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Ethical Debate Continues Over Access to Investigational Cell- and Gene-Based Interventions
July 1, 2025 6 minutes read
By Stacey Kusterbeck
Some patients with serious or life-threatening conditions have expanded access (outside of clinical trials) to investigational cell- and gene-based interventions. However, there are continued ethical concerns, both ongoing and new, as the field rapidly evolves. “Early access to gene therapies can be challenging because a lot of gene therapies are ‘one and done;’ that is, it is a single, irreversible treatment,” says Lindsay McNair, MD, MPH, principal consultant at Equipoise Consulting. Clinical trials are designed with close oversight to gather all the information about the safety, efficacy, and feasibility of treatments. Expanded access does not include the same guardrails and close monitoring.
To qualify for expanded access, there are criteria to meet. Typically, an individual must have a disease in which there is no standard alternative known to be effective, with a serious disorder that is degenerative or even fatal. “As a result, there are people who can’t qualify for expanded access, so there’s always been agitation about it,” says R. Alta Charo, JD, the Knowles professor emerita of law & bioethics at University of Wisconsin-Madison.
In May 2025, Montana adopted legislation that presumably would give physicians the ability to be licensed by the state and offer unapproved therapies that have only been through Phase I trials.1 “It really is a complete challenge to federal authority, by saying that the state can license doctors to do something that is not allowed by federal law, absent the FDA (U.S. Food and Drug Administration) giving you approval for the expanded access option. It has not gotten a lot of coverage. I don’t know how much effect it will actually have, because companies still have to provide the therapies, and there are a lot of reasons why companies don’t want to provide things outside of a clinical trial,” says Charo. If an individual is seeking treatment outside of a clinical trial, it often is because they have comorbidities or that their conditions are too complex to meet eligibility criteria. Such individuals are likely to have adverse events or fail to respond to the treatment being studied. “That provides bad data points that must be shared with the FDA, which can make the drug look bad when it otherwise would be approvable,” says Charo.
Another recent controversial development: A company advertising a cruise ship as “the world’s first stem cell-based hospital,” offering unapproved cell and gene therapy in international waters.2 “It presents itself as a way for people to get access to futuristic medicine, without any regulatory oversight that ensures it actually will work,” says Charo.
It remains to be seen how these new developments will evolve, but the ethical debate over expanded access continues. “As far as the ethical considerations, I understand the debate around personal autonomy and willingness to take a risk. That makes sense if people understand actually what the risk is and what the probability of success is. The problem is that these therapies are beyond typical levels of comprehension,” says Charo.
There are many previous cases of treatments that initially appeared to be effective but actually were not. Sometimes the way the treatment was tested was not rigorous enough to include conflating variables, or researchers found things that were correlated but were not causally related. “Even sophisticated reviewers can be misled by what they think they are seeing by way of evidence. The personal autonomy argument is premised on the idea that people understand what they are choosing and have the right to make the choice. I question whether that understanding is really present. That’s why you want expert reviewers who can bridge that gap,” says Charo.
Clinicians and researchers face continued ethical challenges in balancing access and oversight. There now is a new resource to guide them in using ethical frameworks and equitable practices. The International Society for Cell & Gene Therapy (ISCT) developed a position statement to address the growing ethical and logistical challenges of providing investigational cell/gene therapies through expanded access pathways.3 “With rapid scientific advancements and increasing patient demand for these potentially curative therapies, the paper aims to guide clinicians, researchers, and policymakers in balancing therapeutic access with patient safety and research integrity,” says Bruce Levine, PhD, chair of the ISCT’s Ethics in Cell and Gene Therapy committee and one of the senior authors on the paper. Some key ethical considerations:
Equitable allocation. There is a need for clinicians to ensure access is not influenced by income, nationality, race, or other sociodemographic factors. “Geographic and logistical barriers pose particular challenges for bespoke therapies requiring specialized facilities,” says Levine. Physicians at large academic institutions likely have more awareness of the expanded access pathway than physicians at smaller community centers or rural practices. All physicians should be familiar with cell and gene therapy advances, approved treatments, and current clinical trials to effectively counsel patients on these options, argue the authors.
Transparency in resource allocation. “Companies must clearly communicate how limited manufacturing capacity or clinical trial priorities might restrict access,” says Levine.
Informed consent complexities. “Patients must understand that these therapies are unproven,” underscores Levine. In particular, patients should know that the investigational therapy has not been approved for the patient’s condition — and also that its safety and effectiveness has not been established. Patients also must know if they receive a treatment through expanded access, it could mean they are disqualified from future clinical trials or precluded from receiving an alternative treatment that might become available in the future. For instance, if patients receive a gene-editing treatment, this could be an exclusion criterion for a future gene-editing therapy.
Clinicians need to help patients to distinguish between FDA-regulated expanded access, which has a 99% approval rate, and less-regulated right-to-try pathways. “Clinicians must protect clinical trial integrity while addressing urgent patient needs,” says Levine. Clinicians are ethically obligated to communicate transparently with patients. This entails avoiding terms such as “medicine,” “therapy,” or “treatment” that imply established efficacy and certainty about benefits.
Clinicians also must be upfront with patients about logistical and financial burdens, such as travel requirements and time commitment. Other nonmedical consequences might include loss of earnings for patients or family members during treatment and the cost of services such as home help, childcare, or transportation. Some therapies require patients to be within 30 minutes of the treatment center for weeks after receiving an infusion. That might be an insurmountable burden for patients who live far away.
There are additional ethical concerns for pediatric patients, who are unable to make their own decisions about whether to use an unproven investigational therapy, according to the position statement. Parents or caregivers often face an extremely difficult decision when weighing the risk of receiving the therapy against the risk of delaying or forgoing the treatment.
“There is a need to design pathways that are accessible to diverse patient populations,” adds Levine. Researchers must address barriers such as geographic limitations to specialized treatment centers. For informed consent processes, researchers must consider language and cultural differences.
Given that clinicians are facing multiple ethical complexities, ethics consultations can be helpful in these situations, says Levine:
- Cases in which conflicts arise between what the patient or family demands and clinical reality;
- Cases in which clinicians question how to allocate scarce resources between trial participants and expanded access patients;
- Pediatric cases where parents are struggling with high-stakes decisions about unproven therapies.
Ethicists also can help to address ethics concerns involving expanded access to cell and gene therapies at their institutions. Levine offers these examples:
- Ethicists can help to develop standardized expanded access policies.
- Ethicists can create educational programs about non-trial access pathways.
- Ethicists can help to establish independent review boards for allocation decisions.
- Ethicists can help to implement monitoring systems for adverse outcomes.
“Ethical expanded access requires coordinated efforts between clinicians, manufacturers, and institutions to prevent exploitation of vulnerable populations while advancing transformative therapies,” concludes Levine.
Stacey Kusterbeck is an award-winning contributing author for Relias. She has more than 20 years of medical journalism experience and greatly enjoys keeping on top of constant changes in the healthcare field.
References
1. LegiScan. Montana Senate Bill 535. Revise laws related to experimental treatments. Passed May 16, 2025. https://legiscan.com/MT/text/SB535/2025
2. Helixa Cruises. https://www.helixacruises.com
3. Maryamchik E, Ikonomou L, Roxland BE, et al. International Society for Cell & Gene Therapy Expanded Access Working Group position paper: Key considerations to support equitable and ethical expanded access to investigational cell- and gene-based interventions. Cytotherapy. 2025; Feb 7. doi: 10.1016/j.jcyt.2025.01.016. [Online ahead of print].
Expanded access to unapproved gene and cell therapies raises ethical concerns around safety, informed consent, fairness, and regulatory compliance. Ethicists help balance compassionate access with clinical oversight, protecting vulnerable populations amid rapidly advancing science.
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