several new surgical materials and tools that require a fundamental understanding of regenerative science. Moreover, all surgical training programs have basic science didactic requirements that usually cover the topics of stem cell biology and tissue regeneration in the context of surgical wound healing. However, a lack of precise language could have professional consequences for surgeons.

With changing legislative activity and state medical board regulations, section IV competency requirements are increasingly being used to justify which specialties are more clinically qualified to be legally and professionally allowed to practice a procedure [1]. Also, with advancing technologies, the possibility of interventional and minimally invasive methods of therapy raises the peculiar question as to whether internal medicine specialties might come into the picture with either minimally invasive or parasurgical regenerative techniques. For example, in the near future it will be possible for cells to be induced to form functional hepatocytes that can be injected into the liver instead of whole-organ transplantation [2]. If a physician is needed only for a percutaneous injection, is a surgeon necessarily required to be present or acting as the primary proceduralist? Beyond bone marrow transplant therapy, the notion of interventional hematology–oncology might sound absurd today, but may not be as farfetched when the acceleration of technology is taken into consideration.

To further complicate matters, certification of scientific counterparts will inevitably be needed to fulfill requirements for a comprehensive RS program. Increasingly we are witnessing a growing convergence between gene therapy and regenerative medicine. As more advanced forms of regenerative cellular therapy will rely on greater and more exotic forms of genetic and tissue culture manipulation, a larger role for cellular and molecular biologists (namely, PhDs) as high complex laboratory directors will be necessary. Their role will address quality control issues such as good manufacturing practices, vector transfection, genomic modification, and deep sequencing verification and validation protocols, which usually fall outside the purview of typical surgical training.

Inclusion of the basic scientist or PhD into the RS team would not be a novel concept either, as already there are clinical physicists that work closely with radiation oncologists in calculating dosimetry for various isotope-related therapies. The same can also be said for infertility programs, wherein embryology lab directors (ELD), typically highly trained PhD embryologists, work in conjunction with infertility surgeons by producing and handling high-quality gametes for human therapy. These paramedical and high-level academic experts will require some form of additional certification and training. (At present, ELDs are certified by the American Board of Bioanalysis and clinical physicists are certified by the American Board of Medical Physics, both of which are recognized by state medical boards.) The concept of Alpha laboratory and staff training has been promoted as a reasonable and rational approach met with time-honored success in embryology and infertility and should be looked upon as an initial model for early adoption and route to a certification process for clinical regenerative scientists [3].

Conclusion

In sum, it would be foolhardy to believe that any one surgical specialty or profession should have a monopoly on such a diverse field as RS, although admittedly some of the subspecialties such as transplant surgery hold a greater fundamental of immediate applicable knowledge in the clinical setting to quickly adapt to and monitor rapidly changing therapies and techniques. Transplant surgery typically involves the procurement and transplantation of terminally differentiated tissues. Where common knowledge ends between transplant and RS is the risk pluripotential cells present with tumorigenesis or unintended differentiation of grafts. These unique complications bring forth a valid claim that indeed RS has merits as a new surgical specialty.

As the last medical specialty to gain new recognition has not occurred for over 20 years, there is the real possibility that RS may not be looked upon by the ABMS as a distinct and separate surgical specialty requiring a new certification board. It is the opinion of this author, however, that valid RS training can be obtained presently through appropriate postgraduate medical training. It is the hope of this author that in the near future officially recognized RS training might occur at both the postgraduate and residency level in the form of added certificates of qualification within respective ABMS-recognized specialties. In this way, the interest of public safety and medical education can be addressed simultaneously and within a regulatory and credentialing infrastructure familiar to state medical boards and legislatures.