The impact of post‐market regulatory safety advisories on patients, prescribers, and the healthcare system

Lorri Puil; Joel Lexchin; Lisa Bero; Dee Mangin; Christine E Hallgreen; Gavin WK Wong; Barbara Mintzes

doi:10.1002/14651858.CD013510

. 2019 Dec 19;2019(12):CD013510. doi: 10.1002/14651858.CD013510

The impact of post‐market regulatory safety advisories on patients, prescribers, and the healthcare system

Lorri Puil ^1,^✉, Joel Lexchin ², Lisa Bero ³, Dee Mangin ⁴, Christine E Hallgreen ⁵, Gavin WK Wong ⁶, Barbara Mintzes ³

PMCID: PMC6923522

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The main objective is to assess the impact of post‐market regulatory safety advisories on safety outcomes in patients.

Other objectives are to assess the impact of safety advisories on drug utilisation, health services utilisation (e.g. hospitalisations, clinical monitoring, or diagnostic testing), patient‐health professional interaction (e.g. informed consent), and healthcare professional or patient/carer knowledge, attitudes, beliefs, and intended behaviours. Additional objectives, if feasible, are to identify attributes of prescription drug safety advisories that enhance or jeopardise their effectiveness.

Background

Prescription drugs provide important health benefits but can also lead to serious harm and are a major cause of hospital emergency department visits, hospitalisation, and death (Graham 2005; EMA 2008; Hohl 2013; Roughead 2013; Moore 2014; Downing 2017; ISMP 2017). Rare, serious harm is often discovered, or a harmful effect confirmed, only once a medicine is already on the market and in widespread use. When new safety concerns arise, centralised and national medicine regulatory agencies, including the European Medicines Agency (EMA) and its member states, the United States Food and Drug Administration (US FDA), Health Canada, the Australian Therapeutic Goods Administration (TGA), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), and others, issue a variety of drug safety advisories to health professionals, patients, and the public with the aim of supporting safer medicine use and minimising harm. There is, however, limited evidence about the effectiveness of these communications and whether or not they achieve their intended goals.

Description of the problem or issue

The EMA has reported that 5% of all hospital admissions, and an estimated 197,000 deaths per year in the European Union (EU), are caused by adverse drug reactions (EMA 2008). A Canadian study conducted in the province of British Columbia found that 12% of visits to a large hospital emergency department were medication‐related (Zed 2008), and another in the province of Ontario noted that 0.75% of the total annual emergency department visits by adults over the age of 65 years were related to adverse drug reactions (Wu 2012). In Australia, there are an estimated 230,000 medication‐related hospitalisations per year, at a cost of AUD 1.2 billion (Roughead 2013). Less data are available for resource‐limited countries (Angamo 2016). A study in South Africa reported about 1 in 12 admissions to the medical wards of four hospitals was attributed to serious adverse drug reactions, with the range of events and implicated drugs reflecting the region's high HIV and tuberculosis burden (Mouton 2016).

At the time of regulatory approval of a new prescription drug, a limited number of patients have been exposed to the medicine, often for short periods of time (Lexchin 2006; Moore 2014). For standard drug approval processes conducted by the US FDA in 2008, a median of 2133 people (range 430 to 4110) in total were exposed to active drug in pre‐market testing (Moore 2014). For expedited regulatory approvals, even fewer patients are exposed (Moore 2014). Expedited drug approval pathways are reported to be associated with greater post‐market safety risks (Downing 2017; Mostaghim 2017). In addition, older people, children, women who are pregnant or lactating, and individuals with co‐morbidities are often excluded from pre‐approval trials, conducted under controlled conditions that may not reflect ‘real world' practice.

Limitations of pre‐approval clinical trials (EMA 2008), the use of expedited drug approval processes (Hwang 2017; Lexchin 2018), and an increasing reliance on post‐market drug safety surveillance to detect safety signals underscore the need for effective communication strategies once a drug is on the market. When new safety information arises, in extreme cases a drug may be withdrawn from the market (Aronson 2017; Lane 2018; Onakpoya 2018). More often, overall benefit may still be considered to outweigh potential harm if changes in practice are implemented, incorporating the most current and appropriate knowledge of benefit and risk. Regulators must therefore be able to communicate effectively and quickly with health professionals and patients/carers about new safety information and recommended ways to address the safety concern.

Description of the intervention

A variety of tools for communication of risks of medicines, collectively termed drug safety advisories, are used by regulators to disseminate information about emerging post‐market safety concerns (Health Canada 2008; Yamamoto 2008; McCormack 2013; CCA 2015; EMA 2015; FDA 2015; EMA 2017a). These tools are also referred to as risk communications (CCA 2015). Because the latter term may be used in a broader context, we will selectively use the term drug safety advisories for this Cochrane Review. Recent examples of safety issues that have led to safety advisories include oxycodone‐related deaths (Murphy 2018), and cardiac risks associated with domperidone (Health Canada 2015).

Depending on the jurisdiction, safety advisories are released directly by the regulator, jointly by a regulator and marketing authorisation holder (drug manufacturer), or distributed solely by the marketing authorisation holder at the regulator's request (de Vries 2017). Safety advisories may be posted on the regulator's website or distributed to individual healthcare practitioners (Table 1). Direct Healthcare Professional Communications (DHPCs) (Health Canada 2008; Health Canada 2010; FDA 2014; EMA 2017b) are a commonly used tool (Mol 2010; CCA 2015). Other types of communications are safety alerts, bulletins, and reports posted online. In 2010, the US FDA replaced multiple communication tools (Early Communications about Ongoing Safety Reviews, Public Health Advisory, Patient Information Sheet, Healthcare Professional Sheet and Alerts on Patient Information) with a single primary communication tool termed a Drug Safety Communication (FDA 2012). These communication tools may be ‘stand‐alone' communications or be accompanied by product label changes, such as new contraindications or boxed warnings.

Table 1.

Types of post‐market safety communications

Type of Communication	Description	Examples (regulator)²	Notes
Direct Healthcare Professional Communication (DHPC)	Letters mailed or electronically distributed to individual health professionals¹	Direct Healthcare Professional Communication (EMA) Dear Healthcare Professional Letter (TGA; PMDA) Dear Health Care Professional Letter (HC) Dear Health Care Provider Letter (FDA) Dear Doctor Letter Dear Pharmacist Letter	Letters in the form of Notices to Hospitals (HC) may also be mailed to individual hospitals if the prescription drug is mainly utilised in hospital settings.
Alert	Notification in the safety section of the regulator's website, addressed to a broad but potentially targeted audience (e.g. health professionals) rather than individual clinicians	Drug Safety Communication (FDA) Safety Communication (Biologics ) (FDA) Safety Alert (FDA) Safety Advisory (TGA; HC³) Safety Warnings and Messages for Medicines (MHRA)	Drug Safety Communications are the major communication vehicle for the US FDA as of 2010.
Investigation	Statements regarding ongoing review or analysis of adverse drug reaction reports, early monitoring reviews, and detailed investigation reports	Monitoring Communications (TGA) Summary Safety Reviews (HC) Information Update (HC)
Bulletins and newsletters	Articles appearing in a regulator's newsletter or drug safety bulletin, issued at regular intervals, concerning safety risks associated with a drug or drug class	Adverse Drug Reaction Advisory Committee (ADRAC) Bulletin (TGA) Canadian Adverse Reaction Newsletter (HC) Health Product InfoWatch (HC) Drug Safety Update (MHRA)	These may serve as reminders of prior communications and usually contain multiple articles on drug safety issues; usually published on regulator's website; may be distributed via email but uncommonly mailed by post.
Public	Message on drug safety risks directly targeting or addressing public or media	Public Communication (HC) Public Health Advisory (FDA) Media/press releases Information Update (HC)	Health Canada routinely requires a Public Communication to accompany a Dear Health Care Professional Letter.

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Abbreviations: DPHC = Direct Healthcare Professional Communication; EMA = European Medicines Agency (European Union); FDA = Food and Drug Administration (US); HC = Health Canada; MHRA = Medicines and Healthcare products Regulatory Agency (UK); PMDA Pharmaceuticals and Medical Devices Agency (Japan); TGA = Therapeutic Goods Administration (Australia) ¹Depending on the jurisdiction, DHPCs may be issued by the regulator, jointly issued by the regulator and the marketing authorisation holder (manufacturer of the medicine), or issued by the marketing authorisation holder at the regulator's request. For example, EMA requests and approves content of DHPCs but requires the marketing authorisation holder to disseminate the letters. ²Examples of terms preferentially used by a regulator are provided, with the regulator identified in brackets; other regulators that are not listed may use the same term. ³Advisory is used as a general term for Health Canada communications that are further classified into specific types, including Dear Health Care Professional Letters.

Components of a safety advisory include identification of the target audience of the information (e.g. healthcare professionals or patients, and their carers), a description of the health risk or concern, and recommended actions. Intended effects are those related to the advisory’s recommendations and may include, for example, discontinuing use in a subpopulation that is susceptible to harm, modifying doses or dosing regimens, and increasing laboratory monitoring for adverse effects. Intended effects also include anticipated ‘downstream' consequences of the recommended actions, such as changes in health services utilisation (e.g. doctor's visits), prescription drug use, or clinical outcomes. Unintended effects include ‘spillover' effects; an example of the latter is reduced medicine use in a subpopulation that is not targeted by the safety advisory (DeFrank 2019).

Across jurisdictions, there are discrepancies in decisions to issue an advisory on a particular safety issue (Giezen 2008; Zeitoun 2014; Bjerre 2018; Perry 2019), and lack of a harmonised format or approach to content or type of communication. These discrepancies exist despite increased calls among established regulators for international harmonisation and exchange of information on drug risks (EMA 2015; ACSS 2018; EMA 2018a). There is limited available information about the communication of post‐market drug safety issues in low‐ and middle‐income countries (Nwokike 2015), which have less‐developed regulatory and pharmacovigilance systems for medicines (Olsson 2010).

How the intervention might work

A schematic framework for the assessment of the impact of prescription drug safety advisories is provided in Figure 1. Kesselheim 2015 has also outlined a logic model of anticipated physician and patient responses to a US FDA Drug Safety Communication using the example of zolpidem. Behavioural change theories and other models or theoretical underpinnings may be used to understand the effects of safety advisories on their targeted audiences (Glanz 2010). For a safety advisory to influence behaviour, and ultimately patient health, the advisory must first reach its intended audience (and be read), stimulate awareness of the issue or concern, be perceived as providing a convincing case for the need for change, and lead to actual change in practice or use. The transtheoretical model identifies five stages of change through which an individual progresses in adopting new behaviour: pre‐contemplation, contemplation (awareness), preparation, action, and maintenance (Prochaska 1997; Roughead 2006).

Conceptual framework (logic model) for the effects of prescription drug safety advisories.

The effects of safety advisories on awareness, attitudes, behaviours, and health outcomes occur within a broader context of health system factors and a diverse range of communication channels for health information. Consequences of a safety advisory can include unintended effects, in addition to targeted actions and their anticipated downstream effects (DeFrank 2019). Amplification or attenuation of intended messages can occur through media, information providers, promotional activities, clinical practice guidelines, and reimbursement status. Effective drug safety communication thus requires a broader understanding of the environmental and social context in which the safety advisory and behaviour change occur. Social cognitive theory posits that learning takes place in a social context with a dynamic, reciprocal interaction between personal factors, environmental influences, and behaviour (Glanz 2010). Consistent with these theories, systematic reviews of interventions to improve prescribing have, for example, identified the need for a multi‐faceted approach, including personalised encounters, educational outreach, and audit and feedback (Ostini 2009; Ivers 2012).

A study in the Netherlands reported DHPCs had greater impact if the safety issue was associated with serious risk (death or disability, or both) and if a structured template was used; the latter may have contributed to understandability (Reber 2013). Drugs prescribed by specialists were impacted less by a DHPC than those prescribed by general practitioners. Based on this study (Reber 2013), communication theory (Roughead 2006; Glanz 2010), and research to improve appropriate prescribing (Ostini 2009; Ivers 2012), we hypothesise that the following features of advisory content may contribute to more effective warnings: quantitation of harm; seriousness of harm; accessible evidence; and clear recommendations or actions to take. Acknowledged evidence gaps could also modify uptake of an advisory's recommended actions but in a less predictable direction. Additional contextual features that may influence the impact of an advisory include: available treatment alternatives; underlying risk of the condition if untreated; medicine reimbursement status; and commercial incentives. The impact of a safety advisory may also be influenced by communication and dissemination methods e.g. repeated warnings; integration into clinical and public education; and medical, general, and social media uptake. Safety advisories targeting the public or patients may be affected by the population's literacy levels in addition to the readability and health literacy burden of the advisory (LeBrun 2013; McCormack 2016).

Why it is important to do this review

Recently, Health Canada (CCA 2015), the EMA (EMA 2015; EMA 2017a), and the US FDA (FDA 2015) have emphasised there is a need to better evaluate risk communication on medicines, including safety advisories that are issued in the post‐market period. A recent review (n = 153 studies) was conducted by the EMA and is a scoping review, with the objective to identify published study designs and analytical approaches that have been used to evaluate the impact of pharmacovigilance regulatory interventions, including risk minimisation strategies (e.g. the US FDA Risk Evaluation and Management Strategies or REMS), regulatory safety advisories, and suspensions/withdrawals (Goedecke 2018). Goedecke 2018 did not incorporate an assessment of study quality or risk of bias. Four other published reviews on the effects of regulatory safety warnings, two of which were restricted to US FDA risk communications (Dusetzina 2012; Briesacher 2013), are now outdated based on the extent of newly published literature (Dusetzina 2012; Piening 2012; Briesacher 2013; Gridchyna 2014). Another ongoing review, Weatherburn 2016, is restricted to regulatory safety advisories issued by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.

We identified more than 50 newly published or omitted studies in our scoping search of the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects (DARE), Epistemonikos, and Ovid MEDLINE that potentially fit the eligibility criteria for the review conducted by Goedecke 2018. Because that review did not restrict its inclusion criteria to methodologically rigorous study designs, was a scoping review, and did not assess risk of bias of individual studies or consider whether meta‐analysis stratified by study design, outcomes, or other variables was feasible, we are conducting an up‐to‐date review. Our review will focus on safety advisories, restrict inclusion to studies of sufficient methodological rigor to draw conclusions, and will incorporate an assessment of risk of bias including sponsorship bias. The latter has not been considered in existing reviews, although many examples exist of a strong commercial influence on the production and interpretation of evidence in pharmacoepidemiology (Pearce 2008).

Objectives

The main objective is to assess the impact of post‐market regulatory safety advisories on safety outcomes in patients.

Methods

Criteria for considering studies for this review

Types of studies

We will include a broad range of primary study designs due to the nature of the intervention. We anticipate that most studies will be quasi‐experimental drug utilisation studies (Shadish 2002).

Eligible study designs are:

randomised trials;
non‐randomised trials;
controlled before‐after studies;
interrupted time series studies, and;
repeated measures studies.

Our study design taxonomy and minimal eligibility criteria are those used by the Cochrane Effective Practice and Organisation of Care (EPOC) Group (EPOC 2017c). For cluster‐randomised trials, non‐randomised trials, and controlled before‐after studies, we will include studies that have at least two control and two intervention sites. In controlled before‐after studies, data collection must be contemporaneous and identical methods of measurement used in both groups. For interrupted time series studies, the intervention time point must be clearly defined, and for both interrupted time series and repeated measures studies, at least three data points pre‐ and post‐intervention are required (EPOC 2017c). There will be no restriction on study duration, to allow examination of immediate and sustained effects.

For studies on knowledge (awareness), attitudes or beliefs, and behavioural intent only, we will also include cross‐sectional studies at a single time point if data cover a defined population with a specified sampling frame or a random sample of a defined population, with a response rate of at least 40%. Data on intermediate outcomes, such as awareness and attitudes or beliefs, are not collected routinely and are unlikely to be available prior to release of a safety advisory. In contrast, drug utilisation and clinical outcome data are collected routinely irrespective of the timing of safety advisories. Although cross‐sectional studies cannot establish causality, they can measure associations between different levels of exposure to advisory information and differences in awareness, attitudes, and beliefs.

We will include studies that are available as a full‐study report, regardless of publication status or language. We will exclude conference abstracts alone as they do not provide sufficient information to adequately assess a study's methods. If we identify abstracts of studies that are potentially eligible, we will search for a corresponding publication and also will contact study authors to obtain an unpublished full study report if feasible.

Types of participants

Populations of interest are patients/carers and healthcare practitioners within any jurisdiction worldwide, and include both the targeted audience of the regulatory safety advisory and those affected by the recommendations within the safety communication. Some regulatory safety advisories target the general public directly, which would include patients, carers, and patient advocates. Other regulatory safety advisories are targeted specifically to healthcare professionals whose actions will affect patient outcomes. We will classify safety advisories by their target population(s).

Types of interventions

We will include regulatory safety advisories on the use of prescription drugs (small molecules and biologics such as monoclonal antibodies, vaccines, and blood products).

Eligible safety advisories are issued by a regulator, issued jointly by a regulator and marketing authorisation holder (drug manufacturer or sponsor), or issued by a marketing authorisation holder at the regulator's request. Eligible safety advisories are outlined in Table 1. These include but are not restricted to:

DHPCs (delivered by any means);
public warnings or advisories (includes online advisories);
safety alerts or drug safety communications (includes online advisories).

We will classify safety advisories by their intended outcomes in addition to their target population(s).

Exclusions:

safety advisories for drugs (including vaccines) that are available solely without prescription (over‐the‐counter);
post‐market product label changes such as boxed warnings (e.g. US FDA "black box" warnings) and contraindications unless they are associated with a safety advisory;
notices of market withdrawals or suspensions;
recalls related to, for example, manufacturing quality issues such as contamination;
notices on medication errors (e.g. wrong route of administration; administration of the wrong drug) or drug shortages.

We will exclude drug safety programmes such as risk management programmes, for example the US FDA REMS (Levinson 2013; Boudes 2017) and the EU risk management plans (RMP) (EMA 2018b), prescription drug monitoring programmes, evaluation of adverse drug reaction reporting systems or health information exchanges. Risk management programmes may be implemented at the time of approval as well as in the post‐market period, and contain multiple components such as medication guides, communication plans, and training activities. Although they may include DHPCs, we will exclude risk management programmes because it is not possible to separate out the effect of the safety communications of interest and because we are interested in post‐market safety advisories only.

Types of comparators

interrupted time series (and repeated measures): an interrupted time series compares time periods within a single population before and after a safety advisory is issued, taking into account the underlying trend (Lopez Bernal 2018). In a controlled interrupted time series study, a control group is added so there is both a before‐after comparison and an intervention control comparison. Possible control groups include populations that are not subject to the safety advisory or are subject to a different type of safety communication or risk mitigation programme. Controls may be location‐based (e.g. a population in a country where the prescription drug is approved for the same indication but a safety advisory was not issued) or characteristics‐based (e.g. a subpopulation that is prescribed the same drug but is not targeted by the advisory) (Lopez Bernal 2018). Other comparisons include, but are not restricted to, a related but different outcome not expected to change in the targeted population, or a subpopulation with the same condition but taking an alternative drug, or a group exposed to a combination of safety advisories;
controlled before‐after studies: appropriate control groups are those listed for controlled interrupted time series;
randomised or non‐randomised clinical trials: although controlled trials seem unlikely given the nature of the intervention, appropriate controls arms could either be inactive (no safety advisory) or active (a different type of safety advisory, a combination of safety advisories or a different risk mitigation strategy);
Cross‐sectional studies (included for the outcomes knowledge, attitudes, beliefs, and intended behaviours only) may be uncontrolled or controlled. A control group may be a group that has not received a safety advisory.

Types of outcome measures

We will organise outcomes to assess the overall impact of safety advisories in a hierarchy with those most important to patient populations higher in the hierarchy. In keeping with behavioural change theory, we will include intermediate outcomes, such as effects on awareness and attitudes as well as behavioural change, in addition to health outcomes. We will prioritise clinical outcomes and behavioural change over intention alone, consistent with Cochrane EPOC guidance to prioritise objective outcomes (EPOC 2017d). We will include studies that report on at least one of our primary or secondary outcomes of interest.

Primary outcomes

Our primary outcomes are patient health outcomes:

serious adverse events (EMA 2017c);
adverse events that are not categorised as serious events.

Secondary outcomes

These include:

drug utilisation e.g. overall population prescription volume (including both measures of prescribing level and trend); shifts in rate of initiation of new prescriptions; medication switching or discontinuation; co‐prescribing of drugs;
health services utilisation: hospitalisations; duration of hospital stay; hospital emergency department visits; physician or other healthcare professional visits; clinical monitoring or diagnostic testing;
patient‐health professional interaction e.g. communication about risk‐benefit ratios and informed consent of the patient;
changes in physician, other healthcare professional or patient/carer knowledge, attitudes, beliefs, and intended behaviours.

We will identify intended outcomes as defined in each study by the specific safety advisory's recommendations, or expected outcomes linked to the safety concerns described in the advisory, or both. These are generally expected to include a reduction in volume of use of the drug that is subject to safety concerns, restriction of use in specific patient populations, limits to dose, substitution of alternatives, or specific monitoring and diagnostic testing recommended in the advisory. Outcomes that are regarded as ‘downstream' of the intended goals of the advisory (e.g. reduction in a specific clinical event following dose reduction) will be considered as intended consequences. We will include unintended as well as intended consequences, e.g. worse clinical outcomes, substitution of a less effective or more hazardous alternative treatment, unintended decreases in health services utilisation by the targeted population, or unwarranted treatment discontinuations in non‐targeted subpopulations (‘spillover’ effects) (Valuck 2007; Dusetzina 2012; Carson 2017; DeFrank 2019). In addition to the inclusion of studies that measure effects in the country where the safety advisory was issued, we will include studies that measure impact in another jurisdiction.

Search methods for identification of studies

Electronic searches

A Cochrane Information Specialist will develop the search strategies in consultation with the review authors (Lefebvre 2011), and a second information specialist will peer review the Ovid MEDLINE search strategy, with further input obtained from the Cochrane EPOC Information Specialist. We will search Epistemonikos (www.epistemonikos.org) for relevant systematic reviews. We will search the following databases for primary studies, from inception to the date of search:

Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web);
Ovid MEDLINE (1946 to date of search), MEDLINE In‐Process, and Ahead of Print;
Ovid Embase (1974 to date of search);
Clarivate Web of Science Citation Index Expanded and Conference Proceedings Index– Science (CPCI‐S);
EBSCO PsycINFO;
Proquest Dissertations & Theses Global.

We will base the subject strategies for databases on the MEDLINE search strategy, which will combine Medical Subject Heading (MeSH) terms and keywords related to impact research in pharmacovigilance, regulatory policy, health outcome research, risk communication, health behaviour, and health outcomes. We will not restrict the search by language or publication status. Although we will search all databases unrestricted by date, we note that 1962 is the date when modern systems of drug regulation were implemented and will restrict inclusion of studies from 1962 onwards.

Searching other resources

We will search ClinicalTrials.gov (www.clinicaltrials.gov), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/ictrp), and the EU Electronic Register of Post‐Authorisation Studies (EU PAS Register) (www.encepp.eu/encepp_studies/indexRegister.shtml) for ongoing as well as completed studies.

We will cross‐check reference lists of included studies and relevant systematic reviews for additional, potentially eligible, primary studies. We will contact authors of included studies to clarify reported information and to seek unpublished results/data as necessary. We will contact researchers with relevant expertise, including pharmaceutical regulatory experts, to identify additional potentially eligible studies. We will also conduct targeted searches of regulators' websites including the UK MHRA, the EMA, Health Canada, the US FDA, the Australian TGA, the New Zealand Medicines and Medical Devices Safety Authority (Medsafe), and the Japanese PMDA for reports of research related to outcomes of safety advisories.

We will search conference proceedings of the International Society of Pharmacoepidemiology from January 2016 to the date of the search by keywords to identify recent relevant studies. We will conduct cited reference searches for all included studies in ISI Web of Knowledge.

We will provide appendices for all search strategies (Appendix 1), including a list of sources screened and relevant reviews/primary studies reviewed.

Data collection and analysis

Review authors will not participate in study selection, data extraction, risk of bias or GRADE assessments of any studies they have authored.

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to the reference management database EndNote X9 (Clarivate Analytics 2018) and will remove duplicates. One review author (LP) will screen titles/abstracts initially in EndNote against broad eligibility criteria to remove clearly irrelevant records. We will import the remaining records into suitable systematic review software (e.g. Covidence) or Microsoft Excel for further screening of titles/abstracts against specific eligibility criteria by two independent review authors (from among LP, GW, BM, JL, CH, DM). We will retrieve the full‐text study reports of records that are of potential or uncertain relevance. Two review authors (from among LP, GW, BM, CH, JL, DM) will independently screen full‐text articles using piloted screening questions that use conditional branching (skip logic). For example, if a study is identified as a potentially eligible interrupted time series study, additional screening questions will address whether the study meets methodological inclusion criteria such as a minimum number of data points. We will resolve discrepancies by discussion or if necessary, involvement of a third review author (LP, BM, GW). If necessary, we will translate articles in languages other than English to determine eligibility.

We will record reasons for exclusion at the full‐text level and provide a table of reasons of exclusion for those studies that initially appeared to be eligible. We will collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. A PRISMA flow diagram will be provided (Liberati 2009).

Data extraction and management

Two review authors will extract data independently (from among LP, BM, JL, CH, LB, GW, DM) using standardised data extraction forms developed for each study design, based on the Cochrane EPOC template (EPOC 2017a) and other methods or reporting recommendations (Jandoc 2015; Smith 2018). Data extraction forms will be piloted and subsequently refined, based on feedback, to ensure capture of relevant information. We will resolve discrepancies by discussion or if necessary, adjudication by a third review author.

We will extract the following information from included studies:

publication/report identification details
type of study (e.g. controlled before‐after; interrupted time series or controlled interrupted time series)
study setting (country, regulator issuing the advisory);
characteristics of the population;
characteristics of the intervention(s), including: date(s) issued; type of safety communication; dissemination mode; target audience; drug (single, multiple or drug class) and Anatomical Therapeutic Chemical (ATC) Classification System code; risk issue; level of evidence cited; and intended goals or recommended actions as identified by the primary study investigators (e.g. increased clinical or laboratory monitoring; avoidance of co‐prescribing; avoidance of use in a specified subpopulation; general caution when prescribing or using the medicine; modified dosing regimen) (Dusetzina 2012);
other documented safety communications or co‐interventions during study period;
outcomes, including definitions and methods of measurement; time points reported; and analytical techniques, such as adjustment for clustering, covariates, and analytical models used;
data source (e.g. electronic medical records database; administrative data; pharmacovigilance; registry);
results for outcomes of interest;
study sponsorship and investigator conflict of interest disclosures as part of a ‘Risk of bias' assessment (Lundh 2017).

Whenever necessary, we will contact study investigators for key missing information or data and clarification of analysis methods as needed (maximum three times by email if no response). We will note in the ‘Characteristics of included studies' table if outcome data were reported in an unusable way.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias. Discrepancies will be resolved by discussion or adjudication by a third review author if consensus cannot be reached. We will use the criteria suggested by Cochrane EPOC to assess the risk of bias of included studies (EPOC 2017b). For randomised trials, non‐randomised trials, and controlled before‐after studies, we will use nine standard criteria:

random sequence generation;
allocation concealment;
blinding of participants and personnel;
blinding of outcome assessment;
incomplete outcome data;
selective outcome reporting;
baseline outcomes measurement similarity across groups;
baseline characteristics (balance);
other bias: risks of bias specific to study design.

For interrupted time series studies, we will use the following criteria:

intervention independent of other changes;
shape of the intervention effect pre‐specified;
intervention unlikely to affect data collection;
knowledge of the allocated interventions adequately prevented during the study;
incomplete outcome data;
selective outcome reporting;
other risks of bias e.g. seasonality.

Assessment will be further guided by Cochrane risk of bias tools (Higgins 2011; Sterne 2016), and more recent methodological and reporting recommendations (Jandoc 2015). For example, all interrupted time series applications should report on considerations of autocorrelation, non‐stationarity, and seasonality; these are intrinsically accounted for in autoregressive integrated moving average (ARIMA) models but not in segmented regression models (Jandoc 2015).

For cross‐sectional studies (for the outcomes awareness, attitudes, and behavioural intent only), we will use the five items recommended for cross sectional surveys of attitudes and practices by Agarwal 2011: representativeness of the sample; adequacy of the response rate; missing data within completed questionnaires; conduct of pilot testing; established validity of the survey instrument, and will present the results in a separate table.

Across all study designs, we will also assess risk of bias due to study sponsorship as industry funding has been shown to influence research results (Lundh 2017). We will use all available sources of information on the study to conduct a ‘Risk of bias' assessment and will record the source of information if sources other than a primary publication are used. We will consider study quality in analysis and interpretation of results.

We will judge each potential source of bias as high, low, or unclear and will provide a quote from the study report together with a justification for our judgement in the ‘Risk of bias' table. We will summarise ‘Risk of bias' judgements across different studies for each of the domains listed. We will assign an overall ‘Risk of bias' assessment (no serious limitations = low risk of bias, some limitations = moderate risk of bias; serious limitations = high risk of bias) for each main outcome within each study using the approach suggested in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will consider studies with low risk of bias for all key domains or where it seems unlikely for bias to seriously alter the results, to have a low risk of bias. We will consider studies where risk of bias in at least one domain was unclear or judged to have some bias that could plausibly raise doubts about the conclusions, to have an unclear risk of bias. We will consider studies with a high risk of bias in at least one domain or judged to have serious bias that decreases the certainty of the conclusions, to have a high risk of bias.

We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a study investigator, we will note the source in the ‘Risk of bias' table. We will not exclude studies on the grounds of their risk of bias, but will clearly report the risk of bias when presenting the results of the studies.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome. We will also consider other study methodological features and generalisability.

Measures of treatment effect

Trials and controlled before‐after studies

For randomised and non‐randomised trials, and controlled before‐after studies, we will report relative effects. For dichotomous outcomes, we will report, if possible, the risk ratio from statistical analyses adjusted for baseline differences in the outcome measures, or the ratio of risk ratios (EPOC 2017f). For continuous outcomes, we will use the absolute change, adjusted for baseline differences (e.g. regression models); or if these data are unavailable, the relative change, adjusted for baseline differences in the outcome measures.

Interrupted time series and repeated measures studies

For interrupted time series and repeated measures studies, the preferred analysis method is either regression analysis with time trends pre‐ and post‐intervention (adjusted for autocorrelation and any periodic changes) or ARIMA analysis (Ramsay 2003; EPOC 2017g). If an interrupted time series study has not reported an appropriate analysis but provides data points in a graph or in a table, we will consider reanalysis of the data using segmented time series regression techniques described in Ramsay 2003, with results reported on level changes and change in slope. For repeated measures design, if a study does not report appropriate results, we will not re‐analyse the data because no estimate of within‐patient variability can be obtained from summary graphs and any reanalysis would underestimate or overestimate the standard error of the effect sizes. For repeated measures studies, we will present results reported in the original papers only (EPOC 2017g).

Unit of analysis issues

We will conduct analyses at the same level as the allocation to avoid unit‐of‐analysis errors. If there is a unit‐of‐analysis issue in the reported analysis for a study and there is insufficient information to re‐analyse the results, we will contact the study investigators to obtain the necessary data. If these data are not available, we will not report confidence intervals (CIs) or P values for which there is a unit‐of‐analysis error (EPOC 2017g). If multiple treatment arms are reported in a single trial, we will include only the relevant arms. If two comparisons with the same control group must be entered into the same meta‐analysis, we will halve the control group to avoid double‐counting.

Dealing with missing data

We will contact study authors in order to verify key study characteristics and obtain missing outcome data where possible. We will try to impute missing summary data from other reported statistics. If we are not able to obtain missing data, we will report the results that are available unless they are misleading and contain, for example, a unit‐of‐analysis error (EPOC 2017g). Whenever it is not possible to obtain data, we will report the level of missingness and consider how that might impact the certainty of the evidence.

Assessment of heterogeneity

If meta‐analysis is feasible, we will estimate the proportion of variability due to heterogeneity rather than chance by calculating the I² statistic for each analysis (Higgins 2002). We will report I² estimates with their 95% CIs. If we identify substantial heterogeneity, we will explore it by pre‐specified subgroup analysis.

Assessment of reporting biases

We will attempt to contact study authors, asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results. If we are able to combine more than 10 trials in a meta‐analysis, we will create and examine a funnel plot for small studies effects; one possible cause of which is publication bias (Sterne 2011).

Data synthesis

We will undertake meta‐analyses only where this is meaningful i.e. if the intervention, populations, and outcomes are similar enough for pooling to make sense (Borenstein 2009). Analyses will be conducted using Review Manager 5 (RevMan 5) statistical software (Review Manager 2014), or other statistical software as necessary. We will use a random‐effects model due to anticipated methodological and clinical heterogeneity in interventions, populations, settings, and study methods. We will use a generic inverse‐variance weighted average to pool non‐randomised studies. If sufficient numbers of studies with different study designs assess the same outcome, we will present them in the same forest plot grouped by study design. If feasible, we will also consider synthesizing all available evidence in a meta‐regression that includes a fixed effect that models systematic differences between the different study designs, and random effects that allow heterogeneity to differ between the different forms of evidence. We will report the estimated interaction term coefficient, adjusted for a nominated reference form of evidence, along with its CI. If quantitative analyses are not feasible for a specific outcome, we will summarise all studies by category of intervention in a structured, narrative synthesis (EPOC 2017e).

‘Summary of findings' and GRADE

Two review authors will independently assess the certainty of evidence (high, moderate, low, and very low) for each outcome across studies using the GRADE framework (Guyatt 2008; Balshem 2011) and GRADEpro software (GRADEpro GDT). Features are assessed that can downgrade the certainty of evidence (less rigorous study design or risk of bias; imprecision; inconsistency or heterogeneity; indirectness; publication bias) or upgrade certainty (large effect size; dose response; direction of plausible residual confounding; and bias supporting trust in results) (Balshem 2011). We will use a modified GRADE approach in which we will rate interrupted time series and repeated measures studies initially as ‘moderate' certainty and controlled before‐after studies as ‘low' certainty (Pantoja 2015). We will resolve disagreements on certainty ratings by discussion and provide justification for any ratings that are downgraded or upgraded. We will summarise findings in ‘Summary of findings' tables. We will include the following outcomes in our main ‘Summary of findings' table: clinical outcomes, drug utilisation, and therapeutic drug monitoring. The relevant outcomes to summarise may vary depending on the intended goals or recommendations of the safety advisory (intervention). We will therefore consider grouping outcomes by the type of recommended action of the safety advisory, or the drug and safety issue, or both. We will consider recommendations for re‐expressing results in an easily interpretable way when reporting findings (Higgins 2011).

Subgroup analysis and investigation of heterogeneity

If we conduct meta‐analyses and there are sufficient studies per outcome, we will carry out subgroup analyses or meta‐regression to explore heterogeneity. In addition to study design, categorical factors to be considered and tested for an association with effect size include differences in communication strategy (e.g. safety advisory type including delivery method); drug type (on patent or not; drug class or single drug); risk issue (e.g. seriousness of harm); health system characteristics or setting; and sponsorship or financial links, or both, to drug manufacturers. Any post‐hoc analyses will be identified as exploratory and hypothesis‐generating only. We will calculate between‐subgroup I² statistics and their 95% CIs. For continuous measures, we will carry out meta‐regression with a fixed‐effect model and inverse variance weighting, if there are sufficient studies, to further explore advisory characteristics associated with intended or unintended effects (Thompson 2002), and report point estimates with 95% CIs. If insufficient data are available for meta‐regression, we will identify key potentially influential factors in a narrative synthesis.

Sensitivity analysis

Sensitivity analyses will be conducted to determine the robustness of the results. These may include but are not restricted to undertaking fixed‐effect meta‐analysis, excluding outlier or studies at high risk of bias; and testing methodological decisions undertaken during the course of the review (e.g. adjustment to avoid unit‐of‐analysis errors with cluster randomised trials; imputing missing data).

Acknowledgements

We thank the Cochrane Effective Practice and Organisation of Care (EPOC) Group for their support, including the following individuals for their helpful comments on the protocol: Editors Farouk Chughlay, Carmel Hughes, and Christopher Rose; Managing Editor Daniela Gonçalves‐Bradley; external peer reviewers Priya Bahri and Brian Edwards, and consumer peer reviewers Sandra Paget and Cecilia Fabrizio. We also thank Copy‐Editor Deirdre Walshe for copy‐editing. We thank Douglas M Salzwedel (Cochrane Hypertension) for devising the search strategy in consultation with our author team, Mimi Doyle‐Waters for peer reviewing the MEDLINE search strategy, and Paul Miller (Cochrane EPOC) for reviewing the search strategy in its entirety. Several authors (BM, LP, and JL) are members of our larger research programme's Safety Advisory Database Working Group and we acknowledge our additional working group members Alice Bhasale, Alice Fabbri, and Lucy Perry for input into the foundational work that informs this Cochrane protocol. Our protocol incorporated standard text based on Cochrane EPOC guidance.

We acknowledge the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane EPOC Group. The views and opinions expressed therein are those of the protocol authors and do not necessarily reflect those of the Systematic Reviews Programme, the NIHR, the National Health Service (NHS), or the Department of Health.

Appendices

Appendix 1. Search strategies

1. Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily, and Versions(R)

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 *adverse drug reaction reporting systems/

2 *information dissemination/mt

3 drug labeling/

4 ((agencies or agency or black triangle or drug? or EMA or FDA or "Food and Drug Administration" or health or IQWIG or MEB or medication? or medicines agency or MHRA or product? or public health or regulator? or regulatory or risk or safety or TGA or Therapeutic Goods Administration or toxicity) adj3 (action or actions or advisories or advisory or alert$ or announcement? or bulletin? or communication? or information or message? or notice or notices or updat$ or warning?)).ti,kf.

5 ((agencies or agency or black triangle or drug? or EMA or FDA or "Food and Drug Administration" or health or IQWIG or MEB or medication? or medicines agency or MHRA or product? or public health or regulator? or regulatory or risk or safety or TGA or Therapeutic Goods Administration or toxicity) adj2 (action or actions or advisories or advisory or alert$ or announcement? or bulletin? or communication? or information or message? or notice or notices or updat$ or warning?)).ab. /freq=2

6 ((box or boxed or dear clinician or dear doctor or dear health professional or dear health care professional or dear healthcare professional or dear health provider or dear health care provider or dear healthcare provider or DHCP or DHP or DHPC) adj3 (advisories or advisory or alert$ or announcement? or bulletin? or communication? or information or letter? or message? or notice or notices or warning?)).tw,kf.

7 ((biologic? or biopharmaceutical? or drug? or medication? or pharmaceutical?) adj2 (label$ program$ or surveillance program$)).tw,kf.

8 (regulator$ adj2 action?).tw,kf.

9 or/1‐8

10 exp drug utilization/

11 practice patterns, physicians'/

12 safety‐based drug withdrawals/

13 ((affect or affects or alternat$ or awareness or change? or changing or consequence? or decline? or declining or decreas$ or discontinu$ or effect? or effective$ or evaluate? or evaluati$ or exceed$ or factor? or impact$ or increas$ or influenc$ or method$ or monitor$ or outcome? or reduce? or reducing or reduction? or status or substitut$) adj2 (behavior? or behaviour? or communicat$ or dispens$ or dosage? or dose or formularies or formulary or frequenc$ or indication? or pattern? or practi?e or practi?es or prescrib$ or prescription? or product? or regulat$ or therap$ or treatm$ or "use of" or usage or utilisation or utilization)).ti,kf.

14 ((affect or affects or alternat$ or awareness or change? or changing or consequence? or decline? or declining or decreas$ or discontinu$ or effect? or effective$ or evaluate? or evaluati$ or exceed$ or factor? or impact$ or increas$ or influenc$ or method$ or monitor$ or outcome? or reduce? or reducing or reduction? or status or substitut$) adj7 (behavior? or behaviour? or communicat$ or dispens$ or dosage? or dose or formularies or formulary or frequenc$ or indication? or pattern? or practi?e or practi?es? or prescrib$ or prescription? or product? or regulat$ or therap$ or treatm$ or "use of" or usage or utilisation or utilization)).ab. /freq=2

15 ((dispens$ or dosage? or dose or prescrib$ or prescription? or utilisation or utilization) adj3 (pattern? or practice?)).tw,kf.

16 (safe$ and manag$ and (biologic$ or biopharmaceut$ or drug$ or medicine? or medication? or pharmaceutical? or vaccine$)).tw,kf.

17 or/10‐16

18 9 and 17

19 animals/ not (humans/ and animals/)

20 18 not 19

2. Ovid Embase

1 *drug surveillance program/

2 *information dissemination/

3 *drug labeling/

4 health warning/

5 ((agencies or agency or black triangle or drug? or EMA or FDA or "Food and Drug Administration" or health or IQWIG or MEB or medication? or medicines agency or MHRA or product? or public health or regulator? or regulatory or risk or safety or TGA or Therapeutic Goods Administration or toxicity) adj3 (action or actions or advisories or advisory or alert$ or announcement? or bulletin? or communication? or information or message? or notice or notices or updat$ or warning?)).ti.

6 ((agencies or agency or black triangle or drug? or EMA or FDA or "Food and Drug Administration" or health or IQWIG or MEB or medication? or medicines agency or MHRA or product? or public health or regulator? or regulatory or risk or safety or TGA or Therapeutic Goods Administration or toxicity) adj2 (action or actions or advisories or advisory or alert$ or announcement? or bulletin? or communication? or information or message? or notice or notices or updat$ or warning?)).ab. /freq=2

7 ((box or boxed or dear clinician or dear doctor or dear health professional or dear health care professional or dear healthcare professional or dear health provider or dear health care provider or dear healthcare provider or DHCP or DHP or DHPC) adj3 (advisories or advisory or alert$ or announcement? or bulletin? or communication? or information or letter? or message? or notice or notices or warning?)).tw.

8 ((biologic? or biopharmaceutical? or drug? or medication? or pharmaceutical?) adj2 (label$ program$ or surveillance program$)).tw.

9 (regulator$ adj2 action?).tw.

10 or/1‐9

11 *drug utilization/

12 *drug recall/

14 ((affect or affects or alternat$ or awareness or change? or changing or consequence? or decline? or declining or decreas$ or discontinu$ or effect? or effective$ or evaluate? or evaluati$ or exceed$ or factor? or impact$ or increas$ or influenc$ or method$ or monitor$ or outcome? or reduce? or reducing or reduction? or status or substitut$) adj6 (behavior? or behaviour? or communicat$ or dispens$ or dosage? or dose or formularies or formulary or frequenc$ or indication? or pattern? or practi?e or practi?es? or prescrib$ or prescription? or product? or regulat$ or therap$ or treatm$ or "use of" or usage or utilisation or utilization)).ab. /freq=2

15 ((dispens$ or dosage? or dose or prescrib$ or prescription? or utilisation or utilization) adj3 (pattern? or practice?)).tw.

16 (safe$ and manag$ and (biologic$ or biopharmaceut$ or drug$ or medicine? or medication? or pharmaceutical? or vaccine$)).tw.

17 or/11‐16

18 10 and 17

19 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)

20 18 not 19

21 limit 20 to (conference abstracts or embase)

3. EBM Reviews ‐ Cochrane Central Register of Controlled Trials

1 adverse drug reaction reporting systems/

2 information dissemination/

3 drug labeling/

7 ((biologic? or biopharmaceutical? or drug? or medication? or pharmaceutical?) adj2 (label$ program$ or surveillance program$)).tw,kf.

8 (regulator$ adj2 action?).tw,kf.

9 or/1‐8

10 exp drug utilization/

11 practice patterns, physicians'/

12 safety‐based drug withdrawals/

15 ((dispens$ or dosage? or dose or prescrib$ or prescription? or utilisation or utilization) adj3 (pattern? or practice?)).tw,kf.

16 (safe$ and manag$ and (biologic$ or biopharmaceut$ or drug$ or medicine? or medication? or pharmaceutical? or vaccine$)).tw,kf.

17 or/10‐16

18 9 and 17

4. Clinical trial registries

Database: ClinicalTrials.gov

Study type: Interventional Studies (Clinical Trials)

(black box advisor* OR black box noti* OR black box warning* OR black triangle OR drug box noti* OR drug box warning* OR FDA advisor* OR FDA noti* OR FDA warning* OR health warning* OR medication warning*)

(regulatory risk OR regulatory safety OR regulatory warning OR safety advisor* OR safety alert* OR safety bulletin* OR safety warning* OR warning label*)

Database: WHO International Clinical Trials Registry Platform

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ (adverse drug reaction report* OR black box alert* OR black box advisor* OR black box noti* OR black box safety* OR black box warning* OR black triangle OR drug box noti* OR drug box warning* OR drug surveillance program* OR drug warning* OR FDA advisor* OR FDA alert* OR FDA bulletin* OR FDA noti* OR FDA warning* OR health warning* OR medication warning* OR regulatory risk OR regulatory safety OR regulatory warning OR safety advisor* OR safety alert* OR safety bulletin* OR safety warning* OR warning label*) ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

5. Clarivate Web of Science (Indexes=SCI‐EXPANDED, CPCI‐S)

#34 #33 NOT PMID=(1* OR 2* OR 3*)

#33 #32 AND #20

#32 #31 OR #30 OR #29 OR #28 OR #27 OR #26 OR #25 OR #24 OR #23 OR #22 OR #21

#31 TS=(safe* and manag* and (biologic* or biopharmaceut* or drug* or medicine* or medication* or pharmaceutical* or vaccine*))

#30 TS=(dispens* NEAR/3 pattern* or dosage* NEAR/3 pattern* or prescrib* NEAR/3 pattern* or prescription* NEAR/3 pattern* or utilisation NEAR/3 pattern* or utilization NEAR/3 pattern*) OR TS=(dispens* NEAR/3 practice* or dosage* NEAR/3 practice* or prescrib* NEAR/3 practice* or prescription* NEAR/3 practice* or utilisation NEAR/3 practice* or utilization NEAR/3 practice*)

#29 TS=(reduc* NEAR/2 (dispens* or dosage* or dose or frequenc* or pattern* or prescrib* or prescription* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(substitut* NEAR/2 (dispens* or dosage* or dose or formular* or frequenc* or indication* or pattern* or prescrib* or prescription* or product* or therap* or treatm* or "use of" or usage or utilisation or utilization))

#28 TS=(monitor* NEAR/2 (behav* or dispens* or dosage* or dose or formular* or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or therap* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(outcome* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or therap* or treatm* or "use of" or usage or utilisation or utilization))

#27 TS=(influenc* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or regulat* or therap* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(method* NEAR/2 (dispens* or dosage* or dose or practi*e or practi*es or prescrib* or prescription* or product* or regulat* or therap* or treatm* or "use of" or usage or utilisation or utilization))

#26 TS=(impact* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or practi*e or practi*es or prescrib* or prescription* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(increas* NEAR/2 (dispens* or dosage* or dose or frequenc* or indication* or prescrib* or prescription* or product* or treatm* or "use of" or usage or utilisation or utilization)

#25 TS=(effect* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(evaluat* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or treatm* or "use of" or usage or utilisation or utilization))

#24 TS=(decreas* NEAR/2 (dispens* or dosage* or dose or formular* or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or therap* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(discontinu* NEAR/2 (dispens* or indication* or prescrib* or prescription* or product* or therap* or treatm* or "use of" or usage or utilisation or utilization))

#23 TS=(consequence* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or therap* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(declin* NEAR/2 (dispens* or dosage* or dose or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or therap* or treatm* or "use of" or usage or utilisation or utilization))

#22 TS=(awareness* NEAR/2 (behav* or dispens* or dosage* or dose or formular* or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or regulat* or therap* or treatm*)) OR TS=(chang*NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or indication* or pattern* or practi*e or practi*es or prescrib* or prescription* or product* or regulat* or therap* or treatm* or "use of" or usage or utilisation or utilization))

#21 TS=(affect* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or pattern* or practi*e or practi*es or prescrib* or prescription* or therap* or treatm* or "use of" or usage or utilisation or utilization)) OR TS=(alternat* NEAR/2 (behav* or dispens* or dosage* or dose or frequenc* or pattern* or practi*e or practi*es or prescrib* or prescription* or therap* or treatm* or "use of" or usage or utilisation or utilization))

#20 #19 OR #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1

#19 TS=(regulator* NEAR/2 (action*))

#18 TS=(biologic* NEAR/2 (surveillance program*)) OR TS=(biopharmaceutical* NEAR/2 (surveillance program*)) OR TS=(drug* NEAR/2 (surveillance program*)) OR TS=(medication* NEAR/2 (surveillance program*)) OR TS=(pharmaceutical* NEAR/2 (surveillance program*))

#17 TS=(DHCP NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or letter* or message* or notice or notices or warning*)) OR TS=(DHP NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or letter* or message* or notice or notices or warning*)) OR TS=(DHPC NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or letter* or message* or notice or notices or warning*))

#16 TS=(dear clinician NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or letter* or message* or notice or notices or warning*)) OR TS=(dear doctor* NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or letter* or message* or notice or notices or warning*)) OR TS=(dear healthcare NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or letter* or message* or notice or notices or warning*)) OR TS=(dear health care NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or letter* or message* or notice or notices or warning*))

#15 TS=(box* NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or information or letter* or message* or notice or notices or warning*))

#14 TS=(toxicity NEAR/3 (advisories or advisory or alert* or bulletin* or notice or notices or warning*))

#13 TS=(TGA NEAR/3 (action or actions or advisories or advisory or alert* or announcement* or bulletin* or communication* or information or message* or notice or notices or updat* or warning*))

#12 TS=(risk* NEAR/3 (advisories or advisory or alert* or bulletin* or notice or notices or warning*)) OR TS=(safety NEAR/3 (advisories or advisory or alert* or bulletin* or notice or notices or warning*))

#11 TS=(regulator* NEAR/3 (action or actions or advisories or advisory or alert* or announcement* or bulletin* or communication* or information or message* or notice or notices or updat* or warning*))

#10 TS=(public health NEAR/3 (advisories or advisory or alert* or bulletin* or notice or notices or warning*))

#9 TS=(product* NEAR/3 (advisories or advisory or alert* or bulletin* or notice or notices or warning*))

#8 TS=(MRHA NEAR/3 (action or actions or advisories or advisory or alert* or announcement* or bulletin* or communication* or information or message* or notice or notices or updat* or warning*))

#7 TS=(health NEAR/3 (advisories or advisory or alert* or bulletin* or notice or notices or warning*)) OR TS=(medication* NEAR/3 (advisories or advisory or alert* or bulletin* or notice or notices or warning*))

#6 TS=(FDA NEAR/3 (action or actions or advisories or advisory or alert* or announcement* or bulletin* or communication* or information or message* or notice or notices or updat* or warning*))

#5 TS=(EMA NEAR/3 (action or actions or advisories or advisory or alert* or announcement* or bulletin* or communication* or information or message* or notice or notices or updat* or warning*))

#4 TS=(drug* NEAR/3 (advisories or advisory or alert* or announcement* or bulletin* or communication* or information or message* or notice or notices or updat* or warning*))

#3 TS=(agenc* NEAR/3 (action or actions or advisories or advisory or alert* or announcement* or bulletin* or communication* or information or message* or notice or notices or updat* or warning*))

#2 TS=(black triangle OR black box*)

#1 TS=(adverse drug reaction report*)

6. ProQuest Dissertations & Theses Global

ti,ab(adverse drug reaction report* OR black triangle OR black box* OR drug surveillance program* OR regulatory action* OR ((agenc* OR boxed OR "dear clinician" OR "dear doctor" OR "dear healthcare" OR drug* OR EMA OR FDA OR health OR IQWIG OR medication* OR product* OR regulator* OR risk* OR toxicity) NEAR/3 (advisories OR advisory OR alert OR alerts OR bulletin* OR communication* OR message* OR notice OR notices OR updat* OR warning*)))

AND

ti,ab(dispens* pattern* OR prescrib* pattern* OR prescrip* pattern* OR ((affect* OR alternat* OR awareness* OR chang* OR consequence* OR declin* OR decreas* OR discontinue* OR effect* OR evaluat* OR impact* OR increas* OR influenc* OR method* OR monitor* OR outcome* OR reduc* OR substitut*) NEAR/2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR practice* OR practise* OR prescrib* OR prescription* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)))

7. EBSCO PsycINFO

S45S23 AND S44

S44S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43

S43(safe* AND manag* AND (biologic* OR biopharmaceut* OR drug* OR medicine* OR medication* OR pharmaceutical* OR vaccine*)

S42(dispens* N3 practice* OR dosage* N3 practice* OR prescrib* N3 practice* OR prescription* N3 practice* OR utilisation N3 practice* OR utilization N3 practice*)

S41(substitut* N2 (dispens* OR dosage* OR dose OR fORmular* OR frequenc* OR indication* OR pattern* OR prescrib* OR prescription* OR product* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S40(reduc* N2 (dispens* OR dosage* OR dose OR frequenc* OR pattern* OR prescrib* OR prescription* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S39(outcome* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S38(monitor* N2 (behav* OR dispens* OR dosage* OR dose OR fORmular* OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S37(method* N2 (dispens* OR dosage* OR dose OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR regulat* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S36(influenc* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR regulat* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S35(increas* N2 (dispens* OR dosage* OR dose OR frequenc* OR indication* OR prescrib* OR prescription* OR product* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S34(impact* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR practi*e OR practi*es OR prescrib* OR prescription* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S33(evaluat* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S32(effect* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S31(discontinu* N2 (dispens* OR indication* OR prescrib* OR prescription* OR product* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S30(decreas* N2 (dispens* OR dosage* OR dose OR fORmular* OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S29(declin* N2 (dispens* OR dosage* OR dose OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S28(consequence* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S27(chang* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR regulat* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S26(awareness* N2 (behav* OR dispens* OR dosage* OR dose OR fORmular* OR frequenc* OR indication* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR product* OR regulat* OR therap* OR treatm*)

S25(alternat* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S24(affect* N2 (behav* OR dispens* OR dosage* OR dose OR frequenc* OR pattern* OR practi*e OR practi*es OR prescrib* OR prescription* OR therap* OR treatm* OR "use of" OR usage OR utilisation OR utilization)

S23S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22

S22regulator* N2 action*

S21(biologic* OR biopharmaceutical* OR drug* OR medication OR pharmaceutical*) N2 (surveillance program*)

S20(dear health care N3 (advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR letter* OR message* OR notice OR notices OR warning*)

S19(dear healthcare N3 (advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR letter* OR message* OR notice OR notices OR warning*)

S18(dear doctor) AND (advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR letter* OR message* OR notice OR notices OR warning*)

S17(dear clinician) AND (advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR letter* OR message* OR notice OR notices OR warning*)

S16(box* N3 (advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR information OR letter* OR message* OR notice OR notices OR warning*)

S15(toxicity N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)

S14(safety N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)

S13(risk* N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)

S12(regulator* N3 (action OR actions OR advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR information OR message* OR notice OR notices OR updat* OR warning*)

S11(public health N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)

S10(product* N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)

S9(medication* N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)

S8(health N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)) OR TS=(medication* N3 (advisories OR advisory OR alert* OR bulletin* OR notice OR notices OR warning*)

S7(FDA N3 (action OR actions OR advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR information OR message* OR notice OR notices OR updat* OR warning*)

S6(drug* N3 (advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR information OR message* OR notice OR notices OR updat* OR warning*)

S5(agenc* N3 (action OR actions OR advisories OR advisory OR alert* OR announcement* OR bulletin* OR communication* OR information OR message* OR notice OR notices OR updat* OR warning*)

S4(black triangle OR black box*)

S3adverse drug reaction report*

S2DE "Warning Labels"

S1DE Information Dissemination

8. Epistemonikos

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ (adverse drug reaction report* OR black triangle OR black box* alert* OR black box* safety OR black box warning* OR drug surveillance program* OR regulatory action* OR drug box notice* OR drug box warning* OR drug warning* OR FDA advisor* OR FDA alert* OR FDA bulletin* OR FDA noti* OR FDA warning* OR medication warning* OR product warning* OR regulator* advisor* OR regulator* risk OR regulator* safety OR regulator* warning* OR safety advisor* OR safety alert* OR safety bulletin* OR warning label*) ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Contributions of authors

LP and BM conceived the protocol.

LP designed, co‐ordinated, and wrote the first protocol draft.

DS* and MDW (peer review)* designed the search strategies, with input from LP.

LP, BM, JL, LB, DM, CH, and GW provided input into finalisation of the draft protocol.

BM, LP, LB, DM, and JL secured funding for the protocol.

BM, LP, and JL performed previous work that was the foundation of the current study.

*DS is Douglas M. Salzwedel and MDW is Mimi Doyle‐Waters; who are Information Specialists listed in the Acknowledgements.

Sources of support

Internal sources

No sources of support supplied

External sources

The Canadian Institutes of Health Research, Canada.

Grant funding reference number: CIHR PJT–153275 / 20R10386. What works best to protect public health? An international comparison of post‐market regulatory risk communication on prescription drugs.

Declarations of interest

Lorri Puil: no known conflicts of interest.
Lisa Bero: no known conflicts of interest.
Dee Mangin: no known conflicts of interest.
Gavin Wong: no known conflicts of interest.
Joel Lexchin: from 2015 to 2018, Joel Lexchin was a paid consultant on three projects: one looking at indication‐based prescribing (United States Agency for Healthcare Research and Quality), a second to develop principles for conservative diagnosis (Gordon and Betty Moore Foundation), and a third deciding what drugs should be provided free of charge by general practitioners (Government of Canada, Ontario Supporting Patient Oriented Research Support Unit and the St Michael’s Hospital Foundation). He also received payments for being on a panel that discussed a pharmacare plan for Canada (Canadian Institute, a for‐profit organisation), a panel at the American Diabetes Association, and for a talk at the Toronto Reference Library. He is member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare.
Christine Hallgreen is employed at Copenhagen Centre for Regulatory Sciences (CORS), which is a cross‐faculty university anchored institution involving various public (Danish Medicines Agency, Copenhagen University) and private stakeholders (Novo Nordisk, Lundbeck, Ferring Pharmaceuticals, LEO Pharma) as well as patient organisations (Rare Diseases Denmark). The centre is purely devoted to the scientific aspects of the regulatory field and with a patient‐oriented focus and the research is not company‐specific product or directly company related. She owns stocks in the pharmaceutical company Novo Nordisk A/S, where she was previously employed (2006 to 2013).
Barbara Mintzes: in 2015 and 2016, Barbara Mintzes was retained as an expert witness by the law firm representing the plaintiffs in an application for a Canadian class action on cardiovascular risks of testosterone supplements. She is an author of a potentially eligible study for this review.

New

References

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PERMALINK

The impact of post‐market regulatory safety advisories on patients, prescribers, and the healthcare system

Lorri Puil

Joel Lexchin

Lisa Bero

Dee Mangin

Christine E Hallgreen

Gavin WK Wong

Barbara Mintzes

Abstract

Background

Description of the problem or issue

Description of the intervention

Table 1.

How the intervention might work

Figure 1.

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of comparators

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Trials and controlled before‐after studies

Interrupted time series and repeated measures studies

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

‘Summary of findings' and GRADE

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Acknowledgements

Appendices

Appendix 1. Search strategies

1. Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily, and Versions(R)

2. Ovid Embase

3. EBM Reviews ‐ Cochrane Central Register of Controlled Trials

4. Clinical trial registries

5. Clarivate Web of Science (Indexes=SCI‐EXPANDED, CPCI‐S)

6. ProQuest Dissertations & Theses Global

7. EBSCO PsycINFO

8. Epistemonikos

Contributions of authors

Sources of support

Internal sources

External sources

Declarations of interest

References

Additional references

ACTIONS

PERMALINK

RESOURCES

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