This Therapeutic Area Data Standards User Guide for Vaccines (TAUG-Vax) was developed under the Coalition for Accelerating Standards and Therapies (CFAST) initiative.

The purpose of this TAUG-VAX is to describe how to use CDISC standards to represent data pertaining to vaccines studies. This first version (v1.1) focuses on safety data for reactogenicity events collected during vaccines trials.

• Other standards related to reactogenicity (e.g., collection of data using the CDASH model and Statistical Assessments using the ADaM model) will be covered in subsequent versions of this guide.
• Other topics (e.g., unsolicited adverse events, potential immune-mediated medical conditions (PIMMC), immunogenicity assessment and clinical efficacy assessment) will also be covered in subsequent versions of this guide.

1. First, read SDTM v1.4 and SDTMIG v3.2 to gain some familiarity with basic SDTM modeling. These standards are available from: http://www.cdisc.org/.
2. Next, read Introduction to Therapeutic Area Standards (at http://wiki.cdisc.org/x/SSy8AQ) and/or take CDISC's free training module TA001 - Overview of Therapeutic Area User Guides (at https://secure.trainingcampus.net/uas/modules/trees/store/wcatalog.aspx?cat=1015&ci=4&vtype=2&pi=0) to be sure to know what to expect from a therapeutic area user guide such as this document.
3. Read this guide all the way through (without skipping any sections) at least once.
4. Finally, revisit any sections of particular interest.

All general caveats for TA standards given in the Introduction to Therapeutic Area Standards (http://wiki.cdisc.org/x/SSy8AQ) apply to this document.

This document is divided into the following sections:

• Section 1, Introduction, provides an overall introduction to the purpose and goals of the Therapeutic Area Data Standards User Guide for Vaccines.
• Section 2, Overview, provides some general information on vaccines trials and reactogenicity events, in particular.
• Section 3, Case Description, provides background information about the type of study that the examples are based on.
• Section 4, Trial Design, provides examples used to support the modeling of Reactogenicity Safety Assessments.
• Section 5, Vaccine Administration, provides examples used to support the modeling of Reactogenicity Safety Assessments.
• Section 6, Reactogenicity Safety Assessments, provides examples of modeling reactogenicity data using different data collection methods.
• Section 7, Relating Records, provides information on how domains used in these examples can be linked.
• Appendices provide additional background material and describe other supplemental material relevant to vaccines.

• Timing variables: The time when a reactogenicity event is evaluated within an assessment interval is generally not defined precisely. Instructions to subjects filling out a diary card might refer to calendar days, or might ask the subject to complete the diary card at the end of the day before retiring for the night. Other than the value of "END DAY X" used to represent the planned assessment time point (--TPT), it is difficult to represent the imprecise timing of the collection of data on reactogenicity events. The variables --EVLINT and --EVINTX are used to capture the evaluation interval. However, the values such as -P1D are not intended to imply that data are collected in strict 24-hour intervals based on the time of day of vaccination (e.g., 10:30 on one day to 10:30 on the next day). For point-in-time measurements (i.e., not taken over an interval) such as temperature and diameter of swelling or redness, the timing variables other than --DTC are not populated, as one cannot assume that those values remain constant over the entire interval.
• Representation of the evaluator: Generally, the person who provides the evaluation of an event or finding can be represented in the variable --EVAL. In some vaccine studies where the subject self-reports reactogenicity events using a diary card, the investigator's assessment of the reported reactogenicity event may complement or possibly conflict with that of the subject (e.g., event severity). In some cases, the conflicting portions of the investigator's assessment may replace the subject-reported data. Both the study subject and the investigator contribute to the evaluation of a reactogenicity event. This topic is under discussion. Currently there is no agreed-upon solution to attribute specific variables within a record to more than one evaluator, to represent multiple values from conflicting assessments for a specific variable, or to document why the investigator modified the subject data. Sponsors should discuss how this should be handled with the relevant regulatory authority prior to data submission.
• Representation of event end dates that continue beyond the planned observation interval: When reactogenicity events continue beyond the planned assessment period, it is important to follow the subject until the event resolves. When these are considered clinical events, another record can be added in FA along with the planned daily assessments. It is important to capture the date that the event resolves, but the best way to do this within a Findings structure is unclear. The variable --ENDTC is generally only used in a Findings structure to represent the end date of specimen collection, where --DTC represents the start of the specimen collection. For that reason, --ENDTC was not used in FA or VS. Instead, the summary CE record was expanded and CEENDTC was used to represent the end date of the event.
• Representation of the maximum number of vomiting episodes when vomiting continues beyond the planned observation interval: During the planned observation period a subject may be asked to report the total number of vomiting episodes experienced each day. In this scenario, the evaluation period of "one day" can be represented in ISO8601 format as "-P1D" using the variable --EVLINT. However, when vomiting continues beyond the planned assessment period, the subject may be asked to report the maximum number of daily episodes experienced over the entire continuation period. Because the follow-up period beyond the planned observation period is not pre-specified, the timing around the concept of "maximum daily episodes" is challenging to represent unambiguously. For this case, we decided to represent the concept of "maximum" in the NSV, COLSRT (Collected Summary Result Type) and to populate the variable FAORRESU with "/day", as the value in FAORRES represents the maximum number of daily episodes and not the total number of the episodes during the period. We acknowledge that this may be an awkward solution and should be addressed in an update to the SDTM/SDTMIG.
• Representation of daily maximum temperature, redness at administration site, and severity when only one record is recorded: If subjects assess their temperature, redness at administration site, or event severity multiple times throughout the day, the protocol may specify for subjects to record only the maximum measurement taken. The examples in this guide show the concept of "maximum" represented in the non-standard variable, COLSRT (Collected Summary Result Type). However, the discussion around this topic is ongoing and may be subject to change at a later date.
• Variables for occurrence and severity: The representation of the occurrence and severity of an event in SDTM is dependent on the type of data collected. If data are collected for the entirety of an event, the variables CEOCCUR and CESEV are used. If data are collected for a part of the event, the data are represented as findings about the event, using the FATESTs "Occurrence Indicator" and "Severity/Intensity". This modeling decision is based on recommendations from an SDS sub-team looking at best practices at representing occurrence data.
• EPOCH of TREATMENT: At the time of publication, the current published controlled terminology CDISC definition of TREATMENT is "a period in a clinical study during which subjects receive therapeutic treatment. Since vaccines studies are generally preventive, this does not fall under the current definition. The consensus is that the definition can be expanded to "a period in a clinical study during which subjects receive investigational product," which will cover vaccines studies. This amendment has undergone public review and will be published in Controlled Terminology Package 30. Based on this decision, this user guide uses the term TREATMENT in the data examples.
• CDASH and ADaM: The scope of this version of the TAUG did not include CDASH and ADaM components. CDASH and ADaM components will be considered for development in either a supplement or subsequent version of the user guide. SDTM examples showing multiple collection strategies are shown in this TAUG. It is recommended, however, that sponsors consult with the regulatory agencies regarding the data to be collected and the SDTM mapping strategy to be used.
• Vaccine examples in previously published TAUGs: Prior to the publication of this guide, vaccine reactogenicity data examples have been published in the Influenza, Tuberculosis, and Ebola TAUGs. When in conflict, the Vaccines TAUG should be considered the authoritative source for best practices on modeling vaccine reactogenicity examples. During a future update, the Influenza, Tuberculosis, and Ebola TAUGs will be updated to be consistent with the Vaccines TAUG.
• Use of --DTC variable for CE summary records: The --DTC variable is used to indicate the collection date/time of an observation. It can also be used as the anchor date for the Evaluation Interval variables (--EVLINT and --EVINTX). Generally, these two uses do not conflict with each other. However, when a sponsor is creating a summary CE record based on the daily records in FA, the variable CEEVINTX is populated with "SINCE VACCINATION" to reflect that the record is showing whether or not there was a reactogenicity event over the planned observation period. In this case, the variable CEDTC needs to reflect the last day of assessment in order to anchor the variable CEEVINTX. Thus, CEDTC in this scenario represents the last day of assessment and not the date that the CE record was transcribed.
• Representation of redness at the site of administration: A diary card that is completed by the study subject may use the term redness to refer in layman's terms to the concept of erythema. In the examples shown in this guide it is assumed that the CE domain is subject to MedDRA coding, so the term "Redness" is used to populate the --TERM variables while --DECOD is populated with the MedDRA term "Erythema". As described in Section 6.4.3 of the SDTMIG v3.2 Variables Unique to Findings About, FA examples that include assessments of redness use the term "Erythema" to populate FAOBJ so that this term matches the value in --DECOD in the dictionary-coded parent domain.
• Reactogenicity Events that become reportable as Adverse Events:  Reactogenicity events are usually expected and relatively mild, and so are represented in the CE (clinical events) domain in SDTM. However, protocols usually include criteria specifying when unusually severe or long-lasting reactogenicity events should be reported as adverse events. It is not clear whether a reactogenicity event that becomes a reportable adverse event should be represented only in the AE domain, or in both the CE and AE domains. Sponsors should consult with regulatory authorities for direction on this point.
• Use of CESTDTC and CEENDTC in global CE reactogenicity records: Reactogenicity examples in this guide are based on the assumption that if a reactogenicity event occurred anytime during the planned observation period, the overall start and end dates of the reactogenicity event were collected on the eCRF in addition to the individual dates from the daily diary collection. Individual dates from the daily diary collection are represented in the FA domain using the variable FADTC and the overall start and end dates of the event are represented in the CE domain using the variables CESTDTC and CEENDTC respectively. Please note that if only the daily diary collection dates were collected, CESTDTC and CEENDTC would not be populated.

Vaccines are preparations containing antigenic substances capable of inducing a specific and active immunity against a disease or infection. Such immunity may then result in the reduced transmission of that disease or infection.

An important aspect of vaccine development is the assessment of the vaccine's reactogenicity. Reactogenicity refers to the property of a substance to produce an expected or common adverse reaction when introduced into the body. For the purpose of this guide, reactogenicity event refers to a specific expected or common reaction following vaccine administration. In vaccine studies, a reactogenicity event(s) is typically caused by an inflammatory response to the vaccine under study and may include reactions like fever or redness at the site of administration. Reactogenicity describes immediate short-term reactions to vaccines, not long-term sequelae.

The term reaction usually implies that the adverse event has a causal relationship with the vaccination, or at least there exists a distinct possibility (see Adverse Drug Reaction in ICH E2A). Note that the causal relationship of a reactogenicity event with a study drug can be assessed during a clinical trial. It is possible for a reactogenicity event to be eventually assessed as not causally related to a study drug.

Reactogenicity is assessed in studies by monitoring a pre-defined set of adverse events over a pre-defined observation period. Pre-defined means identified prior to the start of the trial to support reactogenicity assessments of one or more investigational products in the study protocol. The pre-defined observation period starts immediately after the administration of one or more investigational product(s) and lasts a pre-defined number of days. Typically, this is 3 to 7 days, but it can extend to 21 days or more (e.g., for live attenuated vaccines). This short, pre-defined observation period does not cover the long-term safety assessments of the vaccines. To be considered for reactogenicity assessment, the monitored events, signs, or symptoms should start during the pre-defined observation period, but may extend beyond it.

Reactogenicity events can be classified as either administration site or systemic events.

• Administration site events are those occurring at or around the vaccine's administration site. The term local is also commonly used to refer to events at or around the administration site. Another term, localized event, is used to denote adverse events that have a localized manifestation, but not necessarily at the administration site (e.g., rash that is considered a systemic event, whose manifestation can be localized). To avoid any possible confusion between the terms "local" in the sense of occurring at the administration site and "localized", the term "administration site" will be used instead of "local" in this guide.
• Systemic reactogenicity events are those affecting an entire system or body. These reactogenicity events can be non-localized (e.g., fatigue or fever) or they can have localized manifestations (e.g., rash), where the localization cannot be pre-specified or predicted.

Manifestations of reactogenicity typically assessed in vaccine trials include: pain, tenderness, itching, bruising, erythema/redness, induration, and swelling at the administration site; and fever, fatigue, malaise, myalgia, arthralgia, headache, and nausea for systemic events. Some manifestations are typically associated to a specific sub-population, for example, vomiting, abnormal crying, drowsiness, appetite loss, or irritability for infants and toddlers.

Severity of the reactogenicity event may be assessed by the subject, the investigator, or both. When the investigator assesses the severity, it is common to use a standard toxicity grading scale such as the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials^[1].

Reactogenicity events are solicited and are typically collected on either diary cards (paper or electronic device) or a reactogenicity case report form. Please note that throughout the TAUG, the term "transcribed" is used to define data that are collected on the diary card and subsequently stored in the sponsor's database. Users should be aware that data can be collected on both paper and electronic diary cards; therefore, in this user guide the term "transcribed" is also used to define loaded data from electronic diary cards where applicable.

A hypothetical trial was used as the basis for examples in this user guide. This was a parallel design, comparator-controlled vaccine trial involving two co-administered vaccines, with both vaccines administered on two different occasions. For the purposes of this user guide, "co-administered" is defined as the administration of two or more vaccines at the same occasion, with the administrations being separated only by a short period of time, typically a few minutes. The vaccines would generally be administered at different locations, as presented in this guide, but could be administered at the same location.

Data were collected at four visits:

• Visit 1: Screening and first administration of vaccines
• Visit 2: Second administration of vaccines
• Visit 3: Final assessments following the TREATMENT Epoch (e.g., blood sampling)
• Visit 4: At the end of a 90-day follow-up period

This example was chosen because it can be extrapolated easily to more vaccines and/or more vaccination occasions. It also can be easily simplified to a single vaccine and/or a single administration occasion. This document focuses on parallel design studies. Parallel designs are typically used in vaccines studies due to the long-term persistence of vaccine effects in the body.

Data on reactogenicity events were collected via a reactogenicity collection form (e.g., a subject diary) for a pre-defined observation period of 3 days starting on the day of each vaccine's administration. Examples show data for only two systemic events, "Vomiting" and "Fever," and one administration site event, "Redness at administration site," recorded for each administration site.

• For vomiting, the number of vomiting episodes experienced during the day was recorded on each day (0 in case of no vomiting).
• For fever, the temperature was recorded on each day, whether or not fever occurred. One value was reported per day. The maximum value observed during the day was reported.
• For redness at administration sites, the presence of redness was assessed and, if present, the maximum longest diameter of the redness observed during the day was reported (measured using a provided ruler).

If an event continued past the 3-day observation period and was considered a clinical event, follow-up information was captured on the reactogenicity collection form. Follow-up data consisted of the end date of the event and the maximum value of the measure (e.g., maximum number of daily vomiting episodes) observed over the period starting at the end of the third day and lasting until either the resolution of the event or the end of the study. If an event continued past the 3-day observation period and was considered to be an adverse event, information about the event as a whole was captured on the adverse events collection form.

Investigator-recorded data about reactogenicity events included action taken, resolution, causal relationship to vaccination, and start and end date of the event.

The example below shows a vaccine trial that has two study arms. During screening, subjects are randomized to receive either investigational Vaccine A and Vaccine B (ARMCD="VAXAB") or Comparator A and Comparator B (ARMCD="COMPAB"). In this example, both screening and vaccination activities are performed at the same visit (which is often the case in vaccines studies).

Subjects receive the co-administered vaccines at two different time points during the "TREATMENT" Epoch. This Epoch includes both the vaccination and the planned reactogenicity assessment period.

• The "TREATMENT" Epoch is divided into two Elements, each lasting 21 days.
• The "FOLLOW-UP" Epoch covers all activities related to the long-term safety follow-up and lasts 90 days.

The variable TAETORD represents the planned order of the Element within an arm:

• TAETORD is equal to 1 for the screening Element.
• TAETORD is equal to 2 for the first vaccine administration Element.
• TAETORD is equal to 3 for the second vaccine administration Element.
• TAETORD is equal to 4 for the follow-up Element.

For the study design described above, the Trial Arms (TA), Trial Elements (TE), and Trial Visits (TV) example datasets are shown below. This trial could have been modeled differently, with each vaccination period considered a different Epoch. In either case, the Timing variable TAETORD can be used to distinguish between the first treatment Element, for which TAETORD="2" and the second, for which TAETORD="3". For this trial, the two vaccine administration Elements are the same. However, the vaccine administration Elements could be named differently (e.g., "Booster Vaccination") if the vaccine or combination of vaccines to be administered within the second Element differed from those to be administered within the first Element. For more information on trial design, refer to Section 7.2 of the SDTMIG v.3.2.

A vaccine trial may involve the administration of more than one vaccine at the same time point. In these cases, it is important to be able to distinguish between the administration sites when an assessment is performed. The variable FOCID (Focus of Study-Specific Interest) allows the assignment of identifiers to parts of the body to which treatments are applied and/or on which assessments are made. For vaccine studies, administration sites may be identified using FOCID, with values that distinguish between administration sites.

The Identifier variable FOCID was added to the SDTM in version 1.5. It is expected to be standard for use in human clinical trials in the next version of the SDTMIG; in this guide, however, it is represented as a non-standard variable. The examples in this guide show data for a subject who received two co-administered vaccines, with both vaccines administered on two different occasions. It is recommended that FOCID be populated for all administration site events, even in the case of a single administration. This provides a consistent approach, regardless of trial design, and supports future data aggregation. This guide uses the following naming convention:

Systemic (e.g., fever, vomiting, and headache) and administration site (e.g., redness and pain) reactogenicity events are expected and monitored after vaccination. In this TAUG, the reactogenicity events are represented in the Clinical Events (CE) domain rather than the Adverse Events (AE) domain. However, a study protocol may specify conditions under which a reactogenicity event should also be reported as an adverse event. Those conditions may include seriousness (as defined for adverse events), duration, or other factors. Please note that it is important for sponsors to discuss with regulatory authorities which domain the reactogenicity data should be represented in. The collection and presentation of adverse events to support reactogenicity assessments have some requirements and specificities that set them apart from other adverse events collections and presentation. This will be further explained below.

There are two generally used approaches to scheduling assessments of reactogenicity. One is to schedule daily assessments of reactogenicity for a pre-defined period following the vaccination (typically for 3-7 days). Such assessments are usually performed by the study subject and recorded in a diary or via an interactive voice response system (IVRS). An alternative approach is to schedule assessments by the investigator 3-7 days after the vaccination. These two approaches may also be combined. In all cases, reactogenicity events that are still present at the end of this initial assessment period will generally be followed until they end. The examples in this guide focus on daily assessments performed by the subject and reported on a daily diary card. These subject assessments are complemented by global assessments performed by the investigator at the end of the daily assessments period and reported in a case report form. The concept map below shows the components of a reactogenicity assessment.

In the examples below, after each set of vaccinations, subjects monitor both systemic (fever and vomiting) and site administration (redness) reactogenicity events and record their findings on a daily diary form. Monitoring of symptoms starts immediately after vaccine administration. Monitoring continues through the end of the second calendar day after vaccination (day 3). The Planned Time Point variables (--TPT and --TPTNUM) provide a description of the time when the reactogenicity assessment should be completed (END DAY 1, END DAY 2, END DAY 3) relative to the vaccination as defined by the Time Point Reference variables (--TPTREF and --RFTDTC). The evaluation intervals during which reactogenicity events are monitored can be described using the variables Evaluation Interval (--EVLINT) and Evaluation Interval Text (--EVINTX) and are anchored by the --DTC variable. For all reactogenicity measurements taken on the day the vaccine was given (--TPT="END DAY 1"), the variable --EVINTX is populated with "SINCE VACCINATION". This is to make clear that the assessments do not apply to all of day 1 (i.e., not before the vaccine was given). For all assessments after day 1, the variable --EVLINT is populated with the appropriate ISO8601 evaluation interval .

In the scenario described in this guide, subjects were asked to report their maximum temperature and maximum redness over the course of a day. In this case, the concept of "maximum" is represented in the non-standard variable (COLSRT) and the use of the Planned Time Point, Time Point Reference, and Evaluation Interval variables are appropriate. However, for measurements taken at a single point in time (i.e., not a measurement over an interval), these variables may not be appropriate, as we cannot assume that these values remained constant over time.

It is important to note that in this scenario, subjects are not expected to complete the daily diary precisely at midnight, but to report the assessment(s) performed over the calendar day.

The figure below describes how the timing variables described above are used in the examples shown in this guide.

In the examples shown in this guide, all daily assessments from diary cards are represented in the FA and/or VS domains. If a global record is created to represent the event as a whole, that information is represented in the CE or AE domain (as defined by the protocol). Generally, the --DTC variable is used to indicate the collection date/time of an observation. It can also be used as the anchor date for the Evaluation Interval variables (--EVLINT and --EVINTX). Generally, these two uses do not conflict with each other. However, when a sponsor is creating a summary CE record based on the daily records in FA/VS, the variable CEEVINTX is populated with "SINCE VACCINATION" to reflect that the record is showing whether or not there was a reactogenicity event over the planned observation period. In this case, the variable CEDTC needs to reflect the last day of assessment in order to anchor the variable CEEVINTX. Thus, CEDTC in this scenario represents the last day of assessment and not the date that the CE record was transcribed.

A diary card that is completed by the study subject may use the term redness to refer in layman's terms to the concept of erythema. In the examples shown in this guide it is assumed that the CE domain is subject to MedDRA coding, so the term "Redness" is used to populate the --TERM variables, while --DECOD is populated with the MedDRA term "Erythema". As described in Section 6.4.3 of the SDTMIG v3.2 Variables Unique to Findings About, FA examples that include assessments of redness use the term "Erythema" to populate FAOBJ so that this term matches the value in --DECOD in the dictionary-coded parent domain.

In these examples, a reactogenicity event was considered to have occurred if:

• The subject's maximum temperature was greater than a specific value defined in the protocol (e.g., 98.6°F).
• The subject vomited at least once during the observation period.
• The subject experienced redness at the administration site.

For the examples shown in this guide, there are several important links that need to be made and defined across domains.

When several sets of vaccines are administered over several vaccination time points, it is important, when assessing reactogenicity events, to know which vaccine administration site and vaccination time point the event relates to. These two connections can be made by using the variables FOCID and TAETORD, respectively. These variables are not domain- or observation class-specific and do not use the two-letter domain code as a prefix, thus a RELREC dataset is not needed. The concept map below illustrates how these variables can be used to link administration site and vaccine timing information across domains using FOCID and TAETORD.

However, systemic reactogenicity events are not tied to a specific administration site and relate to all vaccines administered at the same vaccination time point. For that reason, FOCID is not populated for the assessment of systemic events.

Because reactogenicity assessment data can be spread out across several domains, it is important to create links to connect this information. The examples in this guide use the variable --LNKGRP to link the daily reactogenicity assessments that are represented in FA/VS to the global reactogenicity event record in CE. This guide also shows how to link the daily temperature records either to the daily fever finding in FA using --LNKID or to the global fever record in CE using --LNKGRP. The modeling strategy and thus the linking variable used depends on how daily diary cards are transcribed. The connections that use --LNKGRP and --LNKID require that these relationships be defined using a RELREC dataset. The concept map below shows how --LNKGRP and --LNKID can be used to link reactogenicity assessment data across domains.

Team Mission

The mission of the Vaccines Team is to ensure a consistent use and development of the CDISC standards for use in vaccines studies, intended to support regulatory submissions, across all diseases/vaccine-preventable disease areas in all age groups.

Scope

Create a Vaccines User Guide, according to the CDISC Process, describing how to use CDASH, SDTM, ADaM standards and Controlled Terminology to support Vaccines studies intended to support regulatory submissions, across all diseases/vaccine-preventable disease areas in all age groups.

To achieve this goal, the team will:

1. Define requirementsfor using CDISC standards on Vaccines studies and identify gaps and modifications required with current CDISC Standards and related material to meet these requirements.
2. Develop guidelines complementing existing CDASH, SDTM, and ADaM Implementation Guides targeted at use of these standards in Vaccines studies.
3. For Vaccines study needs not covered by existing standards, elaborate and submit proposals for extension/update of these standards to the related CDISC teams (Terminology, SDTM Governance Committee, CDASH, ADaM).

Interact with and provide feedback to other teams, especially the core CDISC and TA teams. All issues and suggestions for improvements identified by the Vaccines Team during the course of its work, and that fall within the scope of another team mission, will be forwarded to the appropriate team(s).

2016 Deliverables

• By Q3-2016: a User Guide on the use of CDISC Standards for Adverse events, including reactogenicity, in Vaccines trials
• Other objectives might be defined for delivery later in the year according to the 2014 Vaccines Survey results and suggestions to the team

When applicable during the course of its work:

• Proposals for extension of the CDISC data collection standards (CDASH), the corresponding data presentation standards (SDTM) and the related Controlled Terminology to cover vaccines needs not already covered in these standards
• Feedback to other teams with issues/suggestions

The following table lists the non-standard variables used in this document, and gives their parent domain and variable-level metadata.

Appendix E1: Works Cited

1. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research (FDA CBER). Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. September, 2007.

Appendix E2: Further Reading

On vaccines

• National Institutes of Health - National Cancer Institute (NIH NCI). Vaccine (code 923). In NCI Thesaurus v17.04d. Release date April 24, 2017. Accessed on June 7, 2017.
• Council of Europe - European Directorate for the Quality of Medicines & HealthCare (EDQM). Vaccine for Human Use. In European Pharmacopoeia 9th Edition 2017 (9.2). Accessed on June 7, 2017.

On adverse events and reactions

• International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2A. Step 4 Version. ICH Harmonised Tripartite Guideline. October 27, 1994.
• European Medicines Agency - Heads of Medicines Agencies (EMA HMA). Guideline on good pharmacovigilance practices (GVP): Module VI - Management and reporting of adverse reactions to medicinal products. EMA/873138/2011 Rev 1. September 8, 2014.

On collection of solicited signs and symptoms, on local and systemic adverse events

• World Health Organization (WHO). Guidelines on clinical evaluation of vaccines: regulatory expectations. WHO/BS/2016.2287. 2016
• European Medicines Agency - Committee for Human Medicinal Products (EMA CHMP). Note for Guidance on the Clinical Evaluation of Vaccines. CHMP/VWP/164653/2005. May 17, 2005.

On reactogenicity events

• National Institutes of Health - National Institute of Allergy and Infectious Diseases (NIH NIAID). DMID Interventional Protocol Template Version 5. March 25, 2011. https://www.niaid.nih.gov/sites/default/files/dmid-interventional-protocol-template-and-instructions.docx. Accessed June 1, 2017.

On adverse events following immunization

• Bonhoeffer J, Bentsi-Enchill A, Chen RT. Guidelines for collection, analysis and presentation of vaccine safety data in pre- and post-licensure clinical studies. Vaccine. 2009;27(16):2282-2288.