Guest Column | August 9, 2023

Navigating Expanded Access For Experimental Cell & Gene Therapies

By Laertis Ikonomou, University at Buffalo, The State University of New York

Captain on ship-GettyImages-1266553964

The field of cell and gene therapies (CGTs) is in steady growth. Tens of CGT products have received marketing authorization in various countries and regions, such as the European Union, the United States, Japan, South Korea, and Australia,1,2 and hundreds of clinical trials in the CGT sector are currently underway.3 Importantly, potentially curative gene therapies for rare monogenic diseases, including CRISPR-based gene editing therapies, have either been approved or are awaiting regulatory decisions. This CGT landscape has justifiably renewed patient interest in and amplified debates about access to novel cell and gene therapeutic approaches. While CGT products are regulated as drugs in most regulatory jurisdictions and considered experimental until safety and efficacy are clearly demonstrated (mostly in the context of randomized clinical trials), there are mechanisms of non-trial access to such products.

One mechanism is the U.S. FDA’s expanded access pathway that permits developers to distribute experimental drugs, including CGTs, to patients with no available therapeutic options who are also ineligible to participate in relevant clinical trials. While FDA had experimented with various forms of non-trial access, mainly for cancer or HIV patients, from the 1970s on, expanded access was formally established in 1987.4

Expanded access requests can be placed by treating physicians, and the vast majority are allowed to proceed by the FDA. For individual patients, there may be charges related to the preparation of the CGT product. It should be emphasized, though, that eventual access to experimental drugs, including CGTs, is at the discretion of the product manufacturer. While expanded access can be a useful mechanism for compassionate use of experimental CGTs, there is a host of potential issues that are bound to emerge as an increasing number of such interventions enter clinical trials and patient awareness of experimental CGTs increases.

ISCT Identifies Potential Issues With Expanded Access To CGT Products

Identifying potential risks with the expanded access pathway, the International Society for Cell & Gene Therapy (ISCT) established the Expanded Access Working Group (EAWG), a subset of the Committee on the Ethics of Cell and Gene Therapy. Comprising scientific, regulatory, and ethical experts, the EAWG aims to address practical, ethical, and regulatory issues related to the use and potential misuse of the expanded access pathway to educate and protect the safety of patients worldwide. In May 2023, the EAWG published a short report, The Future of Expanded Access to Unapproved Cell and Gene Therapies,5 acknowledging that while non-trial pre-approval access can serve as an appropriate route for seriously and terminally ill patients to obtain investigational cell- and gene-based interventions, there are three areas of concern.

  1. There is an inherent tension between CGT clinical trials that are centered on knowledge generation and establishment of treatment safety and efficacy and expanded access that is clearly focused on patient access to experimental treatments. This issue can be particularly accentuated in expanded access treatment programs that are designed for large groups of patients (although it should be noted that at present most expanded access protocols submitted at the FDA Center for Biologics Evaluation and Research (CBER) have been for single patient treatment6). As discussed below, striking the right balance between non-trial compassionate access to experimental treatments, evidence generation, and unimpeded conduct of clinical trials will be critical for the success of future CGT products.
  2. Cell and gene therapy developers may be tempted to use expanded access as a mechanism for premature commercialization of CGTs before a biologics license application (BLA) has been approved. This may lead to situations where experimental CGTs offered through expanded access are akin to products offered by direct-to-consumer businesses with all too familiar ethical issues, such as exaggerated marketing, exorbitant fees without clear demonstration of product safety and efficacy, and exploitation of vulnerable patient populations, including pediatric patients.
  3. The specter of unequitable access to experimental CGTs should not be taken lightly. There is a risk that patients with higher socioeconomic status will be more successful in navigating non-trial access to experimental CGTs and in raising funds to cover the cost of such products through crowdfunding campaigns.7,8 Moreover, well-organized and funded patient groups may engage in pressure campaigns, through successful engagement of the public and the press, for non-trial access to products for specific conditions, exacerbating inequalities in CGT access.

Where Do We Go From Here? Recommendations For CGT Developers

Proactive engagement with emerging bioethical issues in expanded access for experimental CGTs is critical and necessary. CGT developers can play an important, positive role in safeguarding the integrity of expanded access.

Although expanded access has been created mostly as a mechanism for treatment of patients with few or no therapeutic options, data generation on safety and efficacy in an ethical manner is still possible.9 Collection of patient data following provision of experimental CGTs through expanded access will require proper informed consent and coordination of CGT developers with treating physicians. These data can be structured and offered through publicly available registries and/or supplement regulatory submissions with the understanding that they do not offer the same level of evidence as randomized, blinded clinical trials.

Developers should also avoid the use of expanded access as a way to circumvent clinical trials (especially Phase 2 and 3 trials) and/or as a means of monetizing experimental CGTs. This can be achieved in part through transparency over costs for expanded access products, especially for intermediate and large treatment groups. This is particularly important in the case of clinical trials that fail to reach primary efficacy outcomes. CGT developers also can alleviate the risk of premature commercialization through non-trial access by accurately describing the risk-benefit ratio of their experimental CGTs and by avoiding the generation of unrealistic expectations in patients and their loved ones.

Expanded access will remain an important mechanism for non-trial access to experimental CGTs for seriously ill patients with few options. Its judicious use, and acknowledgment of its benefits and limitations, is now more vital than ever. ISCT and the EAWG will continue to work to identify potential ethical issues and educate both the public and the sector on expanded access. In the coming year, the EAWG will publish an expanded report developing a set of guidelines based on accessibility and equity for CGT stakeholders to help ensure that the use of expanded access serves the interests of patients and benefits the field. 

References

  1. Ramezankhani, R., et al., Two Decades of Global Progress in Authorized Advanced Therapy Medicinal Products: An Emerging Revolution in Therapeutic Strategies. Frontiers in Cell and Developmental Biology, 2020. 8: p. 547653.
  2. Cuende, N., et al., Cell, tissue and gene products with marketing authorization in 2018 worldwide. Cytotherapy, 2018. 20(11): p. 1401-1413.
  3. Alliance for Regenerative Medicine, Q4 2022 Data-Clinical Trials. 2023 [cited 2023 June 9]; Available from: https://alliancerm.org/wp-content/uploads/2023/03/Clinical-Trials-2022-Q4-20230328.pdf.
  4. Food & Drug Administration, Expanded Access to Experimental Biologics. 2019 September 16 [cited 2023 June 27]; Available from: https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/expanded-access-experimental-biologics.
  5. Zettler, P.J., et al., An International Society for Cell & Gene Therapy working group short report on the future of expanded access to unapproved cell and gene therapies. Cytotherapy, 2023. 25(7): p. 712-717.
  6. Food & Drug Administration, Expanded Access (Compassionate Use) Submission Data. 2023 May 17 [cited 2023 June 27]; Available from: https://www.fda.gov/news-events/expanded-access/expanded-access-compassionate-use-submission-data.
  7. Snyder, J., et al., Appealing to the crowd: ethical justifications in Canadian medical crowdfunding campaigns. Journal of Medical Ethics, 2017. 43(6): p. 364-367.
  8. Snyder, J., L. Turner, and V.A. Crooks, Crowdfunding for Unproven Stem Cell-Based Interventions. Jama-Journal of the American Medical Association, 2018. 319(18): p. 1935-1936.
  9. Polak, T.B. and H.F. Lynch, The Ethics of Expanded Access Research. Jama-Journal of the American Medical Association, 2023. 329(13): p. 1057-1058.

About The Author:

Laertis Ikonomou is an associate professor in the Department of Oral Biology, University at Buffalo, The State University of New York. His major research interests are in the areas of pluripotent stem cell biology, developmental biology, and stem cell engineering, with emphasis on foregut and neural crest in vivo biology and its applications in directed differentiation of pluripotent stem cells. In addition to his research, Ikonomou has been involved since 2013 in education and information activities regarding unproven and unregulated cell- and gene-based interventions as a member of the American Thoracic Society (ATS) Stem Cell Working Group and the International Society for Cell & Gene Therapy (ISCT) Committee on the Ethics of Cell and Gene Therapy (ECGT). He is the immediate past chair of the ISCT ECGT.