“Direct and indirect impacts of the COVID-19 pandemic on operational conduct of pediatric vaccine clinical trials”

ABSTRACT

The coronavirus 2019 (COVID-19) pandemic, as well as the resulting public health measures, impacted many aspects of society. The conduct of important pediatric vaccine trials was among these. Analyzing data from six ongoing non-COVID-19 pediatric vaccine trials we aimed to assess the operational impact of the COVID-19 pandemic using descriptive analyses. We identified multiple operational disruptions in trial conduct. Additionally, we identified higher percentages of missed routine vaccinations than investigational vaccines throughout the observation period. Overall, the impact of the COVID-19 pandemic was most apparent early in the pandemic period while adaptations to the pandemic were developed; however, some disruptions persisted throughout the observation period. Pediatric vaccine clinical trials are critical to developing new and/or improved vaccines for the pediatric population. Continued evaluation of the impacts of COVID-19 on pediatric vaccine clinical trials is warranted.

KEYWORDS:

• Vaccines
• clinical trials operations
• pediatric vaccine trials
• COVID-19
• operational disruption

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), began causing widespread infections throughout the world in January 2020, resulting in the declaration of a global pandemic by the World Health Organization (WHO) on 11 March 2020.¹ Many countries instituted government-mandated public health measures, including lockdowns, that had broad impacts on society. These impacts included disruption of clinical trials.^2–6 Despite regulatory guidelines instructing the pharmaceutical industry to collect data to evaluate the impact of COVID-19 on the conduct of clinical trials,⁷ much remains to be learned. Using data from six ongoing pediatric vaccine clinical trials whose conduct bridged the pre-pandemic and pandemic periods, we investigated the potential impact of the COVID-19 pandemic on operational aspects.

Participants and methods

Participants

We evaluated the impact of the COVID-19 pandemic on operational aspects of six ongoing pediatric phase III vaccine trials conducted in infants and toddlers in multiple geographic regions initiated before the declaration of the COVID-19 pandemic in March 2020 (Table 1). All six studies were randomized-controlled trials. Study 5 was open label, while the remaining five studies were blinded. Data were collected from the pre-pandemic period, 11 March 2019 to 10 March 2020, through the pandemic period, 11 March 2020 to 27 April 2022 and described by quarter (Table 2). The baseline demographics of trial participants, by trial and overall, are described in Table 3. Overall, there was an even distribution between males and females. Age at enrollment ranged from 2 to 609 days based on study designs. Most participants were white (82.9%) and not Hispanic or Latino (67.4%). All trials were approved by local Ethics Committees/Institutional Review Boards and conducted in accordance with the Helsinki Declaration of 1975.

Table 1. Trials included in the analyses.

	Phase	Region	Countries	Age at recruitment	FVFS	Stage at time of COVID-19 pandemic (March 2020)
Trial 1	III	USA	USA including Puerto Rico	≥42 to ≤89 days	17-Sep-18	Enrolling
Trial 2	III	USA	USA including Puerto Rico	≥42 to ≤89 days	25-Apr-18	Enrolling
Trial 3	III	USA	USA including Puerto Rico	≥168 to ≤224 days or 17 to 19 months	4-Oct-18	Enrolling
Trial 4	III	EU	Czech Republic, Finland, Italy, Poland, Romania, Spain, Sweden	≥42 to ≤89 days	14-Dec-18	Enrolling
Trial 5	III	UK	UK	≥56 to ≤89 days	10-Oct-18	Enrolling
Trial 6	III	Other	Mexico, Russia	≥60 to ≤89 days	17-Oct-18	Enrolling

Table 2. Dates for pre-pandemic and pandemic periods.

Pre-pandemic	Q1	11-Mar-19	10-Jun-19
	Q2	11-Jun-19	10-Sep-19
	Q3	11-Sep-19	10-Dec-19
	Q4	11-Dec-19	10-Mar-20
Pandemic	Q5	11-Mar-20	10-Jun-20
	Q6	11-Jun-20	10-Sep-20
	Q7	11-Sep-20	10-Dec-20
	Q8	11-Dec-20	10-Mar-21
	Q9	11-Mar-21	10-Jun-21
	Q10	11-Jun-21	10-Sep-21
	Q11	11-Sep-21	10-Dec-21
	Q12	11-Dec-21	10-Mar-22
	Q13	11-Mar-22	27-Apr-22

Table 3. Demographics of trial participants.

	Trial 1 (N = 2796)	Trial 2 (N = 2626)	Trial 3 (N = 831)	Trial 4 (N = 1659)	Trial 5 (N = 788)	Trial 6 (N = 525)	Total (N = 9225)
Sex: n(%)
M	2796	2626	831	1659	787	525	9224
Male	1462 (52.3)	1381 (52.6)	439 (52.8)	823 (49.6)	404 (51.3)	254 (48.4)	4763 (51.6)
Female	1334 (47.7)	1245 (47.4)	392 (47.2)	836 (50.4)	383 (48.7)	271 (51.6)	4461 (48.4)
Age: (Days)
M	2796	2626	830	1659	787	525	9223
Mean (SD)	64.7 (6.67)	65.3 (7.95)	280.4 (157.09)	71. (12.08)	64.4 (7.00)	69.5 (8.38)	85.7 (77.71)
Median	63	64	194	73	63	67
Q1; Q3	61; 67	61; 69	186; 223	63; 81	59; 68	63; 74	62; 75
Min; Max	42; 89	42; 89	2; 609	42; 89	55; 106	60; 93	2; 609
Race: n (%)
M	2796	2625	821	1659	787	525	9213
Amercan Indian or Alaskan Native	8 (0.3)	17 (0.6)	1 (0.1)	1 (<0.1)	0	244 (46.5)	271 (2.9)
Asian	40 (1.4)	25 (1.0)	13 (1.6)	9 (0.5)	9 (1.1)	0	96 (1.0)
Black or African American	277 (9.9)	300 (11.4)	137 (16.7)	4 (0.2)	2 (0.3)	0	720 (7.8)
Native Hawaiian or Pacific Islander	15 (0.5)	13 (0.5)	0	1 (<0.1)	0	0	29 (0.3)
White	2297 (82.2)	2149 (81.9)	622 (75.8)	1598 (96.3)	744 (94.5)	225 (42.9)	7635 (82.9)
Mixed origin	134 (4.8)	74 (2.8)	39 (4.8)	11 (0.7)	18 (2.3)	0	276 (3.0)
Not reported	13 (0.5)	23 (0.9)	0	30 (1.8)	0	56 (10.7)	122 (1.3)
Unknown	12 (0.4)	24 (0.9	9 (.1)	5 (0.3)	14 (1.8)	0	64 (0.7)
Ethnicity: n (%)
M	2796	2626	831	1659	787	525	9224
Hispanic or Latino	763 (27.3)	1247 (47.5)	352 (42.4	181 (10.9)	10 (1.3)	299 (57.0)	2852 (30.9)
Not Hispanic or Latino	2024 (72.4)	1362 (51.9)	477 (57.4)	1369 (82.5)	768 (97.6)	218 (41.5)	6218 (67.4)
Not reported	9 (0.3)	10 (0.4)	2 (0.2)	103 (6.2)	4 (0.5)	7 (1.3)	135 (1.5)
Unknown	0	7 (0.3)	0	6 (0.4)	5 (0.6)	1 (0.2)	19 (0.2)

Statistical methods

All statistical analyses were descriptive. The impact of COVID−19 on trial conduct were presented by trial, overall (pooled data from the six ongoing studies), and by region (EU, US, UK, and other countries). Categorical variables were summarized and presented by frequency counts and percentages with 95% confidence intervals (CIs). The CIs for the single proportion were calculated using the exact binomial method (Clopper–Pearson method, quoted by Newcombe⁸).

Results

Overview of COVID-19 pandemic on operational endpoints

We collected data from six ongoing pediatric trials before and during the COVID-19 pandemic. The impact of the COVID-19 pandemic on trial conduct was summarized through the influence on visit procedures, trial completion, and major/critical deviations due to COVID-19 (Table 4). Out of a total of 9225 participants with a case report form (CRF), 273 (3%) were diagnosed with COVID-19 during the period from 11 March 2020 to the end of data collection on 27 April 2022. Most participant diagnoses of COVID-19 occurred in Trials 1 (116 participants, 4.1%) and 2 (95 participants, 3.6%). One hundred fourteen participants (1.2%) were impacted by the COVID-19 pandemic with Trials 2 and 5 reporting the highest percentages of participants impacted by the COVID-19 pandemic (2.1% and 2.3% respectively). Furthermore, 93 participants (1.0%) had at least one major/critical protocol deviation due to COVID-19 (Table 4).

Table 4. Overview of COVID-19 impact on endpoints.

	Trial 1 (N = 2796)	Trial 2 (N = 2626)	Trial 3 (N = 831)	Trial 4 (N = 1659)	Trial 5 (N = 788)	Trial 6 (N = 525)	Overall (N = 9225)
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Participants with a CRF	2796 (100)	2626 (100)	831 (100)	1659 (100)	788 (100)	525 (100)	9225 (100)
Participants diagnosed with COVID-19	116 (4.1)	95 (3.6)	12 (1.4)	21 (1.3)	24 (3.0)	5 (1.0)	273 (3.0)
Participants impacted by COVID-19 pandemic situation*	32(1.1)	56 (2.1)	2 (0.2)	6 (0.4)	18 (2.3)	0	114 (1.2)
Participants with at least one major/critical protocol deviation due to COVID-19 pandemic situation	28 (1.0)	41 (1.6)	1 (0.1)	6 (0.4)	17 (2.2)	0	93 (1.0)
Early termination due to COVID-19 pandemic**	10 (3.0)	31 (5.7)	18 (13.4)	0	2 (7.7)	0	61 (5.4)
Reason
Adverse event	0	0	0	0	0	0	0
Protocol deviation	0	6 (1.1)	1 (0.7)	0	0	0	7 (0.6)
Withdrawal by participant	10 (3.0)	24 (4.4)	17 (12.7)	0	2 (7.7)	0	53 (4.7)
Lost to follow up	0	1 (0.2)	0	0	0	0	1 (<0.1)
COVID-19 Visit not done	12 (0.4)	66 (2.5)	30 (3.6)	2 (0.1)	1 (0.1)	0	111 (1.2)
COVID-19 Visit partially done	39 (1.4)	5 (0.2)	1 (0.1)	4 (0.2)	54 (6.9)	0	103 (1.1)
Blood sample not performed	0	0	0	0 (0)	41 (5.2)	0	41 (0.4)
Vaccination not performed	0	0	0	1 (<0.1)	2 (0.3)	0	3 (<0.1)
No solicited safety data available	0	1 (<0.1)	0	0	3 (0.4)	0	4 (<0.1)
COVID-19 At least one procedure out of time window	77 (2.8)	134 (5.1)	51 (6.1)	43 (2.6)	18 (2.3)	1 (0.2)	324 (3.5)
Blood sample out of time window	0	43 (1.6)	35 (4.2)	25 (1.5)	12 (1.5)	0	115 (1.2)
Vaccination out of time window	69 (2.5)	86 (3.3)	6 (0.7)	6 (0.4)	5 (0.6)	1 (0.2)	173 (1.9)
Visit date out of time window	70 (2.5)	125 (4.8)	45 (5.4)	25 (1.5)	18 (2.3)	1 (0.2)	284 (3.1)
COVID-19 No procedure done on site	4 (0.1)	0	1 (0.1)	0	7 (0.9)	0	12 (0.1)
COVID-19 At least one procedure done by phone	66 (2.4)	3 (0.1)	1 (0.1)	0	4 (0.5)	0	74 (0.8)
COVID-19 At least one procedure done at home	0	0	0	0	4 (0.5)	0	4 (<0.1)

We further divided the impact on operations into early terminations due to the COVID-19 pandemic, visits not done, visits partially done, participants with at last one procedure out of time window, no procedure done on site, at least one procedure done by phone, and at least one procedure done at participant home (Table 4).

Overall, 61 participants terminated the trial early due to the COVID-19 pandemic. This represented 5.4% of total early terminations from all trials. Most COVID-19-associated early terminations were withdrawal by participant’s parent/legally appointed representative (4.7%), followed by protocol deviations (0.6%), and lost to follow up (<0.1%) (Table 4).

There were 111 (1.2%) visits not done and 103 (1.1%) visits partially done specifically due to the COVID-19 pandemic. Visits partially done included lack of blood sampling in 41 participants (0.4%) all of whom were from Trial 5. This was, at least partially, due to reallocation of the pediatric phlebotomist to COVID-19-related duties. Vaccinations were not performed for 3 participants (<0.1%), and no solicited safety information was available for 4 participants (<0.1%), which also contributed to partially done visits (Table 4).

The COVID-19 pandemic also led to the performance of trial procedures outside protocol-defined time windows. At least one procedure was performed outside of the time window for 324 participants (3.5%), the majority of which were caused by the visit date being out of window for 284 participants (3.1%). Vaccinations were out of time window for 173 participants (1.9%), followed by blood sample out of time window in 115 participants (1.2%). Additionally, due to constraints associated with the COVID-19 pandemic some procedures were performed by phone or at the participant’s home (Table 4).

In general, operational aspects of these six ongoing pediatric Phase III vaccine trials were adversely impacted by the COVID-19 pandemic in multiple ways. The extent of operational disruption varied by trial.

Quarterly impact of the COVID-19 pandemic on key operational endpoints

In addition to the overall impact on operations, we investigated the impact of COVID-19 on 5 key endpoints by quarter: 1) percentage of participants diagnosed with COVID-19, 2) percentage of early terminations, 3) percentage of visits not done, 4) percentage of visits only partially done, 5) percentage of participants with at least 1 procedure out of window. The periods of the pandemic quarters Q5-Q13 are defined in Table 2. These endpoints varied by quarter. These parameters also varied by trial (Figure 1).

Figure 1. Overview of COVID impact on endpoints by Quarter. See Table 2 for dates of quarters (a) percentage of participants diagnosed with COVID-19 (b) percentage of early terminations due to COVID-19 out of total trial early terminations (c) percentage of visits not done due to COVID-19 (d) percentage of visits only partially done due to COVID-19 (e) percentage of participants with at least 1 procedure out of window.

The highest percentage of participants diagnosed with COVID-19 occurred during quarter Q12, corresponding to the period between 11 December 2021 to 10 March 2022. Trial 1 had the highest percentage of participants diagnosed with COVID-19 during this quarter (1.6%), followed by Trial 4 (1%), Trial 2 (0.9%), Trial 5 (0.6%), and Trial 3 (0.2%). Trial 6 had no participant diagnoses of COVID-19 during this period (Figure 1a).

Early terminations due to the COVID-19 pandemic were highest immediately after the declaration of the global pandemic (quarter 5, 11 March 2020 to 10 June 2020). These occurred at a higher percentage in Trial 5 (7.7%), compared to Trial 1 (1.8%) and Trial 2 (0.9%), while Trials 3, 4, and 6 had no COVID-19-associated early terminations during quarter 5 (Figure 1b). Although Trial 3 had no early terminations due to COVID-19 during quarter 5, it had the highest percentages of COVID-19-associated early terminations for quarters 6–10, ranging from 0.7% to 5.2% (Figure 1b). Of note, there were no early terminations due to the COVID-19 pandemic reported in quarters 11–13 (Figure 1b).

The percentage of visits not performed due to COVID-19 was highest during quarter 8, corresponding to the period from 11 December 2020 to 10 March 2021. During this period 1.4% of participants in Trial 3 missed a visit. Trial 3 also had the highest percentage of visits not performed due to COVID-19 during quarters 6, 7, 9, 10, and 11, while Trial 2 had the highest percentage (0.7%) of visits not done during quarter 5. There were no visits not performed due to COVID-19 during quarters 12 and 13 (Figure 1c).

Most visits partially done due to COVID-19 occurred in Trial 5, ranging from 0.4% to 2.5%. As seen with early terminations and visits not performed, there were no visits partially performed due to COVID-19 during quarters 12 and 13 (Figure 1d).

The percentage of participants with at least 1 procedure out of protocol-defined window was highest during quarter 5 and varied among trials (Figure 1e). Overall, the highest percentage of participants with at least 1 procedure out of protocol-defined window was seen in Trial 3 (6.1%), followed by Trial 2 (5.1%) (Table 4). However, they were distributed among quarters 5–11 (Figure 1e).

Throughout the pandemic period, the impact of the COVID-19 pandemic on key operational endpoints varied by quarter and trial. Interestingly, there was limited impact during the latest pandemic periods captured (quarters 12 and 13).

Impact of the COVID-19 pandemic on key operational endpoints by region

We next investigated potential regional differences in the impact of the COVID-19 pandemic on key operational endpoints including, rate of blood draws out of protocol-defined window, rate of vaccinations skipped, rate of vaccinations given out of protocol-defined window, and rate of visits canceled or delayed. In the United States of America (USA – includes Puerto Rico), the rate of blood draws and vaccinations out of protocol-defined window and the rate of visits delayed or canceled were significantly higher in the pandemic period (quarters 5–13), while there was a trend for lower number of vaccinations skipped in the pandemic period (Figure 2a–d). In contrast the European Union (EU – includes Czech Republic, Finland, Italy, Poland, Romania, Spain, and Sweden), demonstrated no significant difference in the rate of blood draws or vaccinations out of protocol-defined window. However, there was a significant increase in rate of vaccinations skipped and visits canceled or delayed during the pandemic (Figure 2e–h). The pattern in the United Kingdom (UK) was more like that of the USA with significant increase in the rates of out of window blood draws and vaccinations and rate of visits canceled or delayed, but no significant difference in the rate of vaccinations skipped (Figure 2i–l). The “Other” region which includes Mexico and Russia demonstrated a significant increase in the rate of blood draws out of protocol-defined window and a significant decrease in the rate of vaccinations skipped in the pandemic period. These changes were likely the result of technical discrepancies with no relationship to the pandemic. There was no significant difference in either the rate of vaccinations out of window or the rate of canceled or delayed visits (Figure 2m–p).

Figure 2. Pre- and post-COVID operations by region. Green = pre-COVID-19 pandemic, purple = during COVID-19 pandemic. X represents rate, boxes are 95% confidence intervals. (a, e, i, & m) rate of blood draws out of protocol-defined window. (b, f, j, & n) rate of vaccinations skipped. (c, g, k, & o) rate of vaccinations given outside of protocol-defined window. (d, h, l, & p) rate of trial visits canceled or delayed. Regions: United States (US – includes Puerto Rico) A-D. European Union (EU – includes Czech Republic, Finland, Italy, Poland, Romania, Spain, & Sweden) E-H. United Kingdom (UK) I-L. Other (includes Russia & Mexico) M-P.

There were different regional patterns of operational disruption in the pandemic period. However, there were some similarities, particularly between the USA and UK. Notably, the significant decrease in the rate of vaccinations skipped in the pandemic period in the “Other” region is likely due to the higher-than-expected rates of skipped vaccinations during the pre-pandemic period.

Impact on both investigational and routine immunizations by the COVID-19 pandemic

Potential differences between the percent of routine immunizations (non-investigational products) and trial vaccines (investigational products) were also examined. Although the rates of vaccinations skipped varied by Trial, all trials demonstrated equal or higher rates of skipped routine immunizations compared to investigational vaccines (Figure 3a–f). In Trial 4, there were higher percentages of vaccinations skipped during the pandemic period, mostly consisting of routine immunizations (Figure 3d). Trial 4 corresponds to the EU region in which a significant increase in the rate of vaccinations skipped in the pandemic period was observed (Figure 2f). Importantly, these figures do not include those routine immunizations that may have been performed by the participants’ general practitioner rather than the trial site.

Figure 3. Investigational and routine vaccinations skipped by quarter pre-pandemic and during the pandemic. (a) Trial 1, (b) Trial 2, (c) Trial 3, (d) Trial 4, (e) Trial 5, (f) Trial 6.

Overall, the percentages of vaccinations skipped was only higher during the pandemic period in Trial 4, while Trials 1–3 and 5 demonstrated fluctuations throughout the observed time frame. The extremely high percentage of skipped routine immunizations in Trial 6 could not be explained by COVID-19 disruptions.

Effects of public health measures in the UK associated with the COVID-19 pandemic on trial operations

The UK instituted public health measures, including three government-mandated lockdowns, at multiple well-defined times following the declaration of the COVID-19 pandemic (Figure 4a).⁹ Thus, for Trial 5, we were able to align the timing of trial operation disruptions with the government-mandated lockdowns (Figure 4). The first lockdown in March 2020 aligned with quarter 5, the second lockdown in November 2020 occurred during quarter 7, and the third lockdown in January of 2021 occurred during quarter 8 (Figure 4a). While trial enrollment began in 2018, enrollment was ongoing at the time data collection commenced until 31 December 2021 (last participant enrolled November 2021). There was a decrease in the number of participants enrolled during the first two pandemic quarters; however, this did not strictly align with the timing of the government-mandated lockdown as the lockdown was in effect during quarter 5 but not quarter 6. Furthermore, there was a resurgence of enrollment during the second government-mandated lockdown occurring during quarter 7, which reached pre-pandemic enrollment numbers (Figure 4b). The other key operational endpoints that were measured in relationship to the government-mandated lockdowns included percentage blood draws out of protocol-defined window, percentage of vaccinations skipped, percentage of vaccinations performed out of protocol-defined window, and percentage of visits canceled or delayed (Figure 4c–f).

Figure 4. Effects of UK lockdowns on protocol deviations in study 5. (a) timeline of COVID-19 pandemic lockdown measures in the UK. (b) number of participants enrolled through the end of enrollment 31Dec2021. (c) percentage of blood draws out of window. (d) percentage of vaccinations skipped. (e) percentage of vaccinations out of window. (f) percentage of visits canceled or out of window. Yellow line = start of COVID-19 pandemic shaded red boxes = COVID-19 lockdowns in UK.

While there were significant clinical trial operational disruptions during the pandemic in the UK (Figure 2i–l), there were no clear associations between lockdown measures in the UK and operational disruptions in Trial 5. It is important to note that only country-wide government-mandated lockdowns were included in this timeline, not accounting for local restrictions that may have been in place during varying periods affecting individual sites.

Discussion

The declaration of the COVID-19 pandemic by the World Health Organization (WHO) occurred on 11 March 2020.¹ There were many necessary public health measures, including lockdowns, which resulted in numerous downstream effects. Among these were operational challenges during clinical trials.^2,3 Here, we report the results of this analysis of the operational outcomes of multiple randomized studies, specifically the impact of the COVID-19 pandemic on key operational endpoints in six ongoing pediatric non-COVID-19 Phase III vaccine clinical trials in various parts of the world.

Despite high levels of SARS-CoV-2 circulation during the pandemic period, only 3% of trial participants were diagnosed with COVID-19 during the period of data collection. This may represent under-reporting in the pediatric population due to fewer, less severe symptoms or lack of test availability early in the pandemic.^10,11 Smit, et al., noted a poor correlation between SARS-CoV-2 symptoms and RT-PCR positivity in children screened in 2020.¹¹ In fact, in this study only 5.6% of children, with or without symptoms, tested positive for SARS-CoV-2 by RT-PCR, while SARS-CoV-2 positivity was 15.5% in asymptomatic caregivers.¹¹ Interestingly, the highest percentage of participants diagnosed with COVID-19, for most trials, occurred during quarter 12 followed by quarter 8 (Figure 1a), which correspond to the emergence of the omicron and delta variant, respectively.^1,10 The delta and omicron variants demonstrated higher numbers of cases in children than previous variants.¹⁰ Thus, the percentages of participants with diagnosed COVID-19 may reflect the dynamics of circulating variants at the time of data collection.

Bakouny, et al., identified differences in COVID-19 disruptions that were more apparent in academically sponsored oncology trials compared with industry sponsored trials.³ We found no reports of COVID-19 disruptions on vaccine trials by sponsor type. In line with other reports, we demonstrated that the impact of the COVID-19 pandemic on operational endpoints was more notable during the earlier pandemic period.³ This is not surprising given the availability of vaccines against SARS-CoV-2 and reduced restrictive public health measures during the later pandemic period. Operational disruptions following the COVID-19 pandemic were multiple and the relative impact on specific operational endpoints varied by region. This may reflect differences in public health measures, including lockdowns, mask mandates, and social distancing requirements. Alternatively, this may represent differences in risk mitigation strategies instituted by the individual trials.

It is important to consider not only the impact of COVID-19 on the conduct of pediatric vaccine clinical trials, but also the important effects the pandemic had on routine immunization rates.¹² We identified higher percentages of missed routine vaccinations than investigational vaccines throughout the observation period; however, an increase following the onset of the pandemic was only obvious in Trial 4. Critically, these data do not include routine immunizations that may have been received at a general practitioner’s office rather than at the trial site. Thus, while there was likely an effect of the COVID-19 pandemic on administration of routine pediatric vaccines, particularly early in the pandemic period, ultimately, in most regions, this effect was not large.

We specifically looked at the potential association of public health mitigation strategies in the UK and operational disruptions of pediatric vaccine clinical trials. As did many countries, the UK instituted government-mandated lockdowns during different phases of the pandemic.⁹ We selected the UK for these observations due to well documented country-wide lockdowns. Although we did not identify specific associations among national lockdowns and operational disruption, it is important to consider the potential lag in effects between public health mitigation measures and their outcomes, as well as the potential contributions of local/regional government-mandated lockdowns.

Due to the obvious difficulties associated with the major global disruptions from COVID-19 ongoing pediatric clinical vaccine trials have been impacted. The magnitude of the impact was no doubt affected by mitigation strategies developed throughout the pandemic. Critical impacts of this analysis and learning points for the future, include¹ the need for a flexible approach when faced with such unexpected situations,² working closely with ethics committees and regulators,³ maintenance of open communication with investigators, encouraging them to maintain an open line of communication with study participants, and⁴ the importance of closely monitoring critical operational parameters during the study recruitment and follow-up phases of the studies allowing the teams to respond early to disruptions. Importantly, during the COVID-19 period, regulators appreciated that disruptions occurred and have been accommodating in working with trial sponsors to modify analysis plans appropriately.

Limitations

Some of the limitations of this analysis include the fact that data were extracted while the trials were ongoing, thus these do not represent the final trial data after database lock. Additionally, the reporting of participants impacted by the COVID-19 pandemic required the sites to appropriately complete an additional form in the CRF potentially resulting in under-reporting. For analysis of the impact on routine immunizations, we are inferring from participants in clinical trials potential impacts on non-participants. Additionally, we were unable to account for routine immunizations that may have been received at locations other than the trial sites.

Conclusions

Although there were many operational challenges associated with the COVID-19 pandemic in ongoing pediatric vaccine clinical trials, the majority of these occurred early in the pandemic period and subsequently resolved. Furthermore, impacts were regional and varied by trial. However, the current analyses did not identify a clear association with specific government-mandated lockdown measures. Through coordinated efforts by the Sponsor, Investigators, and site staff, these studies continued despite the operational challenges imposed by the COVID-19 pandemic, a testament to the hard work and dedication of the teams. The unique assessment of differences in disruption of investigational and non-investigational vaccines contributes to the importance of this manuscript. Additionally, Study 5, conducted only in the UK, allowed examination of the impact of government-mandated lockdowns on pediatric clinical trial conduct.

Disclosure statement

No additional potential conflcit of interest was reported by the author(s).

Additional information

Funding

All the studies described in the manuscript were funded by Sanofi. All the authors are current or ex-employees of Sanofi and may hold shares and/or stock options in the company.