Effectiveness of antibiotic prophylaxis effective at preventing iGAS in persons exposed to iGAS cases

Q#20-07 –Effectiveness of antibiotic prophylaxis effective at preventing iGAS in persons exposed to iGAS cases


Infection by Streptococcus pyogenes (group A streptococci, GAS) causes a wide range of syndromes ranging from localized illness, such as pharyngitis, to invasive and serious disease, including bacteremia, pneumonia, necrotizing fasciitis, and streptococcal toxic shock syndrome (STSS)1. Invasive GAS (iGAS) infection causes significant morbidity and mortality in both children and adults. An estimated of 9557 cases (3.8 cases per 100 000 persons per year) with 1116 deaths (case-fatality rate, 11.7%) resulting from invasive GAS occurred in the United States from 2005-2012. The risk of contracting iGAS disease is higher amongst close contacts of iGAS cases relative to other contacts or the general population. However, very few population-based studies have been published quantifying the risk of secondary household transmission. In a recent study in the UK, the authors suggested the use of selective prophylaxis for contacts with particular risk factors (pregnancy, women in the postpartum period, neonates, adults older than 75 years).


We will use two distinct data sources. The first one is MarketScan (2010-2018), a database that contains millions of healthcare claims information from large employers, managed care organizations, and Medicare program in the United States. The second source is the Quebec Pregnancy Cohort (QPC), an ongoing population-based cohort with prospective data collection on all pregnancies of women covered by the provincial prescription drug insurance that occurred between January 1998 and December 2015 in the province of Quebec. Data on the mothers and children after the end of pregnancy are also collected. Individual-level information is obtained from province-wide databases and linked using unique personal identifiers. QPC contains up to 17 years of follow-up for mothers and children.

Safety and effectiveness of influenza vaccine during pregnancy

Q# 19-08 – Safety and effectiveness of influenza vaccine during pregnancy

Research question:

Are influenza vaccines safe and effective for women and their newborns if received at any time during their pregnancy?


A number of recent studies on the safety of influenza vaccine in pregnancy have been published. In addition to the review, it would be beneficial to determine the safety and effectiveness of influenza vaccine during pregnancy using primary research completed within Canada. A retrospective study using an existing cohort of pregnant women would be the most feasible to assess AEFIs during pregnancy and neonatal birth outcomes and may be possible to use for assessing the vaccine effectiveness in pregnant women and children less than 6 months of age.  Vaccinated mothers pass protective antibodies via the placenta to provide passive immunity to newborns.  These antibodies are generally considered to provide passive protection to newborns up to 6 months of age, and protecting infants <6 months (before infants can receive their own vaccines) is an important outcome of the vaccine program for pregnant women.


Given that administrative databases do no have readily available information on vaccine use in any given populations, and thus cannot be performed within the Canadian Mother-Child Cohort Initiative, CAN-AIM’s proposal will use data from the 3D Cohort Study to answer the query. A Bérard is a co-investigator within the 3D Cohort Study, and thus has direct access to the study data. The 3D Cohort has been described in Fraser et al. 2016 (Fraser et al. (including A Bérard) 3D Study Group. 3D Cohort Study: The Integrated Research Network in Perinatology of Quebec and Eastern Ontario. Paediatr Perinat Epidemiol. 2016 Nov;30(6):623-632) and is presented at https://www.maelstrom-research.org/mica/individual-study/3d.

Current status:

Feasibility assessment has been approved by DSEN. Ethics approved at Ste-Justine. Transfer fund agreement has been drafted. Meanwhile, we have almost completed the analyses. Our content expert, Dr Caroline Quasi, will soon meet with us to provide further feedback and insight. After that, we are planning a meeting with the query submitters to present results.

Comparativeness effectiveness of influenza vaccines in elderly persons

Q# 19-07 – Comparativeness effectiveness of influenza vaccines in elderly persons

Research question:

Which influenza vaccine available for adults 65 years of age and older is the most effective?


Influenza respiratory infections are caused primarily by influenza A and B viruses with worldwide annual attack rate estimated at 5–10% in adults. Influenza is recognized as a cause of a broad spectrum of morbidity and mortality. In Canada, it is estimated 12,200 hospitalizations and 3,500 deaths attributable to influenza annually [1].

Vaccination is the most effective way to prevent influenza and its complications. In Canada, there are currently four types of influenza vaccines available for adults 65 years of age and older, the target population of the present project: trivalent standard dose (Agriflu®, Fluviral®, Influvac®), quadrivalent standard dose (Afluria® Tetra, Influvac® Tetra, Flulaval Tetra®, Fluzone® Quadrivalent), trivalent adjuvanted (Fluad®), and trivalent high dose (Fluzone® High-Dose). The National Advisory Committee on Immunization (NACI) informs that there are insufficient head-to-head studies directly comparing efficacy, effectiveness, and immunogenicity of trivalent adjuvanted, trivalent high dose, and quadrivalent standard dose [1]. Further investigations are required to provide real-world evidence on comparative effectiveness of influenza vaccine in seniors.

CAN-AIM proposes a retrospective cohort study to compare the effectiveness of the above four types of influenza vaccine in adults 65 years of age and older using administrative databases from the United States.

Current status:

The PMAP for the current study was approved in December 2019. The analytical protocol has been developed and was sent to DSEN. In the study we will use six cohorts based on MarketScan® databases (2012-2018). We have constructed our first cohort covering the 2017/2018 influenza season. After applying the inclusion and exclusion criteria, we have included 218,592 adults 65 years of age and older that had received influenza vaccination during this period (53.3% trivalent high dose, 31.0% quadrivalent standard dose, 11.4% trivalent standard dose, and 4.3% trivalent adjuvanted). In the next months we will proceed cohort selection for the other periods and start the analysis of all six cohorts.

Cough and cold products containing opioids: prescribing and patient utilization patterns in the pediatric population.

Q# 19-06 – Cough and cold products containing opioids: prescribing and patient utilization patterns in the pediatric population.

Research question:

What are the physician’s prescribing patterns and patients’ use patterns of prescribed cough and cold opioid-containing medicines (CCOMs) in paediatrics?

Context and rational:

Opioid-related harms constitute a major public health concern in Canada, currently ranked as second in per capita prescription opioid use, after the United States. The last Canadian national report of apparent opioid-related deaths, updated in December 2018, revealed that there were more than 9,000 apparent opioid-related deaths between January 2016 and June 2018. Of them, 2,066 occurred between January and June 2018 and 94% were accidental. Most accidental apparent opioid-related deaths involved fentanyl and fentanyl analogs and occurred among males (76%), and middle age adults. Only 1% of accidental apparent opioid-related deaths occurred in <19 years of age1. There are no data that discuss the role of CCOMs in the opioid related harms occurred in Canada.

Given the identified knowledge gap, studies aiming to address the potential role of CCOMs in the opioid-related risks among the pediatric population, should help to provide Canadian prescribers and patients with meaningful information for decision making, validate the recommendation provided in the SA and help to understand the individual contribution of CCOMs to the National opioid crisis.


Within each provincial administrative/hospital databases, a birth cohort will be formed including all births that occurred in the province between 1998-2018. Date of entry in the cohort will be the date of birth (DOB) and children will be required to be publicly insured for their medications.

Follow-up will be done from DOB until i) the child is 18 years of age, ii) end of medication coverage, or iii) December 31, 2018, whichever comes first.

CCOMs considered will be fentanyl, codeine, hydrocodone, normethadone, dextroethorphane alone or in combination forms (i.e. acetaminophen and codeine, etc.); pills, syrups, oral formulations or elixirs will be studied.

Current status:

The query was obtained at the end of December 2019. Contracts for transfer funds and detailing collaboration with sites from four provinces, including University of Saskatchewan, Ottawa Hospital Research Institute, University of Alberta, University of Manitoba, are in progress. We plan to start the study soon as our research center re-opens after COVID-19, and the contracts finalized. The protocol was presented to the team at the CAMCCO symposium on February 20th, 2020 (CHR KT funding). We are on track with proposed timeline.

Hydrochlorothiazide and risk of non-melanoma skin cancer

Q# 19-05: Hydrochlorothiazide and risk of non-melanoma skin cancer

Research question:

In the adult patient population, is hydrochlorothiazide therapy causally associated with the risk of non­ melanoma skin cancer (i.e. squamous and basal cell carcinomas)?

If so, is there a cumulative dose-response relationship?


Non-melanoma skin cancer (NMSC) represents the most commonly diagnosed malignancy in Canada1 . The two most frequent histologic variants of NMSC are cutaneous squamous cell (SCC) and basal cell carcinomas (BCC). One in 8 (12.5%) Canadian will develop BCC in their lifetime and 1 in 20 (5%) will develop SCC2 . Ultraviolet exposure, photosensitizing drug use, and immunodeficiency are important risk factors  for  NMSC,  with  light skinned individuals most at risk1 .

Hydrochlorothiazide containing products are widely prescribed in Canada for a variety of indications, most commonly hypertension and edematous conditions. Hydrochlorothiazide is known to increase the sensitivity of the skin to sunlight and ultraviolet radiation3  •  The current product monographs  of hydrochlorothiazide containing products are not labelled for the risk of skin cancer or NMSC; photosensitivity, however, is labelled as an adverse reaction. In the US, labelling is similar for hydrochlorothiazide containing products.

Prompted by recent pharmacoepidemiologic studies, Health Canada recently completed a signal assessment for hydrochlorothiazide and the risk of non-melanoma skin cancer . The signal assessment leveraged EMA’s systematic review of the relevant evidence and updated the searches to identify subsequently published studies. An up-to-date systematic review of the literature and meta-analyses were performed and the  certainty  of evidence was rated with the GRADE approach. Total 5 pharmacoepidemiologic studies (from Europe and the US) including thousands of patients were directly relevant to the topic. Very low certainty evidence (for causal inference) suggested that the risk of NMSC increases with increasing use of hydrochlorothiazide (compared with its non-use); after several years of use, the risk could be four times higher for SCC and 1.25 folds higher for BCC. The certainty of evidence was downgraded for important methodological limitations identified in the included evidence. For example, sun exposure data and smoking status was not available or substantially missing; underlying disease, its duration and follow-up time were not matched;  unclear disposition of exposure classification during the lag period in some studies; unclear adjustment for death as a competing risk for non­ melanoma skin cancer in other studies, etc.

Because of the existing uncertainty about an important patient-oriented outcome, Health Canada seeks researchers’ input and feasibility regarding the conduct of an observational study based on existing Canadian/foreign administrative digital healthcare data that could answer the aforementioned research questions with a higher degree of certainty by minimizing important biases identified in the existing literature on the topic in particular, and otherwise known to impact administrative database studies in general. Ideally, the observational study protocol would be designed emulating a hypothetical randomized trial of adult patients starting and adhering to hydrochlorothiazide therapy in particular and photosensitizing thiazide class of drugs in general versus alternative patient management strategies (e.g . use of non-photosensitizing, non-thiazide class of alternative pharmacological therapy; non-pharmacological therapies; or both, etc.). Subgroups of interest and important effect modifiers would be pre-specified.


CAN-AIM proposes to use data from three cohorts of the Canadian Partnership for Tomorrow Project (CPTP), all linked with administrative data collected by provincial Ministries of Health. The following cohorts are involved:

  • The CARTaGENE cohort
  • The BC Generations Project (BCGP)
  • The Ontario Health Study (OHS)

Current status:

The PMAP is finalized and approved for the current project. We are currently working on the analytical protocol and initial sample selection from the first CPTP cohort, the Ontario Health Study (OHS). We have also granted access to more recent years of data from the BC Generation Project (up to December 2019) and we are in process to apply for the same update with Cartagene cohort

Active surveillance for Safety and Effectiveness of Health Products

Q# 19-03/18-08: Active surveillance for Safety and Effectiveness of Health Products

Research Question:

To conduct a systematic review of active surveillance methodologies and perform pilot studies on active surveillance using the Canadian Healthcare system data and other types of data that may inform pharmacovigilance in Canada.

Decision-making context:

The MHPD logic model specifies the ultimate program outcome of “sustainable, integrated, responsive and science-based national regulatory system”.  A more strategic approach to active surveillance that considers methodologies and resources suitable to the Canadian regulatory context would contribute to this outcome.

Further the ministerial mandate to address access, affordability and appropriate use has resulted in a Directorate initiative to enhance the use of real world evidence within the post-market arena.  A DSEN study could support MHPD’s advancement in the use of real world data to support decision-making.

This review will inform pro-active planning and help prioritize the use of third party research networks in meeting Health Canada’s active surveillance needs; the development of data analytics capacity within Health Canada; and the development of an active surveillance strategy.


Traditional and emerging that would be suitable for drugs and devices for 1) safety surveillance and 2) effectiveness surveillance.

•Evaluation of existing tools and methodologies: characteristics, strengths, and limitations, resource requirements and sustainability considerations, suitability for Canadian applications given the current and potential future state of Canadian health systems data.

•Methodological guidelines building on those created by other organizations and identification of gaps or areas of focus where Canadian regulatory and policy initiatives could contribute to international active surveillance.

•A review and evaluation of privacy and governance models that could support a federal active surveillance strategy in Canada.

It is anticipated that this query might be answered with a scoping review, but other types of methodologies will be considered, including proposals of possible active surveillance pilot projects that help establish a federal approach to active surveillance within the context of Market Authorization Holder responsibilities to conduct active surveillance related to their authorized products.

FDA has developed key elements [i]that would be required to successfully implement an active surveillance strategy. The review could address some of these concerns at a high level, but the intent of the investigation is focused on methodologies and the feasibility of their implementation in Canada at a federal level.

Current status:

We have developed a website for the current study (motherchildcohort.ca). The methodology sharing platform has been developed and used by participating provinces/team members. The repository is underway but slow downed due to COVID-19. We have obtained a CIHR KT grant that allowed all team members to meet face-to-face in Montreal on February 20, 2020.