Why CGT success depends on redefining pharmacovigilance for long-term risk
Cell and gene therapies (CGTs) may offer transformative benefits to patients living with rare and complex diseases and are increasingly being used for more common conditions and a wider patient population. However, their promise of one-time or durable treatments also comes with safety risks that are more complex and longer-term than traditional drugs.
This has led regulatory authorities to adopt a lifecycle-based approach to how they review the benefit-risk profile of CGTs, reflecting both the life-changing potential of these therapies as well as their unique risks and uncertainties.1
For industry, the complex nature of CGTs and the potential for delayed or life-threatening adverse events (AEs) redefine the role of pharmacovigilance (PV). Regulators are also taking a forward-looking approach, which increases the need for PV teams to adapt.
While PV professionals have traditionally been responsible for detecting, assessing, understanding, and seeking to prevent AEs and other drug-related problems, the unique safety challenges of CGTs and how regulators are now approaching CGTs mean PV teams must adapt and, as a result, become a core driver of a product’s value throughout its lifecycle.
In this article, we explore the risks specific to CGTs and what they mean for signal detection, how the health authorities have responded, and what the pharmacovigilance role needs to look like to ensure the continued success of these transformative products.
Assessing and managing adverse events with CGTs
Industry and regulators are accustomed to assessing and managing AEs from small molecules, which are typically dose-dependent and generally reversible, or from biologics, where AEs are often driven by immune responses or manufacturing variability.2
CGTs fundamentally change the way we think about PV. They shift the benefit-risk conversation toward acute high-severity events, delayed irreversible risks, and long-term uncertainty (see Table).
Table: The Early and Long-Term Risks of CGTs
| Acute high-severity events | Delayed risks | Issues causing long-term uncertainty |
|---|---|---|
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|
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Acute high-severity events
Early phase risks are a concern for CGTs, particularly for cell therapies like CAR-T, and can include Cytokine Release Syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).3,4 These are often experienced within two weeks of administration and are driven by strong immune activation and can range from mild flu-like symptoms to severe, life-threatening complications. Patients may also experience prolonged cytopenias and infections,5 reflecting both the therapy’s mechanism and its impact on the immune system.
Delayed risks
In the longer-term, the risk profile shifts – particularly for gene therapies. One major concern is hepatotoxicity, a sign of immune-mediated liver inflammation post-treatment.6 Symptoms may arise several weeks to months after administration and can be life-threatening.
Rarer risks include thrombotic microangiopathy (TMA) and secondary malignancies linked to insertional oncogenesis7 – particularly stemming from viral vector-mediated transgene insertion. Insertional oncogenesis is an off-target effect where altered gene regulation can contribute to tumor formation.8 These secondary malignancies are new, independent cancers that develop after treatment. In some reported CAR T cases, T-cell malignancies, including lymphomas or leukemias, have contained the engineered CAR transgene.7
Another example of long-term risk is that of durability of effect: a therapeutic transgene can be lost over time depending on the molecular mechanism of the gene therapy.9 Loss of transgene expression may mean the patient no longer receives therapeutic benefit. For AAV-based therapies, anti-vector immune responses can limit readministration of the same vector.
These delayed risk factors have led health authorities to require follow-up periods of up to 15 years for high-risk systems.10
Issues causing long-term uncertainty
There are also other issues across CGTs that are a source of uncertainty. One concern is the risk of immunogenicity. Patients may experience immune responses against modified cells, leading to loss of efficacy – especially in allogeneic, or donor-derived, products.11
With gene editing therapies, one area that requires vigilance is the potential for unintended off-target changes to DNA.12,13 This has led the FDA to issue draft guidance recommending next-generation sequencing studies to evaluate the off-target editing risk and to report findings to the agency.14
How CGT risks change signal detection
The risk factors associated with CGTs require a fundamental shift in how PV teams monitor safety signals. These risks and uncertainties put the onus on PV teams to change how they monitor safety signals – from quickly responding to acute AEs to conducting long-term risk management assessments for any permanent adverse changes in the body. Across all these modalities, several areas require ongoing monitoring. These include how long the therapeutic effect persists, whether immune responses develop over time, and whether there are risks of germline transmission15 — where vector or genetic material is unintentionally transferred to reproductive cells and could affect genetic material passed to offspring — or delayed inflammation.
Managing signal detection for these products, however, is complicated by structural and scientific limitations in the data. Typically, CGTs have been used in very small patient populations, often in rare diseases, which limits statistical power and makes it difficult to apply standard quantitative tools like disproportionality analyses.
Additionally, patients and treatments are highly heterogeneous, and differences in disease severity, prior therapies, and even procedural variability introduce significant noise into the data.
Compounding this, many important safety signals have long latency periods, meaning adverse events may not appear until months or years later. These signals can also be difficult to distinguish from underlying disease progression or procedural complications, further obscuring causality.
Other factors confound data interpretation, including the fact that patients heavily exposed to chemotherapy before CAR T are more likely to develop secondary malignancies. Additionally, a phenomenon known as genomic instability makes some patients more prone to secondary malignancies, with or without CAR T.16
Understanding health authority expectations for CGT safety
The immediate and potential long-term risks – as well as uncertainty – that CGTs present are well understood by the health authorities, which have responded by introducing modality-specific guidance,17 enhanced post-authorization oversight, long-term follow-up requirements, and mandatory risk management plans. Both the FDA and the EMA have sought to balance transformative potential with inherent uncertainty by adopting a lifecycle-based approach to benefit-risk assessment of CGTs.
Health authority tools for managing the CGT risk-benefit profile
To manage the specific benefit-risk that CGTs therapies present, health authorities leverage several established tools.
- Long-term follow-up studies to monitor delayed effects: For example, the FDA has advised sponsors of gene therapy products to observe subjects for delayed AEs for as long as 15 years, including a minimum of five years of annual examinations followed by 10 years of annual queries of subjects.18
- Patient registries and real-world evidence (RWE) to capture longitudinal outcomes: Unlike traditional products, where spontaneous reporting dominates, advanced therapies rely heavily on patient registries and continuous engagement. These registries often become the primary mechanism for detecting safety signals, reassessing benefit-risk, understanding durability over time, and informing regulatory guidance.7
- Risk management frameworks tailored to a product’s mechanism of action: Risk management plans (RMPs) support long-term safety characterization through planned pharmacovigilance activities, studies, and risk-minimization measures. FDA risk evaluation and mitigation strategies (REMS) are required only when needed to manage specific serious risks.7
- Patient-level traceability to ensure each treated individual can be followed over time: Because CGTs are typically used in small, highly selected populations and are often administered once, with potentially permanent effects, safety monitoring must shift to individual patient-level traceability, requiring a much deeper, longitudinal understanding of each patient’s journey.19
While there are some differences between EMA’s more formalized approach to follow-up studies and RMPs and the FDA’s more flexible approach, both agencies generally adopt a different mindset toward CGTs than toward small molecules and biologics. They accept some uncertainty upfront, particularly in serious or rare diseases with unmet needs. The expectation, however, is for rigorous risk management after approval, supported by ongoing data collection and reassessment. Additionally, because the clinical benefits of CGTs may also be delayed as compared with small molecules or biologics, regulators emphasize the importance of long-term follow-up through extended observation periods.17
As more patients are treated and new data expand knowledge of a product class, regulators expect concomitant updates to labeling, safety measures, and overall benefit-risk conclusions. This places the PV role in the spotlight – shifting it from a compliance requirement to a strategic capability central to the long-term success of a CGT.
Redefining the role of PV early on and across the CGT lifecycle
Given their complex safety and benefit profiles – and the long-term follow-up approach regulators are taking – CGTs require that pharmacovigilance be redefined well beyond its traditional role of collecting and reporting adverse events after approval. In this more intricate environment, PV should be embedded early to support patient safety, regulatory trust, and long-term asset value. With this broader role, pharmacovigilance can become recognized as a core driver for long-term CGT success.
Traditional PV already includes detection, assessment, understanding, and prevention of medicine-related problems. With CGTs, PV teams need longer follow-up, deeper biological interpretation, and more individualized safety monitoring. Unlike traditional small molecules or monoclonal antibodies, CGTs often require biological processes such as cellular engraftment, durable gene expression, and downstream pathway modification. This uncertainty further emphasizes the crucial strategic role that PV plays in contextualizing the benefit-risk assessment at early timepoints together with long-term follow-up.20
It is therefore vital that patient lifecycle stewardship be embedded in safety plans, meaning that safety monitoring extends well beyond post-marketing, when uncertainty is highest. In these safety plans, PV teams must proactively manage delayed signals, irreversible effects, and limited clinical datasets. They must ensure data continuity across life stages, for example, as patients move from pediatric to adult care.
What embedded PV means for CGT companies
That means planning for sustained PV funding — even beyond the product's commercial lifecycle. It means investing in robust PV processes that enable companies to respond quickly to emerging AEs, a crucial requirement for both patient safety and regulatory compliance.7
This model also requires long-term accountability, often spanning decades. Companies must build systems that support ongoing data generation through patient registries, RWE, and sustained patient engagement, ensuring that safety and effectiveness are continuously understood.
There is potential to leverage digital solutions to support the PV role, including advanced analytics and artificial intelligence (AI) tools. These technologies can help identify subtle patterns in small, fragmented datasets and integrate diverse data sources such as registries and literature. However, they are positioned as complements to – not replacements for – scientific and clinical judgment.
In addition to embedding early, the PV analytical approach needs to change. Rather than rely on traditional quantitative methods to detect and interpret safety data, CGTs should rely on expert-led, qualitative assessment. In practice, this means medically trained safety experts must actively review individual cases in depth – looking at clinical context, biological plausibility, timing of events, and patterns across small numbers of patients to form a more holistic view of potential risk.
PV teams at CGT companies must, therefore, understand vector biology, patterns of immune response, and potential differences in AEs across similar therapies, as well as distinguish treatment-related effects from disease progression or procedural complications.
Another important change PV teams should undertake is to think beyond individual products. PV teams must actively monitor class effects and emerging scientific knowledge, adapting safety strategies for their products as the field evolves.
Conclusion
CGTs are transforming medicine, and with that ambition comes new risks and a changed regulatory approach. To realize their potential, it is incumbent on companies to manage patient safety through continuous, long-term follow-up to fully understand benefit-risk over time and to be ready for increased regulatory scrutiny.
Pharmacovigilance must become far more than an operational function. Companies should recognize PV as a central pillar of value preservation and a source of innovation across the product lifecycle. It must be accepted as a scientific discipline, grounded in biology and clinical interpretation; as a strategic asset that can help shape development and access decisions; and as core to ensuring CGTs deliver on their promise safely over the long term.
