Characterizing Gene Therapy Medicinal Products Post-Marketing Safety Reports based on WHO Pharmacovigilance Database, VigiBase

doi:10.21203/rs.3.rs-4705551/v1

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Research Article

Characterizing Gene Therapy Medicinal Products Post-Marketing Safety Reports based on WHO Pharmacovigilance Database, VigiBase

https://doi.org/10.21203/rs.3.rs-4705551/v1

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Background

Safety assessments of gene therapy medicinal products (GTMPs) require comprehensive data collection from a variety of sources to ensure thorough evaluation. This study aimed to analyze the characteristics of adverse event (AE) reports for GTMPs, dividing them into Solicited Reports (SRs) and Unsolicited Reports (USRs), and to provide insights for developing effective pharmacovigilance strategies customized for GTMPs.

Methods

Individual case safety reports (ICSRs) collected from GTMPs were retrieved using VigiBase. We identified GTMPs approved by the United States Food and Drug Administration (US FDA) and/or European Medicines Agency (EMA) by December 31, 2022, and maintained their approval status as of July 28, 2023. Descriptive statistics were used to summarize the ICSRs’ characteristics. The reported AEs were classified into System Organ Classes (SOCs) and Preferred Terms (PTs).

Results

A total of 12,180 ICSRs for 13 GTMPs were retrieved from VigiBase. Of these, 27.6% were SR and 72.4% USR. As the number of ICSRs increased, the proportion of USR tended to increase. Compared to the SR, consumer reports were much less common in the USR. The majority of the reported events were serious in both groups. In the drug-AE pairs, cytokine release syndrome and pyrexia were the most commonly reported in both the SR and USR. Meanwhile the most frequently reported SOCs were “Investigations” in SR and “Nervous system disorders” in USR, respectively.

Conclusions

Our study highlights the need for robust pharmacovigilance measures customized for GTMPs. The continued refinement of pharmacovigilance strategies customized for GTMPs is essential to ensure their safe and effective use.

Gene therapy medicinal products

Pharmacovigilance

Solicited reports

Unsolicited reports

Adverse Events

Gene therapy is a medical approach that treats diseases by altering gene expression or repairing abnormal genes. Since the first application of gene therapy to a patient with severe combined immunodeficiency in a clinical trial [1], gene therapy has been continuously developed, and various gene therapy medical products (GTMPs) have been approved for marketing by health authorities, including the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA); the number of GTMPs in the clinical developmental stage is increasing rapidly [2, 3].

Gene therapy holds significant promise as a treatment modality, offering the potential to treat genetic disorders by directly replacing or repairing faulty genes in affected cells or tissues [3, 4]. This targeted approach minimizes the off-target effects and has the potential for long-lasting or permanent therapeutic effects. However, it is also associated with inherent risks, including immune responses to the introduced gene, off-target effects leading to unintended consequences, and potential overexpression or underexpression of the therapeutic gene. Additionally, it has a risk of insertional mutagenesis, where the integration of the therapeutic gene into the host genome may disrupt normal gene function, potentially leading to adverse events (AEs), such as cancer. AEs associated with gene therapy may manifest shortly after administration or may have a delayed onset [5]. Careful consideration of these benefits and risks is essential to ensure safe and effective application of gene therapy in clinical practice.

Considering the potential risks of gene therapy, regulatory authorities recommend long-term safety monitoring of GTMPs for patients exposed to GTMPs both in clinical trials and post-marketing situations. The follow-up period is determined based on the characteristics of GTMPs and typically ranges from 5 to 15 years [5]. Consequently, long-term safety data for GTMPs approved through special designations, such as orphan, fast-track, or breakthrough therapy, are continuously being collected, and the results are being published. Early investigations of GTMPs faced developmental setbacks owing to their severe toxicity, including fatalities. In 1999, there was a case of death due to immune response during a phase 1 clinical trial to develop an adenovirus vector-based gene therapy for patients with ornithine transcarbamylase deficiency in the United States (US) [6]. In 2002, gene therapy was performed on 10 children in France to correct X-linked severe combined immunodeficiency (SCID-X1) by transferring a retroviral-mediated gene into the patients' bone marrow cells. Although the treatment was effective, four of the children developed leukemia within 30–68 months of receiving gene therapy and one of them died. Retroviral vectors appear to cause leukemia by integrating near oncogenes that can cause cancer [7]. Although there are still GTMPs whose development has been discontinued owing to safety concerns [2, 8], assessment of the long-term follow-up results of currently approved GTMPs suggests that while the administration of GTMPs may pose serious risks, these risks can be effectively managed through attentive standard care and have not raised significant safety issues [9–16].

However, relying solely on clinical trials or long-term post-marketing follow-up studies is not sufficient to acquire sufficient safety data owing to limitations such as the rarity of the disease, low patient numbers, and potential loss to follow-up. Therefore, safety assessment requires data collection from various sources, including voluntary reports, to ensure a comprehensive evaluation of the GTMP safety profiles [17].

GTMPs are generally administered as a single treatment. It is anticipated that AEs occurring shortly after administration can be easily reported, but associating a GTMP with AEs occurring several years after GTMP administration and reporting them as adverse drug reactions (ADRs) of the GTMP will be challenging. Therefore, when developing a pharmacovigilance plan prior to product approval, it is essential to prepare additional pharmacovigilance plans, such as long-term follow-up studies or registries, and develop routine pharmacovigilance plans that incorporate the characteristics of GTMPs [18].

AE reports can be categorized as Solicited Reports (SRs) and Unsolicited Reports (USRs). SRs are systematically collected from structured data collection systems, such as clinical trials, registries, and other patient support programs. USRs are reports not derived from structured data collection systems and encompass voluntary reports from healthcare professionals or consumers to a company or other organization as well as individual case reports from the literature, the Internet, or other sources [19]. Both solicited and unsolicited reports contribute to our understanding of drug safety and aid in monitoring the real-world effects of medications.

In this study, we analyzed the characteristics of AE reports for GTMPs by dividing them into two categories: SR and USR. Additionally, we sought to provide insights for the development of an effective pharmacovigilance plan specifically tailored to GTMPs.

Data sources

We used VigiBase, the Global Drug Safety Database of the World Health Organization (WHO). This database includes individual case safety reports (ICSRs) submitted from more than 170 countries. The dataset used had all ICSRs from 1968 to July 28, 2023.

VigiBase contains ICSRs from various sources, including spontaneous reporting, clinical studies, and post-marketing surveillance. In many countries, post-marketing safety reporting requirements mandate that marketing authorization holders (MAHs) to report serious ADRs in clinical trials and observational studies to regulatory agencies [20, 21]. Therefore, data from clinical trials, observational studies, and spontaneous reporting are collected through post-marketing spontaneous reporting systems in each country. As these data are transferred to VigiBase, they include not only unsolicited spontaneous reports but also solicited reports, such as reports from clinical studies or post-marketing surveillance [22].

The VigiBase contains information on patient demographics, drug characteristics, and AEs. Narratives, which usually contains detailed descriptions of the AEs experienced by individuals, are not disclosed for research purposes to ensure the protection of individuals' privacy rights. We extracted the patients’ sex and age, drug information, AE terms, time-to-onset, outcome, seriousness, region reported from, reported date, type of reporter, and type of reporting source from VigiBase.

The likelihood of a reported event being caused by a medicinal product varies based on the AE reporting requirements in different countries. Some countries gather only suspected ADRs with potential causality to the medicinal product, whereas others collect all AEs associated with drug use, regardless of their relationship with the drug [22]. Causality assessments of drug event associations have different practices across countries, and the Uppsala Monitoring Centre (UMC) does not independently validate causality assessments [23]. Therefore, in this study, we referred to the reported events as AEs rather than ADRs.

AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), and medicinal products were coded using WHODrug. This standardized terminology allows for consistent reporting and facilitates comparisons across different sources and countries.

Because this study utilized publicly available, pre-existing, and anonymized data, ethical approval was not required.

Products

Our study targeted GTMPs approved by the US FDA and/or EMA as of December 31, 2022, and maintained their approval status in at least the US or the European Union (EU) as of July 28, 2023. Considering the time required to be prescribed after their approval and the gathering of AEs, GTMPs approved by the end of 2022 were included in this study. Valid GTMPs were identified using information from the US FDA and EMA websites [24, 25]. The GTMPs were classified by indications based on the Anatomical Therapeutic Chemical (ATC) code.

Dataset

We retrieved all ICSRs associated with valid GTMPs. ICSRs not having any AE terms or with only “No adverse event” as an AE term were deleted. Patients with suspected duplications were excluded from the study. Cases in which the onset of AEs occurred before the administration of the suspected drug or interacting drug were excluded. If the type of report for an ICSR was checked as “Report from study” or “Post-Marketing Surveillance (PMS)/Special monitoring”, it was classified as a SR. Otherwise, it was classified as a USR.

Statistical analyses

Descriptive statistics were used to summarize the ICSR characteristics. As multiple AEs could be reported in one ICSR, the characteristics of each ICSR were summarized at the case and event levels. At the case level, the demographic (sex and age group of patients) and the report characteristics (number of AEs per case, reporter type, region reported from, reporting year) in total were explored, and at the event level, the event characteristics (seriousness, serious criteria, outcome, time-to-onset [TTO] group) in total were explored, and compared by dividing them into SR and USR. To assess TTO, we calculated the number of days that elapsed from the date of GTMP administration to the onset of the relevant AE. In our descriptive analysis, categorical variables were summarized as numbers and percentages and continuous variables as medians with interquartile ranges (IQRs). Data were compared using chi-square (χ2) tests, Wilcox, or Fisher tests, as appropriate.

AEs were summarized by primary System Organ Class (SOC) and Preferred Term (PT). The MedDRA software (version 26.0) was used.

Statistical significance was set at p < 0.05. Data were analyzed using the statistical software program SAS (version 9.4; SAS Institute Inc., Cary, NC, USA).

We identified 17 GTMPs approved by the US FDA and/or EMA by December 31, 2022, and maintained their approval as of July 28, 2023 (Table 1).

Of the 17 GTMPs, 10 (58.8%) had approved and maintained marketing in both the US and the EU. Three (17.6%) products (GSK2696273 [Strimvelis], atidarsagene [Libmeldy], eladocagene [Upstaza]) were approved in the EU but not in the US. The remaining four (23.5%) products maintained their approval in the US but not in the EU. Betibeglogene (Tecartus) and elivaldogene (Skysona) were initially approved in the EU in 2019 and 2021, respectively, but the products were withdrawn from the EU market for commercial reasons [26, 27]. Subsequently, they obtained approval and remained marketed in the US.

All GTMPs have been designated as orphan drugs in the US and the EU. According to the ATC Classification System, antineoplastic agents (ATC code: L01) were the most common, with eight (47.1%) products, followed by other nervous system drugs (ATC code: N07) with two (11.8%) products. Most GTMPs (88.2%, n = 15) were labeled for use once or as a single-dose, except for two products (talimogene [Imlygic] and nadofaragene [Adstiladrin]) administered either every 3 months or 2 to 3 weeks apart.

Number of ICSRs by GTMPs and by-products

Among the 17 approved GTMPs, a total of 12,180 ICSRs, describing 42,907 drug-AE pairs, were retrieved from VigiBase for 13 products, excluding the 4 drugs (elivaldogene [Skysona], valoctocogene [Roctavian], etranacogene [Hemgenix], nadofaragene [Adstiladrin]) recently approved between 2022 and 2023 (Fig. 1).

According to the ATC Classification System, antineoplastic agents have more ICSRs than non-antineoplastic agents. The ICSRs reported for seven antineoplastic agents accounted for 84.5% (n = 10,296) of the total. Among non-antineoplastic agents, the number of ICSRs was less than 10 for each product, except for onasemnogene (Zolgensma) (n = 1,628) and voretigene (Luxturna) (n = 238).

Of the 12,180 ICSRs, 3,358 (27.6%) were reported as SR and 8,822 (72.4%) as USR. Figure 1 shows the distribution of the SR and USR reported for each product. More ICSRs were reported as USR in all products except for eladocagene (Upstaza) and GSK2696273 (Strimvelis). The rate of ICSRs reported as USR for the seven antineoplastic agents was 70.6–80.3%, which is approximately three times more ICSRs than that reported for SR. For onasemnogene (Zolgensma) and voretigene (Luxturna), USRs showed similar portion with SRs at 54.1% and 52.1%, respectively. For two other products, eladocagene (Upstaza) and GSK2696273 (Strimvelis), less ICSRs were reported as USR, however, it is not meaningful due to the small number of total ICSRs (9 [6 SRs, 3 USRs] and 1 [1 SR, 0 USR], respectively). In general, as the number of ICSRs increased, the proportion of USR tended to increase.

Characteristics of ICSRs by Reporting Sources

Among the 12,180 ICSRs, 3,358 cases were categorized as SR, all of which reported as “Report from study,” with none reported as “PMS/Solicited”. The remaining 8,822 cases were classified as USR: 8,811 cases (99.9%) were reported as “Spontaneous”, 10 cases (0.1%) as "Other", and 1 case (0.01%) designated as "Not available to sender (unknown).”

Table 2 shows ICSR characteristics relevant to the GTMPs. At the case level, there were more ICSRs from male (47.9%) than female (34.1%), with a similar pattern observed in SR and USR (male: 49.9% in SR and 47.2% in USR). The overall missing value was 18.0% (11.6% in SR and 20.4% in USR). Missing values were more in age group showing 32.6% in total (27.1% in SR and 34.7% in USR). USR had more missing than SR for both sex and age group. The average number of adverse events included in one ICSR was more in SR with 4.4 (IQR 1, 5) events compared to USR with 3.2 (IQR 1, 4) events. The majority of ICSRs were reported from professionals (physician 46.6%, other healthcare professional 34.8% and pharmacist 5.6% in total). In SR, the portion of ICSRs from patient were 20.6%, which was less than from physician (57.2%) and other healthcare professional reports (21.3%), but more than the one from patient in USR (8.6%). By region, ICSRs were 64.0% provided from America, 32.2% from Europe, and 3.8% from other countries, with similar patterns observed in SR and USR. The number of ICSRs was constantly increased by year, especially in USR. SR was peak in 2021 and slightly decreasing after that.

At the event level, GTMP was reported as a suspected drug in most events (99.96%), with a similar pattern observed for SR (100.0%) and USR (99.9%). Additionally, GTMP was reported to be an interacting drug in 0.04% (SR 0.0% [none], USR 0.1%) of events. AEs were reported as serious in 89.0% of events (SR 88.5%, USR 89.3%), with the most common serious criteria being “Other” (31.1%), followed by “Caused/Prolonged Hospitalization” (26.7%), and “Death” (23.9%). Outcome was reported as “Unknown” in 43.3% (SR 48.4%, USR 40.6%), and it became more than half (Total 56.7%; SR 49.8%, USR 60.2%) if included missing. A significant proportion of patients (total, 82.6%; SR, 82.9%; USR, 82.4%) did not have time-to-onset (TTO). The events with TTO of “less than 30 days” was 12.9% (SR 11.4%, USR 13.7%), “between 30 and 90 days” was 2.2% (SR 2.7%, USR 1.9%) of events, and “equal to or more than 90 days” in 2.3% (SR 2.9%, USR 2.0%) of events.

Adverse Events reported from the use of GTMPs

Table 3 shows the reported AEs categorized according to SOCs. The most frequently reported SOC was “nervous system disorders” (14.9%), followed by “general disorders, administration site conditions” (13.4%), and “investigations” (13.3%). By groups, the most frequently reported SOC in SR was “Investigations” (20.4%), followed by “General disorders and administration site conditions” (11.5%) and “Nervous system disorders” (10.3%). In the USR, the most reported SOC were “nervous system disorders” (17.2%), “immune system disorders” (14.8%), and “general disorders and administration site conditions” (14.5%).

Table 4 shows the AEs reported by PTs. As for PT, in both SR and USR, “Cytokine release syndrome” (SR 6.3%, USR 13.5%) and “Pyrexia” (SR 4.6%, USR 4.9%) were the most frequently reported. However, the next most reported PTs showed different patterns between SR and USR, with “Platelet count decreased” (1.9%), “White blood cell count decreased” (1.8%), “Lymphocyte count decreased” (1.8%), “Vomiting” (1.8%) in SR, and “Neurotoxicity” (4.6%), “Immune effector cell-associated neurotoxicity syndrome” (3.6%), and “Hypotension” (1.8%) in USR.

Given the novel mechanisms and technical intricacies of GTMPs, there is a potential for emerging risks to patients, emphasizing the need for early risk detection and the implementation of effective risk mitigation strategies [5]. This study aimed to contribute to the establishment of a comprehensive pharmacovigilance plan for GTMPs by analyzing the characteristics of the ICSRs in VigiBase.

Because most GTMPs are orphan drugs administered to a limited number of patients, we expected that USR would be quite rare. Contrary to our expectations, USR comprised 72.4% of the total ICSRs of the GTMPs, surpassing SR. The proportion of USR remains high, although safety studies have been actively planned for GTMPs following regulatory requirements. There is no question that proactive initiatives such as long-term follow-up studies and registries are important for safety assessment of GTMPs. However, as shown in this study, a significant portion of ICSRs have been reported as USR, mainly as spontaneous reporting. Therefore, we need to plan an effective implementation of spontaneous reporting for GTMPs. Despite its limitations in data quality, spontaneous reporting has been recognized as a valuable tool for detecting safety signal or generating hypotheses in pharmacovigilance [28, 29].

Upon closer examination, it was observed that the proportion of USR was high in anticancer drugs with a relatively large patient population, but the proportion of USR was low in products with a small patient population. For Voretigene (Luxturna) and Onasemnogene (Zolgensma), utilized for patients diagnosed with inherited retinal dystrophy and spinal muscular atrophy, respectively, the proportion of USR was 52.1% and 54.1% each. This was lower than the USR proportion of 70.6–80.3% for anticancer GTMPs. This could be attributed to the limited patient pool utilizing GTMPs, prompting efforts to engage those available in regulatory-committed studies, or to the rarity of the disease, leading to increased research activities. Consequently, it is imperative to develop strategies for capturing USR to increase AE reporting in patients not enrolled in clinical trials or observational studies, particularly those with ultra-rare diseases.

In this study, the analysis of USR characteristics revealed that reports from physicians were the most prevalent (42.5%), followed by reports from other healthcare professionals (39.9%), whereas reports from consumers or non-health professionals were notably low (8.6%). The proportion of ICSRs reported by consumers or non-health professionals in our study was significantly lower compared to the range of 36–46.9% reported by consumers for other drugs in other studies [30, 31]. Given the nature of the diseases targeted by GTMPs, patients typically maintain regular contact with their healthcare providers, suggesting that AEs are often reported indirectly by physicians. However, safety concerns associated with GTMPs may manifest long after administration, highlighting the importance of patients being informed and empowered to report AEs, either directly or through healthcare providers. When patients assess potential ADRs, they often consider temporal relationships and provide information [32]. Patient reporting of ADRs increases when they know the purpose of the ADR reporting system and receive guidance on ADR reporting from healthcare professionals [33]. Hence, strategies to enhance patient awareness and facilitate ADR reporting are imperative to ensure comprehensive pharmacovigilance of GTMPs.

One of the main concerns when collecting safety information related to GTMPs is whether AEs that occur long after GTMP administration can be reported. Therefore, this study examined TTO. However, TTO had a significant proportion of missing information (82.6%), which was similar to SR and USR. Contrary to our expectations that more detailed data would be collected in SR, as ICSRs collected in a program with a planned data collection system were classified as SR, there were many missing TTOs even in SR. Clinical and observational studies have separate study databases to analyze the study data and write study reports. Thus, ICSRs could have been reported to regulatory authorities or national drug safety centers with the minimum elements to meet AE reporting requirements. Additionally, if the date is unclear when reporting an AE, the approximate time may be described only in the narrative instead of entering the date as the year, month, or day in the appropriate fields. In this study, the TTOs were calculated using information regarding the date of GTMP administration and AE occurrence. If dates were not entered into the relevant fields, the TTO could not be calculated, even though the information existed somewhere in the report. This may be the cause of many misses in TTO. Because the TTO is one of the key data points in evaluating causal relationships between drugs and events, it needs to be considered to ensure that it is collected well.

Among ICSRs with TTO, cases reported within 30 days accounted for 11.4% of all SRs and 13.7% of USRs, approximately 3.9 times and 6.9 times higher than those reported more than 90 days later (SR 2.9%, USR 2.0%). Although there were numerous missing values, making it challenging to draw general conclusions, the results aligned with our expectation that AEs occurring long after administration would be reported less frequently as USR than as SR.

In this study, Serious Adverse Events (SAEs) accounted for 89.0% of all ICSRs (SR, 88.5%; USR, 89.3%). Moreover, in patients with TTO > 90 days, the proportion of SAE was notably higher in the USR group (95.7%). In contrast, the proportion of SAE in the SR with TTO exceeding 90 days decreased to 79.1%. Encouraging the reporting of SAEs affecting the risk-benefit balance is emphasized for long-term safety assessments. Despite the relatively small proportion of cases reported beyond 90 days in the USR, important safety information is consistently reported in the USR.

Meanwhile, when considering the frequently reported AEs categorized by SOC, “Investigations” was the most frequently reported in SR, whereas “Nervous system disorders” was the most frequently reported in USR. This suggests that in the USR, there is a tendency to report signs, symptoms, and diagnoses with clinical significance, whereas in the SR, AEs related to tests are often reported according to the study protocols. This difference is further highlighted when examining PTs; none of the top 10 PTs reported in USR were classified as “Investigations,” whereas 50% of the top 10 PTs reported in SR were classified as “Investigations.”

One of the most prevalent concerns associated with GTMPs is their potential risk of cancer induction through gene therapy. Although many AEs were reported under the SOC of “Neoplasms benign, malignant, and unspecified (including cysts and polyps)” (SR 937, USR 1,434), they were reported from antineoplastic GTMPs except one event of meningioma reported as USR for voretigene (Luxturna). When evaluated with the PTs, such as malignant neoplasm progression and diffuse large B-cell lymphoma, many events were judged to be related to pre-existing conditions rather than suspected secondary malignancy. Therefore, a careful review is required to determine the association between the reported AEs and GTMPs.

To the best of our knowledge, this study is the first attempt to assess the characteristics of adverse events reported by GTMPs according to their reporting sources. This study had some limitations. First, the accuracy of the AE reporting sources was unknown. While most national monitoring centers review ICSRs before sending them to VIgiBase, and the WHO-UMC also evaluates the quality of ICSRs with vigiGrade [32, 34], the reliability of specific data, including reporting source records, remains uncertain. Second, our analysis was conducted in an aggregated manner without considering the indications or manufacturing characteristics of the GTMPs. Given that GTMPs target diverse diseases and may use different vectors for gene delivery, disease-specific characteristics and safety issues may vary. However, because of the limited number of patients eligible for GTMPs, analyzing each product individually could have posed challenges in obtaining sufficient data for review; hence, an integrated analysis was performed. Future studies should explore products with similar characteristics in greater detail. Thirdly, when evaluating the safety of GTMPs, it is crucial to assess both short-term and potentially delayed AEs. However, the lack of TTO data in many cases makes it difficult to ascertain the extent of long-term safety reports. Although AEs with TTO were evaluated, the high missing rate (> 80%) raised concerns regarding potential biases in interpretation. The results of our study should be interpreted in consideration of these limitations.

In conclusion, our study highlights the need for robust pharmacovigilance measures customized for GTMPs given their unique risk profiles. Despite active safety studies, establishing effective spontaneous reporting mechanisms and enhancing patient awareness are crucial for leveraging USRs for signal detection. Addressing missing TTO data and encouraging the reporting of SAEs, particularly delayed SAEs that may occur years after administration, is crucial for a comprehensive safety assessment. Proactive initiatives, such as long-term follow-up studies and education campaigns targeting healthcare professionals and patients, are essential for optimizing the risk-benefit balance of GTMPs and maintaining public health. The continuous refinement of pharmacovigilance strategies is imperative to ensure the safe and effective use of GTMPs.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Funding statement

No funding was received for this study.

Author Contribution

Min-Jung Lim designed the study with support from Eunah Paek and Ju-Young Shin. Lim and Paek performed data management and analysis. Min-Jung Lim and Eunah Paek wrote the first draft of this manuscript. All the authors have read and approved the final version of the manuscript.

Acknowledgement

We would like to thank Editage (www.editage.co.kr) for editing and reviewing this manuscript for English language.

Data Availability

Availability of data and materialsRequests for VigiBase data should be directed to the Uppsala Monitoring Centre (UMC). However, specific subsets of the data utilized in our study can be made available from the corresponding author on reasonable request.

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Tables 1 to 3 are available in the Supplementary Files section.

No competing interests reported.

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Characterizing Gene Therapy Medicinal Products Post-Marketing Safety Reports based on WHO Pharmacovigilance Database, VigiBase

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Abstract

Figures

Introduction

Methods

Data sources

Products

Dataset

Statistical analyses

Results

Number of ICSRs by GTMPs and by-products

Characteristics of ICSRs by Reporting Sources

Adverse Events reported from the use of GTMPs

Discussion

Conclusions

Declarations

Conflict of interest statement

Funding statement

Author Contribution

Acknowledgement

Data Availability

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1