Guidance for the collection of case report form variables to assess safety in clinical trials of vaccines in pregnancy

a b s t r a c tVaccination in pregnancy is an effective strategy to prevent serious infections in mothers and their infants. Safety of this strategy is of principal importance to all stakeholders. As the number of studies assessing safety of vaccines in pregnancy increases, the need to ensure consistent collection and reporting of critical data to allow comparisons and data pooling becomes more important. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project aims to improve data collection and create a shared understanding of maternal, fetal and neonatal outcomes in order to progress the global agenda for vaccination in pregnancy.The guidance in this document has been developed to harmonize the data collected in case report forms used for safety monitoring in clinical trials of vaccination in pregnant women. Data to be collected is prioritized to allow applicability in diverse research settings, including low and middle-income countries. Standardized data will enable the research community to have a common base upon which to conduct meta-analyses, strengthening the applicability of outcomes to different settings.

## A b s t r a c t
Vaccination in pregnancy is an effective strategy to prevent serious infections in mothers and their infants. Safety of this strategy is of principal importance to all stakeholders. As the number of studies assessing safety of vaccines in pregnancy increases, the need to ensure consistent collection and reporting of critical data to allow comparisons and data pooling becomes more important. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project aims to improve data collection and create a shared understanding of maternal, fetal and neonatal outcomes in order to progress the global agenda for vaccination in pregnancy.
The guidance in this document has been developed to harmonize the data collected in case report forms used for safety monitoring in clinical trials of vaccination in pregnant women. Data to be collected is prioritized to allow applicability in diverse research settings, including low and middle-income countries. Standardized data will enable the research community to have a common base upon which to conduct meta-analyses, strengthening the applicability of outcomes to different settings.
O 2016 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Preamble

## Background and need for this guidance
Vaccination in pregnancy is an effective strategy to prevent serious infections in mothers and their infants [bib_ref] Influenza vaccination of pregnant women and protection of their infants, Madhi [/bib_ref] [bib_ref] Tetanus toxoid immunization to reduce mortality from neonatal tetanus, Blencowe [/bib_ref] [bib_ref] Effectiveness of maternal pertussis vaccination in England: an observational study, Amirthalingam [/bib_ref] [bib_ref] A case-control study to estimate the effectiveness of maternal pertussis vaccination in..., Dabrera [/bib_ref] [bib_ref] Effectiveness of maternal influenza immunization in mothers and infants, Zaman [/bib_ref]. Recommendations exist for use of tetanus and influenza vaccines in many countries and the number of countries recommending pertussis vaccination continues to increase. Other vaccines are recommended in pregnant women where there is perceived benefit, such as hepatitis A, hepatitis B and meningococcal (serogroups A,C,W,Y). Novel vaccines targeting group B streptococcus (GBS) and respira-tory syncytial virus (RSV) are in various stages of development [bib_ref] An update on vaccination against group B streptococcus, Heath [/bib_ref] [bib_ref] Respiratory syncytial virus in infants: is maternal vaccination a realistic strategy?, Munoz [/bib_ref].
Safety of vaccination in pregnancy is a key consideration for pregnant women, healthcare providers, vaccine manufacturers, regulators, sponsors and ethics committees. The number of studies assessing safety of vaccination in pregnancy continues to increase; however, inter-study variability makes comparisons and pooling of data challenging [bib_ref] A systematic review of adverse events following immunization during pregnancy and the..., Fulton [/bib_ref]. The failure to collect and consistently report critical data and the absence of guidance for data collection were identified at two international conferences, which concluded that data collection and presentation should be harmonized across different studies and settings [bib_ref] Maternal immunization: challenges and opportunities, Merieux [/bib_ref].
The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project (http://gaia-consortium.net), coordinated by the Brighton Collaboration Foundation (https://brightoncollaboration.org), aims to improve data collection and create a shared understanding of maternal, fetal and neonatal outcomes in order to progress the global agenda for vaccination in pregnancy. The guidance proposed in this document have therefore been developed to harmonize the data collected in case report forms (CRFs) used for safety monitoring in clinical trials of vaccination in pregnant women. Guidance on the prioritization of the data to be collected is also provided to promote collection of at least a minimal set of high priority parameters in various settings, including low and middle-income countries (LMIC).

## Use of this guidance
The aim of this guidance is to provide a standard for the collection of data in CRFs in clinical vaccine trials involving pregnant women where safety is an outcome. The guidance is presented as a series of tables and is referred to henceforth as a data collection matrix. It is intended as a tool to optimize data collection and to do so in a standardized manner in order to improve accuracy and comparability between clinical trials of vaccines in pregnancy. A standardized set of data will enable the research community to have a common base upon which to conduct meta-analyses, strengthening the applicability of outcomes to different settings. This data collection matrix is intended to be useful in all phases of clinical trials, from Phase I to Phase IV, from initial planning to implementation and evaluation. It is aimed at all stakeholders, from investigators, research networks, ethics committees and sponsors. It is also intended to be applicable in all resource settings; however, it is acknowledged that there are particular challenges to implementation in low and middle income countries (LMIC).
In consideration of this wide remit, data variables are prioritized into Priority 1 and Priority 2 data as follows:
Priority 1: Essential: data considered essential for the understanding of the trial results and/or required by national and/or international regulatory authorities Priority 2: Complementary: data considered complementary, but not essential.
This data collection matrix is intended as a tool to assist all stakeholders; it is not regulatory or mandatory in nature. It is not intended to guide or establish criteria for clinical management. It is also not all-encompassing; it should be considered as a minimal data set in clinical trials where safety is an outcome. It is also expected that it may be adapted according to the specific aims and objectives of the individual clinical trial and that additional variables and data may also be collected.
It is intended that this guidance will be used alongside other existing guidelines from the Brighton Collaboration and the GAIA project. In particular, it is complementary to the ''Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women" [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. The existing case definitions of key neonatal and maternal outcomes for clinical trials of vaccines in pregnancy, produced as part of GAIA should be referred to [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref] as relevant and as new case definitions are developed these should also be used for safety assessments in future clinical trials. They will become available at www.brightoncollaboration.org.

## Development process of data collection matrix
This data collection matrix was constructed using an iterative process. Six CRFs from investigator initiated and industry sponsored clinical trials carried out in diverse geographical settings, including Africa, Asia, Europe and North America, and assessing different vaccines were collected and all variables were extracted into Microsoft Excel (see acknowledgments section for contributors of the CRFs used). Each variable was then coded according to whether or not it was collected in each study. This enabled a visual representation of the variables in each study to be displayed. Each member of the Data Collection Matrix Working Group (CEJ, MS, PTH, SB, UH), then independently assessed each variable as essential, important or non-essential in clinical trials assessing safety of vaccination in pregnancy. Any other variables considered essential but missing from this master list were added at this stage. Each variable was then scored according to the number of individuals who considered it as essential or important. The list of variables for inclusion or exclusion was then reviewed and agreed by all members of the working group during a series of telephone conferences. Included variables were further refined during a process of review by the Executive Committee of the GAIA consortium by telephone calls and face to face meetings. Variables were grouped into tables and harmonized with the Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women (referred to forthwith as the Guidelines document) [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. The data collection matrix was then refined following structured peer-review by the broad global Brighton Collaboration Reference Group and review by subject matter experts attending the Harmonized Safety Monitoring of Immunization in Pregnancy International Consensus Conference and Investigators Workshop, 28-30th March 2016, National Institutes of Health, Bethesda, USA. This guidance should be considered as a 'living document', which will be reviewed periodically and updated to take account of emerging data and feedback from investigators implementing this guidance, these will be available at www.brightoncollaboration.org.

## Rationale for overall structure of the data collection matrix
The data collection matrix is presented as a series of tables of variables to be collected in case report forms. Each table relates to a different time-point or section of the case report forms. The data collection matrix and the Guidelines document are discrete documents, which are highly inter-related. It is expected that both documents will be used in parallel. The Guidelines document provides higher level information whereas the data collection matrix provides greater granularity. For example, the Guidelines document advises that safety follow-up should include a symptom diary to record solicited and unsolicited local and systemic adverse events following immunization (AEFI). The data collection matrix provides the detail of what variables should be collected in this symptom diary and suggests how signs and symptoms should be measured or graded. Each table in the data collection matrix relates to a section in the Guidelines document. Therefore, whilst distinct documents, they are harmonized and should be used together.

## Guidance for the collection of case report form variables
The tables define data that should be collected prior to vaccination [fig_ref] Table 1: Pre-vaccination screening data [/fig_ref] , at the time of vaccination and in the follow-up period. Early phase clinical trials may select pregnant women at low risk of obstetric complications, whereas in other studies, particularly late phase clinical trials, it may be preferable to enroll pregnant women regardless of their obstetric risk. In recognition of this, an example of variables that may be collected to assess obstetric risk is provided .
In order to assess safety of vaccination in pregnancy, it is recommended that the minimum follow-up period for women is 6 months post-delivery or the early termination of pregnancy; the minimum recommended follow-up period for infants is until 1 year of age. It is acknowledged that there are significant logistical challenges with extended follow-up periods; where a shorter follow-up period is pre-defined in the study protocol, adequate justification should be given, for example, based on biological characteristics of the vaccine, the vaccine-targeted disease or of the adverse event of specific interest, including patterns identified f Guidance on the assessment of gestational age can be found in the GAIA case definition of preterm birth at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref].

## Table 2
Example table of data that may be collected to inform obstetric risk assessment. org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. b Case definition of stillbirth is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. c Case definition of neonatal death is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. d Case definition of congenital anomaly is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref].

## Priority

## Maternal medical history

## Table 3
Vaccine and immunization related data.

## Priority
Investigational vaccine and immunization procedures Participant baseline vital signs (including blood pressure, heart rate, respiratory rate, and temperature) Need for analgesia or antipyretic 2Follow-up monitoring data (including data pertaining to the mother pre-delivery, fetus, the delivery and the neonate, mother and infant until completion of follow-up). 1 Infant ethnicity/race 1 Infant APGAR score (or other immediate assessment for signs of life) at 1, 5 and 10 min 1 Need for infant resuscitation with details 1 Specify any abnormalities on newborn examination 1 Infant feeding: breast milk (mother/donor), formula feeding, parenteral nutrition, mixed feeding, other (specify nutrient given), with start dates 2 Results of any neonatal laboratory tests specified in the protocol (minimum of full blood count, differential, transaminases, bilirubin, glucose, blood urea nitrogen and creatinine) [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. b Case definition of gestational hypertension is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. c Case definition of postpartum haemorrhage is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. d Case definition of stillbirth is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. e Case definition of neonatal death is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. f Guidance on the assessment of gestational age can be found in the GAIA case definition of preterm birth at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. g Case definition of congenital anomaly is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. h Case definition of neonatal infection is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref].
in previous trials. There may also be reasons for extending safety follow up further based on the above factors, or the characteristics of the vaccine recipient (e.g. nutrition, underlying diseases such as immune-depressing illnesses and other pre-existing conditions), or the intention to assess child development and late onset outcomes as part of the Risk Management Plan (which may require follow-up periods of 5 years or more). [fig_ref] Table 5: Adverse event monitoring data [/fig_ref] provides guidance for the collection of high quality data in order to allow interpretation of adverse events following immunization (AEFI); the purpose is not to provide guidance on assess-ment of a causal relationship. More detailed guidance on protocol development for clinical trials assessing vaccines is available elsewhere [bib_ref] Template protocol for clinical trials investigating vaccines-focus on safety elements, Bonhoeffer [/bib_ref] (see [fig_ref] Table 6: Protocol deviations and additional data [/fig_ref].

# Conclusions
This guidance is intended as a tool to optimize data collection in all phases of clinical trials of vaccination in pregnancy where safety is an outcome. The aim of standardizing data collection is to improve accuracy and comparability and to allow pooling of data a Case definition of congenital anomaly is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. b Guidance of causality assessment can be found at: https://brightoncollaboration.org/public/resources/standards/guidelines.html. c Case definition of maternal death is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref]. d Case definition of neonatal death is available at brightoncollaboration.org [bib_ref] Pathways to preterm birth: Case definition and guidelines for data collection, analysis,..., Harrison [/bib_ref].
between studies. The remit of this guidance is wide and therefore data variables are prioritized into essential data (priority 1) and data that are useful but less essential (priority 2). Variables collected in CRFs are expected to be dependent on the pre-specified aims and objectives, study setting and resources in the clinical trial. It is acknowledged that there are particular challenges of collecting all data variables in LMICs. Evaluation of this tool will be the subject of future work in order to continue to improve the utility of the data collection matrix to all stakeholders in clinical trials of vaccines in pregnancy.

## Disclaimer
The findings, opinions and assertions contained in this consensus document are those of the authors. They do not necessarily represent the official positions or views of their respective institution or organization (e.g., government, university, or corporation).
[fig] 1. 4: Relationship of the data collection matrix to the ''Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women" [/fig]
[table] Table 1: Pre-vaccination screening data. Date of birth (dd/mm/yy or mm/yy, if actual date unknown) and age (completed years) of pregnant woman If maternal HIV infection: WHO clinical HIV staging c 1 If maternal HIV infection: CD4 result (% and absolute), with date of test 1 If maternal HIV infection: Viral load test, with date 1 Concomitant medications (name of drug, route, start and stop date, reason for medication) 1 Medication history, including 1 month prior to pregnancy, to include prescription and non-prescription drugs, recreational drugs, herbal and homeopathic preparations and nutritional supplements 1 History of allergies, including allergen and reaction 1 Tobacco use in this pregnancy (e.g. daily, less than daily, never) d 1 Tobacco consumption in this pregnancy (e.g. average number per day or week/NA) 2 Alcohol consumption in this pregnancy (e.g. daily, several times a week or month, never) e 1 Gravity and Parity 1 Details of previous pregnancy complications (e.g. antepartum hemorrhage, post-partum hemorrhage, incompetent cervix) 1 Dates of previous deliveries, noting singleton or multiple births 1 Gestational age at delivery of previous infants 1 Type of previous delivery (vaginal, elective or unplanned cesarean section) 1 Outcome of previous pregnancies (live birth, still birth or abortion) 1 Previous neonatal deaths 1 Current pregnancy Date (dd/mm/yy) of last normal menstrual period (LMP) 1 Date of LMP: not known, unsure, sure 2 Estimated due date (EDD) 1 Method of EDD estimation (LMP, ultrasound, symphysis-fundal height or combination) 1 Dates of antenatal care visits in current pregnancy 1 Results of routine screening for infection 1 Results of routine screening to assess pregnancy and fetus (e.g. ultrasound, amniocentesis) 1 Vaccines received within 1 year prior to enrollment, with date of administration, where documentation available 1 Acute medical condition or pregnancy complication during current pregnancy 1 Results of non-routine laboratory testing during pregnancy relevant to current medical conditions 1 At high risk of serious obstetrical complications (Y/N) (example of obstetric risk assessment, Table 2) 2 Maternal Body Mass Index, BMI, (or other validated nutritional indicator) 1 Vital signs, including: resting heart rate (bpm), Systolic and diastolic blood pressure (mmHg), Respiratory rate (breaths per minute), Body temperature (degrees Celsius or Fahrenheit) General physical examination of mother (including general appearance, dermatological, cardiovascular, respiratory, hematological, gastrointestinal, urogenital, musculoskeletal, neurological, ocular/visual and endocrine/metabolic signs) Obstetric examination (including scars from previous deliveries, fundal height, fetal heart tones and fetal movement) 1 Maternal laboratory examinations Date and results of general investigations (including Full blood count, differential, Urea, Creatinine, AST  , ALT  , GGT  , Bilirubin, Na, K, Cl, Glucose [  or equivalent]) Date and results of baseline investigations for infections that may impact on immunogenicity, efficacy and safety of pregnancy vaccines or aid interpretation of events that occur in the mother, fetus, neonate or infant Date and results of investigations relevant to the target infection (e.g. GBS colonization in a GBS vaccine trial) 1 Date and results of urine tests (protein, glucose, bacterial culture) 1 [/table]
[table] Table 5: Adverse event monitoring data (including maternal, fetal and infant). Adverse event following immunization (AEFI) data collection Participant number 1 Adverse event number 1 Name of person reporting AEFI 1 Contact details of reporter 1 Source of information (e.g. hospital, clinic notes) 1 Role of reporter (e.g. physician, nurse, midwife) 1 Date and time of report 1 Modality to capture event (e.g. scheduled trial visitor phone call, unscheduled visit) 1 Study vaccine allocation 1 Administration route of study vaccine (e.g. oral, intramuscular, subcutaneous, intradermal, intranasal) 1 Date of study vaccination 1 Date and time of first onset/observation & temporal relationship to vaccination 1 Detailed history of event(s), including times/dates Type of AEFI with details (e.g. dermatological, cardiovascular, hematological, gastrointestinal, neurological [includes audiological], respiratory, musculoskeletal, urogenital, ocular/visual, endocrine/metabolic, If infant: Small for gestational age (Y/N) 1 If infant: details of any congenital anomalies a or birth injuries 1 If infant: congenital infection (Y/N, details) 1 If pregnant woman include details of fetal distress, time of miscarriage or still birth 1 Participant seen by physician for complaint: Y/N/U 1 Contact information of physician 2 Hospitalization for current event (Y/N/U) with dates of hospitalization 1 Contact details of hospital 2 Admission date of hospitalization 1 Concomitant symptoms, sign and diseases (other than those described) 1 Findings from physical examination 1 Findings from further investigations (test, date, findings, diagnosis, source of information) 1 Treatment for AEFI (dates, clinical condition and treatment provider) 1 History of recurrence of the event after AEFI 1 Outcome of event/action taken 1 Severity of AEFI (Hospitalization/disability/life threatening event/death [with details of cause and autopsy details]) 1 Causality assessment done: Y/N/U 1 Outcome of causality assessment b : not related/related/indeterminate (definitions and justification should be documented in study documentation) 1 Alternative etiology: Y/N, details 1 Participants condition return to pre-vaccination health status: Y/N/U 1 Resolved (Y/N) and date of resolution 1 Criteria for SAE reached: Y/N/U 1 Outcome of AEFI 1 If died: date of maternal c or neonatal death d 1 Cause of death 1 Autopsy performed Y/N, outcome 1 Further doses of investigational product given: Y/N and dates 1 Details of any concurrent local disease outbreaks pertinent to AEFI 1 [/table]
[table] Table 6: Protocol deviations and additional data. Effects of protocol deviation: AE/termination of FU/product stability 1 [/table]