Lessons from long-term follow-up of gene and cell therapies approved in the EU
Gene and cell therapies (GCTs) offer transformative potential for patients with rare and complex diseases, yet their long-term safety and efficacy remain under close regulatory scrutiny. In the European Union (EU), mandated long-term follow-up (LTFU) studies form a key component of post-marketing requirements, ensuring outcomes are monitored over extended periods. Understanding how these studies are designed is essential for researchers and developers planning future therapies, as it informs regulatory strategy and evidence generation approaches.
In this interview, Nahila Justo (Executive Director, PPD Evidera Real-World Data and Scientific Solutions, Thermo Fisher Scientific) discusses the research “Mandated long-term follow-up studies of patients treated with gene and cell therapies approved in the European Union (EU): An analysis of commonalities and variations” presented at the 2025 ISPE Annual Meeting, highlighting key trends, methodological insights, and implications for advancing long-term evidence generation.
To start, could you set the context for this research presented at the 2025 ISPE Annual Meeting? What prompted your focus on mandated LTFU studies for GCTs approved in the EU?
The impetus for this research stemmed from the increasing use of real-world data (RWD) and existing registries in LTFU studies for GCTs. Sponsors face uncertainty in designing and planning post-authorization studies due to a complex and evolving array of regulations and guidances that are open to interpretation. As a leading global CRO, we aim to understand the complexities of overlapping normative frameworks and anticipate trends, to support sponsors to optimise design and execution of LTFU evidence generation activities that reduce the burden on patients and sites while meeting regulatory needs. This research sought to gain insights by analyzing existing study designs and practices to describe study characteristics and identify commonalities and variations of LTFU studies for GCTs approved in the EU to aid in the planning and design of future LTFU studies.
Could you describe the methodology you used to identify and analyze LTFU requirements for EU-approved GCTs?
The initial aim was to focus exclusively on LTFU studies for GCTs submitted to the European Medicines Agency (EMA). However, only the HMA-EMA catalogue of RWD sources (HMA-EMA) provides information on risk management plans (RMPs) so we expanded the scope to include all LTFU studies conducted for GCTs approved in Europe, conscious that sponsors often supplement mandated studies with findings from similar studies in other regions (if nothing else, for contextualization).
Data on ongoing and completed long-term follow-up of patients treated in clinical trials (LTFU-CTP) and/or in routine clinical practice post authorization (LTFU-PA) was extracted from three sources: ClinicalTrials.gov (CTgov), the HMA-EMA, and EU Clinical Trials Register (EU-CTR). We excluded LTFU studies that were withdrawn, terminated, shorter than 5 years, or included GCTs as add-on therapies rather than investigational drugs. We then deduplicated the remaining studies and extracted data on various parameters, including study objectives, data sources, presence of comparator groups, target sample sizes, length of follow-up, source population by care setting, inclusion of pediatric populations, and EMA's risk management plan categories. Over 200 studies were screened, 77 of which were selected for in-depth analysis, including three studies that evaluated more than one GCT.
What key trends did your analysis reveal regarding the design and implementation of LTFU studies?
I would be hesitant to generalize our findings as “trends” since only 77 studies were selected for in-depth analysis after the exclusion criteria. However, I can describe what we uncovered as interesting and valuable findings:
- Products: There is a predominance of hematological cancers followed by other hematological conditions, and rare diseases in the GCTs that were approved. (Yescarta, Abecma, and Carvykti account for almost 40% of all studies, explaining the predominance of hematological cancers.)
- Partnerships: Numerous partnerships between biotech companies and pharmaceutical companies were observed, mostly due to biotech’s sponsoring of early-phase studies and pharma sponsoring long-term follow-up of trial patients.
- Study focus: The majority of LTFU studies evaluated both safety and effectiveness, followed patients for 15 years or longer, and were based on primary data collection. Of the 18 studies identified in the HMA-EMA catalogue, 17 were part of a RMP imposed as a condition of marketing authorization.
- Approval and study initiation: Of the 77 LTFU studies, two started before 2015, with the first in 2007, and over half initiated in 2020 or later.
- Regulatory influence: 2020 seems to be an inflection where a shift in the interpretation of LTFU requirements occurred, most notably the length of follow-up. This change was likely driven by the introduction of FDA’s guidance on “Long-Term Follow-Up After Administration of Human Gene Therapy Products” in 2020.
- Registry use: The majority of longer studies (over 15 years) use existing clinical registries either exclusively or in hybrid designs.
- Sample size: Although the trend is not significant, the target sample size of LTFU-CTP studies increased over time, probably explained by the successive inclusion of trials in later phases in the products’ development programs. As expected, the target sample sizes were larger for LTFU-PA studies than for LTFU-CTP studies. LTFU studies in hematological cancers had larger sample sizes compared to other therapeutic areas.
The findings highlight the evolving landscape of LTFU studies, driven by regulatory changes, partnerships, and the increasing use of RWD.
What does your analysis indicate about the types of data being collected in these studies, particularly in terms of primary versus secondary data?
Research showed more and more studies using registry and secondary data starting in 2020. In indications where robust clinical registries exist, registry data is primarily used for LTFU and only sometimes supplemented with primary data collection. Existing and de novo clinical registries are valuable sources for LTFU studies. They could support consistent and sustainable research programs as part of an integrated LTFU evidence generation strategy, which includes patients treated with GCTs in both clinical trials or routine clinical practice.
The analysis relied on the HMA-EMA and CTgov as sources. What are the strengths and limitations of these sources when examining LTFU study requirements?
The HMA-EMA provided a lot of the post-authorization safety studies (PASS) but CTgov contributed the biggest share of the studies. Many studies were registered in more than one of these platforms and appeared to be converted from EU PASS register into HMA-EMA. The HMA-EMA and, even more so, the EU-CTR could benefit from better reporting in the structured fields to solve for missing or incomplete information. Facilitating the systematic revision of past and ongoing studies would enable positive learning feedback for all stakeholders involved.
How are patient registries being integrated into LTFU studies, and what challenges or opportunities do they present in supporting long-term safety and efficacy monitoring?
We see three types of registries being used for long-term follow-up studies:
- disease-specific registries that upgraded capabilities to generate regulatory grade data
- product-specific registries expanded to also collect data on other products and/or disease natural history
- de novo registries
In indications where robust clinical registries exist, data is used and only sometimes supplemented. Existing and de novo clinical registries are valuable sources for mandated LTFU studies. They could support consistent and sustainable research programs as part of an integrated LTFU evidence generation strategy, that includes patients treated with GCTs in both clinical trials or routine clinical practice.
“Something we keep running into, in our own experience delivering LTFU studies, is the issue with data governance. Data governance restrictions prevent existing registries from being leveraged more often for these types of studies.”
Looking ahead, how can drug developers and study sponsors adapt their approaches to meet evolving regulatory expectations for LTFU studies, particularly as real-world data sources and analytical methods continue to advance?
One interesting thing is that while some products had one expansive study that was the basis for submission around the world, others had more than 10 separate studies. So, there is much to learn from efficiencies in bringing those studies together.
“Setting up registries, or supporting the upgrade of registries that can serve for the LTFU of in both trial and commercial settings, may seem like a large investment in early development. However, early engagement and proactive support for independent clinical registries to enhance and expand their capabilities is definitely a way to make the research more sustainable and to reduce burden on sights patients and ultimately drug developers.”
There is an opportunity for sustainable solutions through collaboration for multi-sponsor natural history studies that can serve all submission when the time comes, including down the road for PASS and LTFU.
Interviewee
Nahila Justo
Executive Director, PPD Evidera Real-World Data and Scientific Solutions, Thermo Fisher Scientific
Nahila Justo, PhD, MBA, MPhil, is Executive Director, PPD Real-World Data and Scientific Solutions, Thermo Fisher Scientific. She has over 15 years of experience in the industry where she designed and led numerous pharmacoepidemiology research programs including, but not limited to, comparative effectiveness and safety, drug utilization, and burden and cost of illness studies, leveraging diverse sources of data such as clinical registries, claim and administrative databases, retrospective chart reviews and EMR extractions, national surveys and other surveillance instruments. Dr. Justo has also led and conducted projects such as health-economics models, strategic consulting, stakeholder engagement and management, monitoring or regulatory developments and briefings, advocacy pieces, literature reviews and meta-analyses. Dr. Justo represents PPD in multistakeholder fora specialized in RWE (e.g., GetReal Institute, Duke Margolis Collaborative) and serves as an Expert Evaluator for the European Commission in various initiatives and programs, such as EU4Health and Horizon Europe Programmes, including the Innovative Health Initiative (formerly Horizon 2020 and Innovative Medicines Initiative).
Dr. Justo holds a PhD in Medical Science from the Karolinska Institute with a specialization in Epidemiology and Health Economics, an MBA from the Stockholm School of Economics, an MPhil in European studies from the University of Salamanca, an MSc in Economics from the Inter-American Development Bank and the University Torcuato Di Tella, and a BA and MA in Political Science and International Relations from the National University of Rosario.
Acknowledgments
Nahila would like to acknowledge the following contributors:
- Mai Duong, Thermo Fisher Scientific, London, UK
- Pingling Zeng, Thermo Fisher Scientific, Stockholm, Sweden
- Elizabeth Donahue, Thermo Fisher Scientific, Waltham, MA, USA
- Alice Rouleau, Thermo Fisher Scientific, Paris, France
- Sara Angleman, Thermo Fisher Scientific, Stockholm, Sweden
Disclaimer
The opinions expressed in this feature are those of the author and do not necessarily reflect the views of The Evidence Base® or Becaris Publishing Ltd.
Sponsorship for this Peek Behind the Poster was provided by Thermo Fisher Scientific.