An audit of questions asked by participants during the informed consent process for a phase 2/3 COVID-19 vaccine regulatory study at a tertiary referral centreVL Chaudhari, CJ Godbole, SR Bendkhale, NN Desai, NJ Gogtay, UM Thatte
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.jpgm_1216_21
Source of Support: None, Conflict of Interest: None
Keywords: Compensation, content analysis, safety
The International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice guidelines (ICH GCP) defines informed consent as a process by which a subject voluntarily confirms his or her own willingness to participate in a particular trial after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. A crucial aspect of this process is that investigators should provide adequate time to potential participants to ask questions, give them sufficient time to understand all aspects of the study, and clarify all queries to the participant's satisfaction.
Our institute was part of a bridging study for COVISHIELD™ CTRI/2020/08/027170 which began in India in September 2020 during which we captured questions raised by the participants during the consent process from the narratives of the informed consent process. An analysis of these questions would help investigators and policy makers understand the concerns that participants have and also evaluate the adequacy of the informed consent process for the COVISHIELDTM vaccine study. This formed the objective of our study.
We obtained approval for the study protocol along with a consent waiver from the Institutional Ethics Committee [Study reference - EC/OA-40/2021]. The permission to analyze the informed consent documents and the written consent narratives of the participants at our site was also obtained from the sponsor.
Study design and duration
The study was a retrospective audit.
Inclusions were participants who consented and completed the consent process. Those who declined consent were excluded.
We analyzed the ICDs of the participants [which were either in English or Hindi or Marathi language] and the written consent narrative. This refers to the document which captures the entire informed consent process along with the questions asked by the participants during the consent process and the answers given by the person obtaining informed consent. The physicians who were part of the consent process and who themselves were familiar with written and spoken English, Hindi, and Marathi with the requisite qualifications. The confidentiality of the individual participants was maintained using unique identifiers. Four authors evaluated the narratives independently and the quality check was done by the senior authors.
Information gleaned from the Informed Consent Document [ICD] and consent narratives- The following information was collated - participant age, gender, educational status, occupation, annual income, and date and time of consent. The start and stop time was taken from the consent narrative.
Classification of questions identified in the consent narratives
We classified the questions asked under the following domains –efficacy and safety of the Investigational Product (IP), study procedure, scientific aspects of the protocol, post-trial access, payment for participation, IP-related questions, and any additional questions asked. We based this on the Indian Council of Medical Research's (ICMR) National Guidelines for Biomedical and Health Research involving Human Participants (2017), which outlines the essential elements in an ICD.
Assessment of education and socio-economic strata
Based on the school education system in India, educational status was divided into four categories- primary and middle school (up to 8th grade education), high and higher secondary school (9th–12th grade education), graduates (completed college with a bachelor's degree) and post-graduates (completed college with a master's degree). Based on the updated BG Prasad socioeconomic scale 2020, the participants were divided into five socioeconomic categories- upper [Indian rupees (INR) >7,533/months], upper middle (INR between 3,766-7,532), middle (INR between 2260-3765), lower middle (INR between 1,130-2,259) and lower (INR < 1130).
The outcome measures were- number of total questions asked by the participants [dependent variable] including all domains, the proportion of participants who asked questions in each of the domains.
The sample size for our site in the multicentric regulatory trial was N = 100 for which, we had screened N = 129 participants who had given consent for the regulatory trial and none of the potential participants had declined the consent in the regulatory trial. Hence, as per the eligibility criteria, N = 129 thus formed the final study sample.
Statistical and content analysis
Both descriptive and inferential statistics were applied to the data. Categorical data (for example - gender, employment status) was presented as proportions, while numerical data (for example, number of questions asked, time taken to consent) was presented as median (range). Between group comparison (female vs male, unemployed vs employed, primary school vs secondary school vs graduate vs post-graduates, upper vs upper middle vs middle vs lower middle vs lower) for the number of questions asked was done using univariate analysis followed by multivariate regression analysis with post hoc Tukey test. Independent variables were - gender, employment status, education, and socioeconomic status, and the dependent variable was the number of questions asked by the participant. All statistical analysis was done using Statistical Package for the Social Sciences (SPSS) version 20, IBM Corporation, Armonk, New York and the statistical significance was set at <0.05. Content analysis was done by creating the following categories after going through all consent narratives and Informed Consent forms - Study procedure; Safety and risk; Payment related; Scientific aspects of the study; and post-trial access. Each category was subsequently coded independently by four authors. A consensus was reached amongst all the authors about the coding and the categories.
A total of N = 129 adult healthy participants with a median [range] age of 42 years [19-67] formed the final sample. Among the consent narratives, 118/129 (91.5%) were obtained from men and 11/129 (8.5%) were obtained from women. The consents were largely obtained in English 98/129 (76%) followed by Marathi 23/129 (17.8%) and only 8/129 (6.2%) were obtained in Hindi. The median time (range) taken for consenting the participants was 32 (23–86) minutes. A total of five physicians obtained consent from the potential participants.
Of these 129 participants, only one participant was illiterate and we had an impartial witness.
Therefore, amongst the total n = 128 literate participants, 60/128 (46.9%) participants were graduates, 51/128 (39.8%) were post-graduates, 15/128 (11.7%) were those with secondary school education, and only 2/128 (1.6%) had a primary school education. A total of 121/129 (93.8%) participants were employed and while the remainder of 8/129 (6.2%) were unemployed [Table 1]. The majority 120/129 (93%) of the participants were from the upper economic status while only one (0.8%) belonged to the upper-middle and the rest (8, 6.2%) were from the lower economic strata.
Questions asked - The total number of questions asked by the 129 participants was N = 295 with a median of two questions asked per participant (range 0–11).
We categorized questions asked into five main categories. These were - study procedure, safety and risks, payment related, scientific aspects, and post-trial access. These categories were further delineated using several codes [total 18 codes, [Table 2]]. Of the total N = 295 questions asked by the participants, half of the 149/295 (50.5%) questions were on study-related procedures followed by one quarter 76/295 (25.8%) based on safety and risk associated with IP. Whereas, approximately 10% of questions were related to payment and scientific aspects of the study. Only 15/295 (5.0%) questions were asked related to post-trial access of the vaccine.
In the present audit, we evaluated N = 129 informed consent forms and their consent narratives from the participants of the phase 2/3 vaccine COVISHIELD study who were recruited from September to October 2020 in Mumbai. Ninety nine percent of participants asked questions with the median number of questions asked is two (0–11). The majority of the participants were well educated [87%], employed [94%], and from upper socio-economical strata [93%]. The majority [67%] of the questions asked by participants were related to the study protocol followed by the safety of the investigational product [45%]. The predominantly male population in the study again underscores the fact that women are generally underrepresented in clinical trials, for reasons identified earlier. The novelty of the study lies in it being conducted during a pandemic setting.
When we compared this study to a previous study done by Saxena et al., which evaluated a total of N = 297 consent narratives in five regulatory studies conducted over a year in the pre-pandemic situation at our center, they found that participation of women was more as compared to our study (37 vs 8%; P < 0.0001). Similarly, 92% of the consent forms were signed in the local language vs only 24% in our study [P < 0.0001]. In their study, only 18% of the participants were graduates relative to 86% in our study [P < 0.0001]. As regards employment, 63% were employed in the study by Saxena et al. relative to 94% in our study [P < 0.0001]. Details are presented in [Table 3]. We hypothesize that the significant differences seen are due to the fact that the pandemic led to unprecedented media coverage of all COVID -19 vaccine trials leading to the participation of a largely urban population, and employed English speaking male graduates despite the institution being one that largely caters to the lower socio-economic strata.
Nature of questions: In our study, the majority of questions asked were related to the study procedure (67% vs 49%; P = 0.009), while in the previous study they were related to safety (50% vs 77%; P < 0.0001). In the present study, the participants focused on science (28% vs 6%; P < 0.0001). In the present study, the participants focused on science (28% vs 6%; P < 0.0001) of the study, payment) of the study, payment-related issues (21% vs 16%; P = 0.36) but there was limited concern about post trial access (2% vs 6%; P = 0.14). This difference in the nature of questions asked was found to be statistically significant [P < 0.0001; x2 = 48.2 and dF = 7]. The probable explanation for this difference could be the limited knowledge about the corona virus in the early stages of the pandemic when the vaccine study was undertaken leading to a focus on science from an educated male population. Also, given the fact that post trial access was clearly stated in the consent form, this may have been less of a concern.
In the present study, we found that nearly half of the total questions asked and two-thirds of the consent narratives had questions related to study procedures/protocol related such as 'How many visits do I require to complete the study; Where should I come for my next visit; What will happen if I miss my follow up visit date; What are my responsibilities as a research participant; and How much time I have to stay after vaccination?'. This could be attributed to the lockdown restrictions during the pandemic which made the potential participants wary of the travel to the site for the study visits. The potential participants also expressed their concern about the 25% chance of getting a placebo by asking questions such as 'Will I get vaccine or placebo; What is the possibility that I will get the study vaccine?'. This might be due to the surging spread of the disease making the potential participants feel both vulnerable and apprehensive and this could have impacted the nature and type of the questions asked. The potential participants were also worried about the site of vaccination and the number of times the blood will be collected.
Half of the potential participants asked questions about the safety of the vaccine or the placebo-like- 'What are the possible side effects of the study vaccine/placebo; Will the adenovirus in the vaccine cause me harm; Does the vaccine contain live coronavirus and can cause covid 19 disease and What happens if there is a serious/life threatening side effect?' indicating that safety featured high on their list of questions given the limited understanding at the point of the vaccine study. The lack of association between the number of questions asked by the potential participants and independent variables is likely due to the small sample size and considerable homogeneity [English speaking, well-educated and male participants] in our population which are the major limitations of our study. The present study is also limited by being from a single center in a metropolis and with just one historical comparator and that too from our own center.
In summary, our audit found that in a regulatory COVID-19 vaccine trial majority of the questions/doubts [67%&x93; asked by the participants during the informed consent process were about study-related procedures followed by the safety of the COVID vaccine. We did not find an association between the number of questions asked during the consent process and their age, gender, educational status, occupation, and socioeconomic status.
We are grateful to Dr Unnati Saxena for providing the data on the demographic characteristics and questions asked by the participants in pre-pandemic era in the form of publication. We are also grateful to all the participants in our study. The authors are also grateful to Dr Milind Nadkar, Professor and Head of Medicine, for the help and support provided during the conduct of this original regulatory study.
Financial support and sponsorship
Conflicts of interest
[Table 1], [Table 2], [Table 3]