Committee Spotlight: ISCT Ethics of Cell and Gene Therapy

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Hind Al Belushi BSC, Mres, PhD
Senior specialist, advanced cell and gene therapy
Royal Hospital
Muscat, Sultanate of Oman

Overview of Committee and Scope
The ISCT Committee on the Ethics of Cell and Gene Therapy (ECGT)1 was founded in 2013. It was formerly known as the ISCT Presidential Task Force on the Use of Unproven and/or Unethical Cell and Gene Therapies. The committee was initially focused on characterising unethical and unproven direct-to-consumer businesses offering cell and gene therapy interventions. The name was changed recently as a reflection of an expanded scope to cover all ethical aspects of the ever-expanding cell and gene therapy field and industry. We work closely with the ISCT executive team and other ISCT committees to promote the ethical use of safe and effective cell- and gene-based products worldwide. Our team is on a mission to identify key ethical issues associated with the development, regulatory authorization, marketing, and distribution of cell and gene therapies. The committee is comprised of selected expertise across various domains of the field that include bioethics, regulatory science, public policy, and basic and clinical research. This structure helps bringing broad range of perspectives to help cover as many facets of cell and gene therapies industry. The ECGT committee is currently Chaired by Dr. Laertis Ikonomou (University at Buffalo, The State University of New York) and Dr. Patti Zettler (Ohio State University), and Vice Chairs: Dr. Daniel Weiss (University of Vermont Burlington VT United States) as Vice-Chair Science, Karen Nichols, Esq. Vertex Pharmaceutical Cambridge, MA. United States as Vice Chair Regulatory, Dr. Aaron Levine, (Georgia Tech Atlanta, GA United States) as Vice-Chair Bioethics), Dr. Miguel Forte, (AdBio Brussels, Belgium) as Vice-Chair, Industry).

New Members’ Guide
The ECGT Committee has sought to achieve its mission and goals through several means. For example: by establishing formal collaborative relationships with regulatory agencies, other professional societies, patient organizations, and industry stakeholders. The team continually surveys the field for relevant/major ethical and scientific issues that must be acted on, then actively work with the relevant stakeholders in implementation of necessary actions to promote the ethical development of cell and gene therapies. Another strategy is to work on developing and dissemination of educational resources using all available ISCT communications platforms, such as webinars, guidance documents, and peer reviewed articles and position statements. These resources provide tools to stakeholders that help them in evaluating a potential cell and/or gene therapy-based treatment. One of the main documents that was developed by the ECGT was the ISCT landmark reference guide (“Talking about unproven cell-based interventions”, 2015)2 that was translated to many languages. Additionally, the ECGT has undertaken to publish an updated cell and gene therapy marketing authorization report biennially. Moreover, the ECGT was the main force behind the creation and adoption of the ISCT member pledge which emphasizes the importance of member’s alignment to the ethical practices of cell and gene therapy research and interventions. Another important role the ECGT team plays is to assist with the planning of the ISCT annual meeting scientific program through organizing roundtable sessions that reflect the mission and current initiatives of the Committee. Furthermore, we focus on promoting rigorous research, appropriate clinical investigation, and application of ethical, equitable access to cell- and gene-based therapies.

Google’s Updated Advertising Policy for Speculative Medicine and Experimental Treatments
The ECGT committee strongly supports developing policies that address the spread of exploitative unproven and/or unethical cell and gene therapies. Companies managing online platforms are key players that can support these efforts to limit the spread of misinformation and prevent clinics from advertising unlicensed and unproven CGT products on their platforms. Many rogue stem cell clinics offering scientifically unproven interventions rely on aggressive marketing primarily through patient testimonials and online information that is often scientifically incorrect and exaggerated. These interventions have resulted in physical, emotional and financial harm to many vulnerable patients. In 2019 Google took a positive step supporting the international move against ads selling unproven therapies and introduced a policy that bans advertising unproven stem cell, cellular and gene therapies3. The ISCT and its allies have strongly applauded this step. Moreover, the ISCT has provided consultation and linked the Google leadership team to a consortium of scientific and patient organizations including World Marrow Donor Association (WDMA), European society for blood and marrow transplantation (EBMT), German Bone Marrow Donor Centre (DKMS) and Anthony Nolan, to discuss the impact of this policy and collaboration to develop it further. In July 2022, Google updated its policy to only permit the promotion of FDA-licensed cell and gene therapies in the United States. However, the updated policy also allows the advertisement of cell and gene therapies that are exclusively educational or informational in nature regardless of their regulatory approval status. In response to this update, the ISCT/ECGT has undertaken an initiative of building a coalition of 21 international organisations to present to Google, to address the misapplication of their updated policy on advertising speculative and experimental cell and gene therapies. The updated policy includes significant loopholes that can be exploited by unscrupulous stem cell clinics seeking to profit from the complexity of the regenerative medicine field. Reports from legitimate providers showed that advertisements for certain proven and effective legitimate therapies have been inadvertently disqualified under this policy. For example, the policy has indiscriminately restricted the WMDA by blocking advertisements recruiting bone marrow and stem cell donors for legitimate stem cell transplant programs and for patients in need. Moreover, ISCT and allies are concerned that companies marketing unproven therapies will adapt their marketing strategies to disguise their offers as educational materials that are permissive under the new Google policy and ultimately drive consumer interest to unproven therapies. These gaps represent a threat of harm to users, and the ISCT is leading this initiative, with its supporting organizations, to offer their broad spectrum of expertise to collaborate with Google in finding solutions to further evolve this policy and improve public knowledge regarding stem cell research.

ISCT/ECGT Issues Response to US Federal Judge Ruling on FDA Regulation of Cell and Gene Therapies
The ISCT/ECGT had issued an initial response4 in September 2022 and raised concerns with regards to US federal court ruling (August 2022) in favour of the California Stem Cell Centre, Inc and the Cell Surgical Network corporation, in a lawsuit brought by the US FDA. In 2018 the FDA had taken legal action seeking permanent injunctions to stop these clinics from marketing unproven autologous stromal vascular fractions (SVF) and culture expanded mesenchymal stromal cells (MSC) that were classified by FDA as new drugs (351 HCT/Ps) but that are lacking the FDA pre-marketing authorisation. Moreover, deviations from current good manufacturing practices were also reported in these centres. The court sided with the defendants claims and declared that the products they offer (SVF and culture expanded MSC) do not fall under the FDA’s jurisdiction and are exempted from FDA pre-marketing approval. The ISCT/ECGT committee indicated that the ruling is flawed and was based on several unfounded and scientifically inaccurate statements and interpretations4,5. Firstly, the ruling mischaracterised SVF as non-drug, being naturally circulating, unaltered biological entity that is simply relocated (within same surgical procedure) from adipose tissue to other diseased parts of the body by surgical means. Secondly, the statement that the defendants used FDA-authorized devices to produce autologous stem cell interventions, does not take into account that the devices may have not been authorized by the FDA, or authorized for other purposes and not the production of stem cell therapies. Thirdly, the statement that culture-expanded MSC should not be regulated as drugs conflicts with scientific evidence. The committee expressed concerns that the scientific inaccuracies in the ruling may have impacted the judge’s decision.

The outcome of this case will have negative consequences and impacts on the cell and gene therapy (CGT) field by creating regulatory uncertainties in the CGT market and a further platform for unscrupulous stem cell businesses offering unproven cellular therapies with potential risks to vulnerable patients. Moreover, the decision contradicts not only current scientific evidence, but also past rulings that have taken FDA’s position on the same treatments in question. In addition, the court decision may undermine the FDA and scientific community efforts to enforce standards against unapproved regenerative medicines. While this ruling was a setback for the CGT field in promoting ethical clinical translation and practice worldwide, it highlighted the need to actively work in developing informative resources that establish scientific consensus, standards, and best practices for all stakeholders.

ISCT webinar (End of FDA Enforcement Discretion Period and its Implications)
The world is witnessing the emergence and development of new technologies and innovative therapies based on cells, tissues, and tissue-based products with promising therapeutics applications that could revolutionise the face of medicine. However, to date relatively few products have been approved by the US FDA. Parallel to this, there is a growing market of biological therapies that lack scientific evidence and are offered by for-profit clinics outside the regulatory framework. This is a global challenge that poses risk to public health and may jeopardize the development of legitimate innovative therapies. In response to this, the FDA had enacted a regulatory policy framework for regenerative medicine (including human cell, tissue, and cellular and tissue-based products (HCT/Ps)6 in 2019 which included a 3-year period of enforcement discretion to give HCT/P manufacturers and providers the time to seek premarket approval and bring their practices into compliance with formal regulatory requirements. The enforcement discretion period ended on May 2021 after a six-month extension period in response to the Covid-19 pandemic, and has generated significant concern with respect to implications on regenerative medicine worldwide especially with the growing industry of direct to-consumer stem cell therapies. Moreover, many questions remain as to the future approaches that will be adopted by the FDA and other stakeholders to support HCT/P compliance and enforcement activities.

In light of this, the ECGT has participated in and shared its views and recommendations in an FDA-sponsored session on the end of enforcement discretion held on April 13, 2021. The ECGT subsequently organised and hosted a webinar8 to discuss the end of the FDA enforcement discretion period and its implications on direct-to consumer business market. The session was held on 17th June 2021 and was chaired by Dr Laertis Ikonomou (Chair ISCT ECGT). The panel of invited speakers included, Dr. Wilson Bryan (Director of the Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research (CBER), FDA), Dr. Virginia Lyons (Vermont state senator), Dr Michael Lehmicke (Senior Director, Alliance for Regenerative Medicine (ARM)) and Dr Leigh Turner (Professor in the Department of Health, Society, and Behavior at UC Irvine).

Dr. Bryan presented a lecture about the regulations of human HCT/Ps in the context of the end of the enforcement discretion. Dr. Bryan highlighted that there was an encouraging trending increase of investigational new drug applications (INDs) of both research IND, and expanded access IND during the period of enforcement discretion.

In the second part of the webinar Senator Lyons presented the newly enacted Vermont law on stem cell clinics regulating rogue stem cell clinics offering unapproved cellular interventions. The law was officially signed by the Vermont Governor on June 2021 and parallels recent legislation passed in California and Washington State. She stressed that the key for their success lay in the strong collaborative work and support from a coalition of professional groups including the Vermont State Medical Practice, Ethics, and Licensing boards along with the State District Attorney and Department of Justice offices, each contributing within their scope of expertise, as well as on building on evidenced based policies.

In the third part of the webinar, Dr Lehmicke, presented the industry perspective with regards to end of FDA enforcement discretion. Dr Lehmicke expressed in his perspective that the greatest impact will be on stem cell clinics offering unproven interventions. He concluded his talk highlighting the need for the FDA to step up activities against unscrupulous stem cell clinics as well as working to update and provide additional guideline documents for stakeholders to ensure safe effective development of regenerative therapies.

In the last part of the webinar, Dr. Turner presented about end of enforcement discretion in the context of the substantial booming of businesses selling unapproved stem cell interventions. Dr Turner argued that corporate self-determination of the regulatory status of their products, with the FDA focusing its regulatory oversight only on higher-risk interventions, is not the ideal strategy to manage this challenge. He explained that this strategy will end up encouraging more unscrupulous actors misclassifying their products and entering the market to seize the opportunity of making more profit with an unlikely chance of getting a prompt or significant response from FDA.

The webinar was concluded by an overall agreement that the era after FDA enforcement discretion will need more coordinated and collaborative efforts from all entities that play a role in the field to foster responsible and flexible regulation that can leverage the potential of regenerative therapies to advance public health as well as highlighting the critical role of promoting public education through a wide range of media platforms.

As the field of cell and gene therapy continues to evolve, complex ethical, scientific, and social challenges will continue to emerge. The ISCT ECGT Committee will continue its role in promoting the ethical use of safe and effective cell- and gene-based products worldwide. The ECGT future plans will continue collaborative initiatives with other scientific/medical and professional organizations and regulatory bodies on issues of regulatory convergence, enforcement of current regulations, and public education. It will also maintain a steady output of educational resources (webinars, peer-reviewed articles, and guides) and will promote increasing outreach to patient advocacy groups and patient foundations.

More information regarding the ECGT committee and upcoming activities is located on the ISCT Committee website.¹

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