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Nigel SB Rawson,1–3 John Adams4 1Eastlake Research Group, Oakville, ON, 2Canadian Health Policy Institute, Toronto, ON, 3Fraser Institute, Vancouver, BC, 4Canadian PKU and Allied Disorders Inc., Toronto, ON, Canada Abstract: In democratic societies, good governance is the key to assuring the confidence of stakeholders and other citizens in how governments and organizations interact with and relate to them and how decisions are taken. Although defining good governance can be debatable, the United Nations Development Program (UNDP) set of principles is commonly used. The reimbursement recommendation processes of the Canadian Agency for Drugs and Technologies in Health (CADTH), which carries out assessments for all public drug plans outside Quebec, are examined in the light of the UNDP governance principles and compared with the National Institute for Health and Care Excellence system in England. The adherence of CADTH's processes to the principles of accountability, transparency, participatory, equity, responsiveness and consensus is poor, especially when compared with the English system, due in part to CADTH's lack of genuine independence. CADTH's overriding responsibility is toward the governments that "own," fund and manage it, while the agency’s status as a not-for-profit corporation under federal law protects it from standard government forms of accountability. The recent integration of CADTH’s reimbursement recommendation processes with the provincial public drug plans’ collective system for price negotiation with pharmaceutical companies reinforces CADTH's role as a nonindependent partner in the pursuit of governments’ cost-containment objectives, which should not be part of its function. Canadians need a national organization for evaluating drugs for reimbursement in the public interest that fully embraces the principles of good governance – one that is publicly accountable, transparent and fair and includes all stakeholders throughout its processes. Keywords: drug reimbursement recommendation, health technology assessment, governance, Canada, drug insurance

Nigel SB Rawson,1– 3 David J Stewart4,5 1Macdonald-Laurier Institute, Ottawa, Ontario, Canada; 2Canadian Health Policy Institute, Toronto, Ontario, Canada; 3Centre for Health Policy Studies, Fraser Institute, Vancouver, British Columbia, Canada; 4Department of Medicine, The University of Ottawa, Ottawa, Ontario, Canada; 5Division of Medical Oncology, The Ottawa Hospital, Ottawa, Ontario, CanadaCorrespondence: Nigel SB Rawson, Email eastlakerg@gmail.comPurpose: To evaluate whether time targets for Canadian Agency for Drugs and Technologies in Health (CADTH) reimbursement reviews and pan-Canadian Pharmaceutical Alliance (pCPA) price negotiations are being achieved for oncology drugs.Materials and Methods: Recommendations, dates of submission and publication, and indications for oncology medicines issued between January 2014 and December 2023 were recorded from CADTH’s reimbursement reports webpage. The date any negotiation began and the date it was completed (successfully or not), or when a decision was made not to pursue negotiation was extracted from the pCPA’s webpage. The duration of each CADTH review and pCPA negotiation was calculated, together with time between CADTH’s recommendation and start of the pCPA negotiation or a decision not to negotiate. Percentages of reviews completed within CADTH’s target and of times taken by the pCPA to decide whether to negotiate and by its price negotiations completed within the relevant targets were calculated.Results: CADTH achieved its 270-days target in 88.2% to 100% of reviews issued between 2015 and 2019 but only in 65.9% to 73.1% of reviews issued in the last three years of the decade. CADTH’s “typical timeline” of 180 days was achieved in under 40% of reviews issued in 2015 and not attained in any review in 2021, 2022 or 2023. The pCPA’s target of 60 days for deciding whether to negotiate was achieved for all recommendations issued in 2014 but dropped below 40% for the last seven years of the decade; its target of 130 days for negotiations was achieved for over 85% of the recommendations in 2014 but decreased to only 14.3% in 2016 and then gradually increased to 61.5% in 2023.Conclusion: CADTH’s “typical timeline” and the pCPA’s targets were not met sufficiently to be meaningful. Their processes take too long for cancer drugs.Plain language summary: Canadian patients and providers are often frustrated and concerned about the timeliness of the country’s health technology assessment (HTA) and price negotiation processes, especially for cancer drugs. HTAs are carried out to evaluate the benefit of a medicine in comparison with its cost to see whether the drug is of sufficient value to add it to the benefit lists of government drug plans. HTAs are performed by the Canadian Agency for Drugs and Technologies in Health (CADTH) for all of Canada, except the province of Quebec, and price negotiations with drug developers are carried out by the pan-Canadian Pharmaceutical Alliance (pCPA) on behalf of all government drug plans. We used data from the websites of CADTH and the pCPA on HTA reviews of cancer drugs issued between January 2014 and December 2023 and price negotiations for these drugs to assess whether CADTH and the pCPA complied with their stated target times for completing their processes. We found that CADTH’s reviews and the pCPA’s price negotiations failed to meet their targets for cancer drugs in the past 10 years and that the timeliness of their performance has, in most cases, deteriorated. HTA and price negotiation processes for cancer drugs take too long in Canada.Keywords: oncology drugs, health technology assessment, drug prices, Canada

Since late 2020, the Canadian Agency of Drugs and Technologies in Health (CADTH) has been using a threshold of $50,000 (CAD) per quality-adjusted life-year (QALY) for both oncology and non-oncology drugs. When used for oncology products, this threshold is hypothesized to have a higher impact on the time to access these drugs in Canada. We studied the impact of price reductions on time to engagement and negotiation with the pan-Canadian Pharmaceutical Alliance for oncology drugs reviewed by CADTH between January 2020 and December 2022. Overall, 103 assessments reported data on price reductions recommended by CADTH to meet the cost-effectiveness threshold for reimbursement. Of these assessments, 57% (59/103) recommendations included a price reduction of greater than 70% off the list price. Eight percent (8/103) were not cost-effective even at a 100% price reduction. Of the 47 assessments that had a clear benefit, in 21 (45%) CADTH recommended a price reduction of at least 70%. The median time to price negotiation (not including time to engagement) for assessments that received at least 70% vs >70% price reduction was 2.6 vs 4.8 months. This study showed that there is a divergence between drug sponsor's incremental cost-effectiveness ratio (ICER) and CADTH revised ICER leading to a price reduction to meet the $50,000/QALY threshold. For the submissions with clear clinical benefit the median length of engagement (2.5 vs 3.3 months) and median length of negotiation (3.1 vs 3.6 months) were slightly shorter compared with the submissions where uncertainties were noted in the clinical benefit according to CADTH. This study shows that using a $50,000 per QALY threshold for oncology products potentially impacts timely access to life saving medications.

In a research article published in BMC Medicine, Onakpoya and colleagues provide a historical review of withdrawals of medications for safety reasons. However, withdrawn medications are only one part of the picture about how regulatory agencies manage drug risks. Moreover, medications introduced before the increased pre-marketing regulations and post-marketing monitoring systems instituted after the thalidomide tragedy have little relevance when considering the present drug safety picture because the circumstances under which they were introduced were completely different. To more fully understand drug safety management and regulatory agency actions, withdrawals should be evaluated within the setting and timeframe in which the medications are approved, which requires information about approvals and safety warnings. Studies are needed that provide a more comprehensive current picture of the identification and evaluation of drug safety risks as well as how regulatory agencies deal with them. Please see related research article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0553-2.

The processes for granting priority review status to new drug submissions in Canada and the United States are not exactly the same, but reasonable concordance should be expected since the selection criteria are similar in the two countries. This study compared new therapeutic drugs approved by both Health Canada and the Food and Drug Administration (FDA) between 2000 and 2014 to evaluate concordance on priority review status. New therapeutic drugs approved in both countries totalled 301; 86 (28.6%) and 136 (45.2%) were given priority review status in Canada and the United States, respectively, with 73 (24.3%) in both. Sensitivity and specificity were 53.7% and 92.1%. Overall concordance on review type was 74.8%. κ was 0.47 indicating moderate agreement. Agreement on review type was >70% for all drugs, except oncology therapies. Broad agreement exists between Health Canada and the FDA on drugs that should not have priority review status. Concordance on drugs that should have this status was generally satisfactory and, for critical drugs, was high. Agreement would improve if more oncology drugs received priority review status in Canada. Despite a higher number of drugs receiving priority review status in the United States, there is reasonable concordance between the two countries., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Following the publication of a meta-analysis reporting a risk of acute myocardial infarction (AMI) with rosiglitazone that led to severe restrictions being placed on its use, several observational studies of the association were reported. The lifting of restrictions in the United States in 2013 makes a review of these studies pertinent., Objective: To evaluate the quality of population-based observational studies of the rosiglitazone-AMI association., Methods: PubMed and Embase literature databases were searched for observational studies evaluating the association that were published between 2006 and 2010. Publications satisfying the inclusion criteria were reviewed using the Checklist for Retrospective Database Studies., Results: Nineteen studies satisfied the inclusion criteria. Reasons for the research design and data source were absent or unclear in 18 (95%) and 16 (84%), respectively. Administrative data were used exclusively in 14 (74%). Baseline periods for prior diagnoses and medications varied widely. Reimbursement constraints on rosiglitazone use were reported in only seven studies (37%), although all were likely to have been impacted by them. What was being tested in half of the rosiglitazone treatment comparisons lacked specificity and clarity. All relied on risk ratios and, for 90% of the comparisons, the ratios were between 0.5 and two - a level at which residual confounding can lead to spurious significance., Conclusion: Important deficiencies existed in the rosiglitazone studies suggesting that standards for methods and reporting of observational safety analyses need improvement. In particular, detailed clinical data should be included when the risk of confounding by indication is likely to be high.

Background: In Saskatchewan, pneumococcal conjugate vaccination (PCV) was offered to high-risk children in 2002 and to all infants in 2005., Objective: To describe trends in the frequency of medical visits for lower respiratory tract infection (LRI) and otitis media (OM) in relation to PCV use during the period 1990 to 2008., Methods: Statistics regarding the number of children covered by the health insurance plan, PCV administration, and medical visits with a diagnostic code associated with LRI and OM were provided by Saskatchewan Health. Monthly rates were analyzed using dynamic state space models., Results: In all series, there was a marked seasonal cycle and some higher-than-expected winter peak values, possibly associated with epidemics of specific respiratory viruses. Three abrupt decreases in baseline rate were observed for LRI and the final one, in February 2007, could be related to the increased proportion of children vaccinated with PCV. There was no statistical correlation between PCV use and OM visit frequency., Conclusion: Many environmental, biological and administrative factors may influence health services use, and an effect of low magnitude of a particular vaccine pertaining to nonspecific outcomes could be obscured in time-series analyses.

Background: We examined the change in the use of rosiglitazone-containing products (RCPs) Canada-wide between 2004 and 2010 and whether the rates of adverse events in association with RCP therapy in Canadian patients changed in this period to better understand the real world use of RCP medications and as part of a regulatory commitment by GlaxoSmithKline to Health Canada to assess whether there was an impact of a risk communication on cardiac safety., Methods: RCP utilization data were obtained from IMS Brogan's longitudinal de-identified patient database (known as LRx) that tracks prescription activity using store-based data collection from pharmacies in all Canadian provinces. Adverse events (AEs), serious adverse events (SAEs) and cardiac AEs associated with RCP use in Canadian patients between April 2004 and December 2010 were identified from GlaxoSmithKline's AE database and, using the LRx data, rates per 100,000 patients were estimated., Results: A total of 239,184 patients were identified as having received at least one RCP prescription between 2004 and 2010 from the LRx. After excluding those with inconsistent gender or age, only one RCP prescription at the pharmacy, a prescription from a pharmacy that had not consistently reported for the past six years or an unreasonably high number of prescriptions, 180,936 patients remained for the analysis. The number of reports identified from the AE database that occurred between April 2004 and December 2010 was 1,037. The average monthly rates of AEs, SAEs and cardiac AEs decreased by 57%, 43% and 4%, respectively, between the observed periods, April 2004-October 2007 and November 2007-December 2010., Conclusions: The findings of this analysis demonstrate a significant decrease in RCP use in Canada following a meta-analysis publication suggesting harm, which has been maintained. It is not possible to disentangle whether the continuing decline can be attributed to the meta-analysis, the changes in prescribing guidelines, media attention or a combination of some or all of these factors.

Background: New drug approvals in the US and Canada were reviewed in short-term studies in the 1990s. A database of drugs approved in both countries between 1992 and 2011 exists allowing for a longer time horizon to assess trends., Objective: To compare review times of drugs approved in the US and Canada over the 20-year period and their duration on the respective markets until any serious safety risk arose., Methods: Data on submission and approval dates and review type were obtained from the regulatory agencies., Results: 454 drugs were approved in both countries in the 20-year period for which the US median approval time was shorter than the Canadian median by >6 months (382 versus 574 days). Nevertheless, in 2007-11, the median approval times were closer in the two countries (302 and 356 days, respectively). 3% of the drugs were discontinued for safety reasons in both countries. The 10-year survival rate without a serious safety warning was significantly lower in Canada (58.4%) than in the US (69.3%). Being approved in 2002-11 with a shorter review time had the greatest impact on a drug receiving a serious safety warning., Conclusions: Overall, new drug approval times in the two countries in the last five years were closer, although some important differences remain so that Canadians still wait longer for some new drugs to be approved. The survival rate of a drug without a serious warning decreased substantially in the last decade in both countries, especially in drugs approved with shorter review times.

Background: The risk of experiencing an acute myocardial infarction (AMI) increases with age and Canada's population is aging. The objective of this analysis was to examine trends in the AMI hospitalization rate in Canada between 2002 and 2009 and to estimate the potential increase in the number of AMI hospitalizations over the next decade., Methods: Aggregated data on annual AMI hospitalizations were obtained from the Canadian Institute for Health Information for all provinces and territories, except Quebec, for 2002/03 and 2009/10. Using these data in a Poisson regression model to control for age, gender and year, the rate of AMI hospitalizations was extrapolated between 2010 and 2020. The extrapolated rate and Statistics Canada population projections were used to estimate the number of AMI hospitalizations in 2020., Results: The rates of AMI hospitalizations by gender and age group showed a decrease between 2002 and 2009 in patients aged ≥ 65 years and relatively stable rates in those aged < 64 years in both males and females. However, the total number of AMI hospitalizations in Canada (excluding Quebec) is projected to increase by 4667 from 51847 in 2009 to 56514 in 2020, a 9.0% increase. Inflating this number to account for the unavailable Quebec data results in an increase of approximately 6200 for the whole of Canada. This would amount to an additional cost of between $46 and $54 million and sensitivity analyses indicate that it could be between $36 and $65 million., Conclusions: Despite projected decreasing or stable rates of AMI hospitalization, the number of hospitalizations is expected to increase substantially as a result of the aging of the Canadian population. The cost of these hospitalizations will be substantial. An increase of this extent in the number of AMI hospitalizations and the ensuing costs would significantly impact the already over-stretched Canadian healthcare system.

Canadian leadership in population-based therapeutic research.

Background: The male Canadian population is aging and more men will be seeking medical care for benign prostatic hyperplasia (BPH). We examined the projected increase in older Canadian males between 2005 and 2018 to evaluate urologic health-care needs., Methods: We used Statistics Canada population projections to derive predictions of the male population aged 50 or more from 2005 to 2018 and results from the Olmsted County Study of Urinary Symptoms to estimate numbers of males aged >/=50 with moderate to severe lower urinary tract symptoms (msLUTS) in the same period. Data from the Canadian Institute for Health Information were used to estimate the number of urologists in 2018., Results: The number of Canadian men aged >/=50 is projected to rise between 2005 and 2018 by 39.5% and the number with msLUTS by 41.3%. However, the number of practicing urologists in Canada in 2018 is likely to be similar to the 584 practicing in 2007. An increase in the number of urologists proportional to the increase in men aged >/=50 with msLUTS would require 799 urologists in 2018., Interpretation: Little opportunity exists to expand the number of trainees in urology. Other alternatives must be sought to deal with increased numbers of older men with msLUTS. Initial management of BPH has moved towards being a responsibility of primary care physicians, but they appear to view BPH as a quality-of-life issue. It is crucial that urologists work closely with primary care physicians to ensure that the management of LUTS progression is optimized.

Purpose: Administrative healthcare utilization data from Canadian provinces have been used for pharmacoepidemiology and pharmacoeconomics research, but limited transparency exists about opportunities for data access, who can access them, and processes to obtain data. An attempt was made to obtain data from all 10 provinces to evaluate access and its complexity., Methods: An initial enquiry about the process and requirements to obtain data on individual, anonymized patients dispensed any of four anti-viral drugs in the ambulatory setting, linked with data from hospital and physician service claims, was sent to each province. Where a response was encouraging, a technical description of the data of interest was submitted., Results: Data were unavailable from the provinces of New Brunswick, Newfoundland and Labrador, and Prince Edward Island, and inaccessible from British Columbia, Manitoba and Ontario due to policies that prohibit collaborative work with pharmaceutical industry researchers. In Nova Scotia, patient-level data were available but only on site. Data were accessible in Alberta, Quebec and Saskatchewan, although variation exists in the currency of the data, time to obtain data, approval requirements and insurance coverage eligibility., Conclusions: As Canada moves towards a life-cycle management approach to drug regulation, more post-marketing studies will be required, potentially using administrative data. Linked patient-level drug and healthcare data are presently accessible to pharmaceutical industry researchers in four provinces, although only logistically realistic in three and limited to seniors and low-income individuals in two. Collaborative endeavours to improve access to provincial data and to create other data resources should be encouraged., ((c) 2009 John Wiley & Sons, Ltd.)

Objectives: To evaluate the use of two Canadian provincial databases by a systematic review of published studies that used them as a primary data source to answer epidemiologic and health services research questions., Study Design and Setting: PubMed, EMBASE, BIOSIS, and CINAHL (keywords: "Manitoba" 1970-2004 and "Saskatchewan" 1969-2004) and the web sites of the provincial data custodians were searched to address our objective. Broad screening of citations and data abstraction were performed using a predefined collection form. Information on study characteristics, therapeutic areas studied, databases used, authors' affiliation, and issues related to data validity was recorded., Results: Three thousand nine hundred and forty-nine citations were screened, 610 studies retrieved, and 325 included. In Saskatchewan, the principal research type was assessment of exposures and health outcomes (48.2%) with 50.4% using a cohort or case-control design, whereas, in Manitoba, it was health services utilization (47.8%) and 86.6% were descriptive. Local investigators performed 83.3% of the Manitoba studies, compared with 35.5% of the Saskatchewan studies. Only 6.2% of the studies assessed the validity and reliability of the database for research purposes and few incorporated relevant information about the validity of their diagnostic data., Conclusion: Important differences exist in the administration and use of these databases. Similar systematic evidence synthesis should be conducted on other databases.

Background: The provincial formulary review processes in Canada lead to the slow and inequitable availability of new products. In 2004, the exploration of a national pharmaceuticals strategy (NPS) was announced. The pricing policies of New Zealand and Australia have been suggested as possible models for the NPS., Objective: To compare health care indexes and health care use information from Canada, Australia and New Zealand., Methods: The 2006 Organisation for Economic Co-operation and Development health data were used to compare health and health care indexes from Canada, Australia and New Zealand between 1994 and 2002 to 2004. The principal focus of the evaluation was cardiovascular and respiratory disorders., Results: Although the mortality rate from acute myocardial infarction decreased in each country from 1994, it levelled off in New Zealand in 1997, 1998 and 1999. Between 1994 and 2003, the average length of hospital stay for any cause and for cardiovascular disorders was stable in Australia and Canada, but increased in New Zealand, while the rate of hospital discharges for cardiovascular diseases decreased in Canada and Australia, but strongly increased in New Zealand. Over the same period, sales of cardiovascular drugs decreased in New Zealand, while sharply increasing in Canada and Australia., Conclusions: Although only circumstantial, our results suggest an association between decreasing cardiovascular drug sales and markers of declining cardiovascular health in New Zealand. Careful consideration must be given to the potential consequences of any model for an NPS in Canada, as well as to opportunities provided for discussion and input from health care professionals and patients.

Background: Claims data provide rapid indicators of SSIs for coronary artery bypass surgery and have been shown to successfully rank hospitals by SSI rates. We now operationalize this method for use by payers without transfer of protected health information, or any insurer data, to external analytic centers., Results: We performed a descriptive study testing the operationalization of software for payers to routinely assess surgical infection rates among hospitals where enrollees receive cardiac procedures. We developed five SAS programs and a user manual for direct use by health plans and payers. The manual and programs were refined following provision to two national insurers who applied the programs to claims databases, following instructions on data preparation, data validation, analysis, and verification and interpretation of program output. A final set of programs and user manual successfully guided health plan programmer analysts to apply SSI algorithms to claims databases. Validation steps identified common problems such as incomplete preparation of data, missing data, insufficient sample size, and other issues that might result in program failure. Several user prompts enabled health plans to select time windows, strata such as insurance type, and the threshold number of procedures performed by a hospital before inclusion in regression models assessing relative SSI rates among hospitals. No health plan data was transferred to outside entities. Programs, on default settings, provided descriptive tables of SSI indicators stratified by hospital, insurer type, SSI indicator (inpatient, outpatient, antibiotic), and six-month period. Regression models provided rankings of hospital SSI indicator rates by quartiles, adjusted for comorbidities. Programs are publicly available without charge., Conclusion: We describe a free, user-friendly software package that enables payers to routinely assess and identify hospitals with potentially high SSI rates complicating cardiac procedures.

Purpose: Following its licensure, tuberculosis (TB) was reported as a potential adverse effect of infliximab. Subsequently, the product circular was changed to recommend tuberculin skin testing before patients received infliximab, which was reinforced by several risk communication efforts. The aim of this study was to evaluate patterns and predictors of documented tuberculin skin testing in patients before and after manufacturer, federal, and academic risk communications., Methods: Patients administered infliximab were identified from 11 health plans located throughout the United States, and claims data were examined to determine whether the patients had received a tuberculin skin test. Patients were divided into three cohorts depending on the timing of their first infliximab treatment in relation to the risk communication efforts., Results: The overall tuberculin skin testing rate doubled from 15.4% in the first cohort to 30.9% in the last cohort, while the rate of pre-infliximab treatment testing increased from 0 to 27.7% (Chi-squared test for trend, p < 0.0001 for both). Tuberculin skin testing rates were significantly higher in women, those with a diagnosis of rheumatoid or psoriatic arthritis, and those with a rheumatologist as prescriber. After multivariable analysis, only rheumatologist remained significantly associated with tuberculin skin testing., Conclusions: Although the tuberculin skin testing rate was relatively low overall, tuberculin skin testing doubled over 30 months of ongoing risk communication efforts and under ascertainment likely occurred. We also found variation in the tuberculin skin testing rate associated with physician specialty. This study demonstrates a significant change in patient care following risk communication efforts., ((c) 2005 John Wiley & Sons, Ltd.)

Poor concordance exists between medications that receive a priority review in Canada and those given an expeditious review in the United States. The objectives of this study were to obtain an evaluation of the clinical significance of new drugs approved in both countries from expert clinical pharmacologists, and to examine the concordance of their aggregate assessment with whether or not the product received an expeditious review in either country. Five experts assessed 146 new medications approved in both Canada and the United States between 1996 and early 2002. Overall, the concordance between the experts' assessments was poor and there was large variation in products considered to be of sufficient importance for priority status. Nevertheless, the experts' evaluations suggested that several priority-reviewed products did not warrant such a review. Regulatory agencies select new medications of potential clinical significance to receive shorter review times to minimize the delay in access to them, but, in Canada, only a low proportion of priority-status products had review times within Health Canada's performance target. The large variation in the assessment of clinical significance suggests that a more appropriate strategy in Canada is to devote sufficient resources to reviewing all medications in a timely manner.

Background: The cyclooxygenase-2 (COX-2) selective nonsteroidal antiinflammatory drugs (NSAIDs) celecoxib and rofecoxib (before its removal) are marketed as having fewer gastrointestinal (GI)-related complications than nonselective NSAIDs. However, adverse reaction data suggest that the use of COX-2 selective NSAIDs is associated with clinically significant GI events., Objective: To assess whether patients receiving celecoxib and rofecoxib have a greater underlying disease burden than patients prescribed nonselective NSAIDs., Methods: The study population consisted of members of 11 health plans, aged >34 years, with a pharmacy claim for celecoxib or rofecoxib or a nonselective NSAID dispensed between February 1, 1999, and July 31, 2001, who had been continuously enrolled for >364 days before the dispensing date. Celecoxib and rofecoxib patients were randomly selected without replacement from a pool of eligible users in each of the 30 months. Nonselective NSAID users were randomly chosen without replacement within each month on a 2:1 ratio to cases; they could be chosen in more than one month. Univariate analyses comparing 9000 cases and 18 000 controls were performed, followed by a multiple logistic regression analysis conditioned on time., Results: Increasing age, treatment by a rheumatologist or an orthopedic specialist, treatment with a high number of different medications in the past year, treatment with oral corticosteroids in the past year, and having had a previous GI bleed increased the likelihood of receiving celecoxib or rofecoxib, whereas treatment with a high number of nonselective NSAID prescriptions in the past year decreased it. Treatment with a high number of different medications was a predictor of increased prevalence of underlying diabetes mellitus and cardiovascular disease., Conclusions: Patients having a greater underlying disease burden were more likely to receive COX-2 selective NSAIDs than nonselective ones. Paradoxically, patients at higher risk for cardiovascular disease were channeled toward treatment with COX-2 selective NSAIDs, many of which may confer an increased risk of acute myocardial infarction and other adverse cardiovascular outcomes.

Background: To have a drug listed in a province's formulary, manufacturers must submit an application providing data required by the provincial rules and guidelines. The procedures for the scientific evaluation of drugs considered for listing for reimbursement in five provinces have been examined previously., Objective: The present study investigates the clarity of the same five provinces' rules and guidelines about effectiveness and cost data that should be included in listing submissions from the perspective of the pharmaceutical company., Methods: The manufacturers of five recently introduced drugs selected by the investigators received questionnaires asking about the departments within their companies that are responsible for the submission, the data required by each of the five provinces and the clarity of each province's requirements for submission. Each company was also asked similar questions about its own submission experience with its drug. Investigators visited each manufacturer to review the questionnaires and answer questions., Results: The manufacturers perceived the rules and guidelines on effectiveness and economic data of several provinces as being neither clear nor consistent. Consequently, information that companies submit in their attempts at compliance with the rules and guidelines varies substantially., Conclusions: The manufacturers' perceptions of the information required by the provinces on effectiveness and cost information were inconsistent. Previous work indicated that the provinces make significant decisions about listings based on inadequate information resulting in a scientifically flawed system that contributes to considerable inequality in access to new drugs between provinces. The findings of the present work reinforce this conclusion.

Background: Approval times of new drugs are frequently longer in Canada than in the US, but it has been argued that reducing approval times might lead to unsafe drugs receiving marketing approval., Objective: To compare new drug approval times in Canada and the US over a 10-year period and to relate them to safety discontinuations., Methods: Application and approval dates of all new drugs except diagnostic products, new salts, esters, isomers, and dosage forms of already-marketed drugs, as well as combinations containing previously approved substances approved in the US and Canada between January 1992 and December 2001 were obtained from the respective drug regulatory agencies and other sources. Information about drugs discontinued for safety reasons was obtained from the agencies' publications and Web sites and from journal articles., Results: New drug approval times were significantly longer in Canada than in the US. The difference occurs in all drug categories and by review type (priority/standard). However, the proportion of new drugs approved and later discontinued for safety reasons from the Canadian market (2.0%) was just over half that in the US (3.6%)., Conclusions: When serious drug safety problems were identified in a timely manner after US approval, the products were not subsequently approved in Canada. Canada avoided potential dangers because its longer approval times provided an opportunity to observe actual market experience in other countries. However, the trade-off is that new drugs, including those for conditions for which current therapy has limited efficacy, take significantly longer to be approved in Canada and, hence, to be available to Canadians.

Background: The median time to approval of new drugs in Canada decreased considerably in the mid-1990s, although it continued to be longer than in such countries as Australia, Sweden, the United Kingdom, and the United States. Ongoing concern about approval times pointed to a need for a further international comparison., Objective: This study was designed to assess whether there have been continuing improvements in drug approval times in Canada relative to these other countries., Methods: Application and approval dates of new chemical or biological substances approved for marketing from 1999 through 2001 were requested from the Canadian, Australian, and Swedish regulatory agencies. Information for the United States was derived from publications of the Pharmaceutical Research and Manufacturers of America. The regulatory agency for the United Kingdom does not release application dates, although these were the same as the Swedish application dates for most drugs approved in both countries through the centralized European Union (EU) review procedure. Application dates for drugs licensed under the EU mutual-recognition arrangement or in the United Kingdom only were requested from the relevant pharmaceutical companies., Results: One hundred eighty-six new drugs were approved in >/=1 of the countries studied between January 1999 and December 2001: 17 (9.1%) in all 5 countries, 25 (13.4%) in 4, 27 (14.5%) in 3, 39 (21.0%) in 2, and 78 (41.9%) in 1. Approval times were longer in Canada than in Australia, although not significantly so (median time, 645 and 551 days, respectively). Canadian and Australian approval times were significantly longer than those in Sweden (431 days), the United Kingdom (479 days), and the United States (371 days) (P < 0.001). The annual median approval time in Canada increased in each of the 3 years. The approval times of priority-reviewed drugs in Canada were significantly longer than in the United States (median 317 vs 232 days) but significantly shorter than in Australia (509 days) (both comparisons, P < 0.001)., Conclusions: Overall approval times of new drugs in Canada were longer than those in Australia, Sweden, the United Kingdom, and the United States in the period studied. The findings warrant ongoing monitoring of Canadian drug approval times.

Background: Facing financial pressures, the provinces and territories have chosen to use "cost-effectiveness" for making decisions about drug listings. This study examines the scientific basis for the procedures used to determine cost-effectiveness in 5 Canadian provinces., Methods: Questionnaires were mailed to key provincial informants asking about the respondent's expertise and role, the administrative and scientific basis for decision-making, organizational structures and other factors in the scientific evaluation and decision-making process, and the transparency of the process. There were also questions about the data required and received and their importance, the place of cost-effectiveness and other economic impact evaluations, the data sources for them, and the use of follow-up monitoring to evaluate the decisions made., Results: Information required by the provinces for decision-making about cost-effectiveness is not available to them at the time of their decisions about listing new medications. The primary sources of data on both efficacy and cost-effectiveness are pharmaceutical companies. Efficacy information is generated in a scientifically rigorous manner, whereas the effectiveness and cost data are estimates potentially subject to biases and evaluated by judgement (expert opinion) alone. Moreover, there is no collaboration in the assessment process between provinces. The outcomes are large differences between provinces in the decisions made and, hence, in the pharmaceuticals accessible to residents., Conclusions: Current methods for making decisions about provincial drug listings are based on inadequate data, and the lack of consistency in the provinces' decisions suggest they may be scientifically flawed. We recommend establishing a single national scientific review committee, with re-evaluation of each drug's cost-effectiveness after a suitable period of monitored use.

The time required to approve new drugs in Canada is significantly longer than that in Sweden, the United Kingdom and the United States. The timeliness with which a regulatory agency approves drugs may be influenced by the human resources available to review applications. Therefore, the number of full-time equivalent (FTE) staff members who evaluate and approve new drug applications was sought directly from the regulatory agencies of Canada, Australia, Sweden, the United Kingdom and the United States. Information was received from the Therapeutic Products Directorate (TPD) of Health Canada, the Swedish Medical Products Agency (MPA), the United Kingdom Medicines Control Agency (MCA) and the United States Food and Drug Administration (FDA). The Australian Therapeutic Goods Administration (TGA) did not provide data, but the Australian Pharmaceutical Manufacturers Association estimated the number of personnel reviewing drug applications at the TGA to be 102. After adjustment to eliminate staff members whose primary responsibility is reviewing generic applications, there were an estimated 159 FTE staff members at the TPD, 1610 at the FDA, an estimated 76 at the TGA, 60 at the MCA and 46 at the MPA. Thus, the number of personnel in Canada is two to 3.5 times that in Australia, the United Kingdom and Sweden, but less than 10% of that in the United States. Because Sweden, the United Kingdom and the United States all have significantly shorter review and approval times than Australia and Canada, the number of review staff does not appear to be a direct major determinant of the timeliness of an agency's review and approval performance.

Background: Cardiac dysrhythmias are a diverse group of disorders and many are associated with significant morbidity and mortality. Because their recent therapeutic management has not been adequately described, this study details the antiarrhythmia drugs that were dispensed to patients who had not received therapy in the preceding two years, and it evaluates the potential indications for the drugs as well as whether the therapy is consistent with the recommended procedures., Methods: Patients who were dispensed a [Vaughn Williams?] class I or class III antiarrhythmia drug in 1993 or 1994, but not during the two previous years, were identified from the Saskatchewan prescription drug datafile. The drug data were linked with other information that was obtained from the provincial administrative health care utilization datafiles. Further clinical data were obtained from hospital charts and, to a limited extent, from physicians' records., Results: Most patients were elderly (median age of 70 years) and were men (58.0%), although sotalol was prescribed more frequently to women (53.0%). A potential indication was identified for 63.8% of the patients and, of these, the most common was atrial fibrillation (65.3%). Almost half of the patients had a history of myocardial infarction, congestive heart failure or cardiomyopathy, and one-quarter of those were treated with amiodarone., Conclusions: While it is not possible to prove a direct link, the results of the present study are broadly consistent with the 'evidence-based' lessons of the Cardiac Arrhythmia Suppression Trial and other studies. The increasing use of propafenone, however, may indicate a lack of appreciation for the fact that, as a class IC drug, there is at least the potential for an adverse outcome when propafenone is used in patients with structural heart disease.

Purpose: To describe the process of obtaining access to the administrative health care utilization data of the Canadian province of Saskatchewan and the ethical issues involved., Methods: The report focuses on the process of obtaining data for two recent studies. In the first, associations between aplastic anemia and agranulocytosis and prior drug use were evaluated, while the second is an examination of anti-arrhythmia drug utilization. In these studies, data from files containing computerized information on prescription drug use, hospitalizations, physician services and cancer registrations were linked together and also with information from hospital charts, physician records and death registrations., Results: Data on individual patients are available from the Saskatchewan data-files after the removal of identifying variables, and access to external information from hospitals, physicians, death registrations and the patients themselves is possible. However, researchers must accept that data considered to be only indirectly relevant to the objectives of the study or which, due to small numbers, may potentially identify either patients or physicians will only be released in aggregate form., Conclusions: Access to the Saskatchewan data-files and to external information from hospitals, physicians and death registrations is normally straightforward. Restrictions that are applied are discussed.

Conditional release is the approval of a new drug onto the market, subject to specific conditions relating to effectiveness and safety that, if achieved, will lead to full approval. Conditional approval of a new drug, during which time it is used in normal clinical practice, should allow the collection of data on effectiveness and safety to provide a genuine cost effectiveness evaluation. Proposals put forward in 1977 in the United Kingdom for approving a drug on a conditional basis while monitoring for adverse drug reactions are examined, and issues that would affect a present day conditional release scheme are identified. These issues are: who would do the evaluation and who would pay for it; how would patients be identified and registered; would all new drugs be monitored and for how long; what data would be reported and evaluated; and who would do the reporting? How a conditional release scheme would work in Canada in light of these questions is considered and a method based on pharmacists registering patients and on physicians and/or patients reporting data to an independent organization funded by governments and the pharmaceutical industry is outlined. Under certain conditions, conditional release would provide the information to allow true cost effectiveness and safety assessments instead of the current inadequate predictions based on efficacy and safety data from clinical trials. It is important that academics and drug approval and monitoring agencies work together to develop active systems to improve the postapproval evaluation of effectiveness, safety and cost effectiveness of new drugs in Canada.

Accurate and complete registries are an important source of knowledge about cancer. The concordance of the recording of neoplasms in the Saskatchewan cancer registry with that in hospital charts and death registrations was evaluated for 368 patients. The agreement between registry and hospital charts or death registrations was excellent (kappa: 0.93; 95% confidence interval: 0.89, 0.97), with 91.3% of those with cancer having the same neoplasm recorded in their chart or death registration as in the registry. There was only one patient whose hospital chart indicated cancer who was not in the registry and one apparent major discrepancy relating to the cancer site, which was due to the recording of the primary site in the registry and a secondary in the hospital chart. Although based on a relatively small number of patients, these results suggest a high degree of consistency between cancer registry, hospital charts and death registrations in Saskatchewan.

In two previous studies, the times required to approve new drugs in Canada, Australia, Sweden, the United Kingdom and the United States during the periods 1992 to 1995 and 1996 to 1998 were compared. However, during each of these two periods, only a fraction of the drugs that were approved in any of the countries were approved in all of them. Because an analysis based solely on drugs approved in all the countries would provide additional information, data from the previous studies have been used to compare drugs approved in each of Canada, Australia, Sweden and the United States during the period 1992 to 1998. In addition, applications that received a 'priority' or a 'standard' review by the United States Food and Drug Administration were analyzed separately to determine whether differences between the countries diminished for drugs considered to be of potentially greater therapeutic value. For the 87 drugs identified as being approved for marketing in all four countries during the period 1992 to 1998, approval times in Canada and Australia were not significantly different, but both Canada and Australia had significantly longer times than those of the United States and Sweden (P<0.001). Of the 87 drugs, 37 (43%) received a priority review in the United States. In both the priority and standard review categories, the Australian and Canadian median approval times were significantly longer than those in Sweden and the United States. The results demonstrate that, in general, both priority and standard new drug applications are reviewed more expeditiously in Sweden and the United States than in Canada. Canadian patients continue to experience delayed access to potentially valuable medicines.

Background: The timeliness with which national regulatory agencies approve new drugs for marketing affects health care professionals and patients. An unnecessarily long approval process delays access to new medications that may improve patients' health status. The author compared drug approval times in Canada, Australia, Sweden, the United Kingdom and the United States., Methods: Application and approval dates of new chemical or biological substances (excluding diagnostic products, and new salts, esters, dosage forms and combinations of previously approved substances) approved for marketing in the 5 countries from January 1996 to December 1998 were requested from the relevant pharmaceutical companies. Data on new drug approvals during the study period were also obtained from the national drug regulatory agencies in Canada, Australia and Sweden and from publications of the US Food and Drug Administration., Results: A total of 219 new drugs were identified as being approved in at least one of the countries during the study period: 23 (10.5%) in all 5 countries, 23 (10.5%) in 4, 27 (12.3%) in 3, 42 (19.2%) in 2, and 104 (47.5%) in 1 country. By individual nation, 97 drugs were identified as being approved in Canada, 94 in Australia, 107 in Sweden, 55 in the UK and 123 in the US. Approval times in Canada and Australia were similar (medians 518 and 526 days respectively), but both countries had significantly longer approval times than Sweden (median 371 days), the UK (median 308 days) and the US (median 369 days). This pattern was consistent across all 3 years and for the 23 new drugs approved in all 5 countries during the 3-year period. Median approval times in Canada were similar in all of the reviewing divisions of Health Canada's Therapeutic Product Program (539-574 days) except the Central Nervous System Division (428 days) and the Bureau of Biologics and Radiopharmaceuticals (698 days)., Interpretation: Median drug approval times during 1996-1998 decreased by varying amounts from the 1995 values in all 5 countries. However, the median approval time in Canada continues to be significantly longer than the times achieved in Sweden, the UK and the US, and it remains considerably longer than Canada's own target of 355 days for all new drugs.

Linked administrative health care utilization databases offer potential benefits for postmarketing surveillance. The value of the Saskatchewan datafiles in an acute adverse event signalling scheme has been evaluated using two benzodiazepines. The first 20,000 patients dispensed lorazepam and the first 8525 patients dispensed alprazolam were followed through the datafiles over the year after their initial prescription of the relevant drug, and all medical services occurring during treatment were recorded. The most frequent adverse drug reactions to benzodiazepines are drowsiness, depression, impaired intellectual function and memory, lethargy, impaired coordination, dizziness, nausea and/or vomiting, skin rash, and respiratory disturbance. Data from our study showed that sleep disorders, depressive disorders, dizziness and/or vertigo, respiratory symptoms, esophagus and stomach disorders, and inflammatory skin conditions occurred significantly more often in the first 30 days after the initial prescription than in the succeeding six months in both drug groups, indicating that they are important adverse events. There are several limitations to the methodology; however, the results of the analysis indicate that the use of administrative health care utilization datafiles in a systematic assessment to signal potential acute adverse drug reactions is a feasible proposition, but further studies are required to assess whether events are real adverse reactions.

A population-based study to estimate the incidence of hospitalizations for aplastic anemia and agranulocytosis and to evaluate associations between these disorders and antecedent prescription drug use was performed using the Saskatchewan administrative health care databases. Hospital charts and cancer registration data were utilized to apply strict diagnostic criteria to case identification. Estimates of the annual incidence of aplastic anemia and agranulocytosis were 2.7 and 3.0 per million, which are similar to those from other recent population-based studies with comparable case identification criteria. Only a small number of cases were available to evaluate potential drug causes, leading to an analysis of limited power. Nevertheless, significant associations were found between aplastic anemia and tocainide, gold salts, and antidepressants; and between agranulocytosis and anti-thyroids, trimethoprim-sulfamethoxazole, beta-lactams, sulfasalazine, chlorpromazine, carbamazepine, glyburide, and procainamide, although the associations with antibiotics may indicate a response to the disorders rather than a possible cause. These findings are generally consistent with the results of other case-control investigations.

Administrative health care utilization databases have been promoted as resources for pharmacoepidemiologic research for several years, but the validity of the diagnostic data in many systems has not been thoroughly investigated. This work outlines issues in assessing the validity of diagnostic information from a broad perspective, using results from the datafiles of the province of Saskatchewan to illustrate them and, where possible, contrasting them with findings from other databases. An evaluation of the validity of health care utilization data should be more than a simple check of coding and data entry errors. Comparisons of data records with information external to the computer system, an examination of the internal consistency of the data (especially in systems consisting of several data sources) and, where practicable, an assessment of the cohesiveness of the data within the context of current medical knowledge should be performed on a broad range of diagnoses and procedures. Careful consideration should also be given to the generalizability of results from the database. Summaries of such evaluations for all databases used for population-health research purposes should be widely disseminated. We caution researchers to continue to seek ways to validate their results in each use of these databases., (Copyright 1998 John Wiley & Sons, Ltd.)

Administrative data have long been used in psychiatric epidemiology and outcomes evaluation. This article examines the reliability of the recording of schizophrenia and depressive disorder in three Saskatchewan administrative health care utilization datafiles. Due to their comprehensive nature, these datafiles have been used in a wide range of epidemiologic studies. Close agreement was found between hospital computer data and patients' charts for personal and demographic factors (> or = 94.7%). Diagnostic concordance between computerized hospital data and medical charts was very good for schizophrenia (94%) but poor for depressive disorder (58%). Appropriate physician services were identified for 60% and 72% of hospital discharges for schizophrenia and depressive disorder, respectively, and exact diagnostic agreement between hospital and physician datafiles was 62% for schizophrenia and 66% for depressive disorder. Appropriate provincial mental health branch services were found for 83% and 38% of hospital discharges for schizophrenia and depressive disorder, respectively; exact diagnostic concordance between these datafiles was 75% for schizophrenia and 0% for depressive disorder. A significant number of patients with major or neurotic depression appeared to be wrongly coded as having depressive disorder in the hospital file. The differences in diagnostic agreement may also be partly a function of how the two conditions are differentially treated in the health system. These findings suggest that more specific and severe psychiatric diagnoses are likely to be recorded accurately and consistently in the Saskatchewan datafiles. However, disorders with multiple manifestations or those for which there are several possible codes should be examined with caution and ways sought to validate them. Attention should also be paid to which service sectors are involved in the treatment of specific disorders.

Measures of letter (FAS) and category (Animal Naming) fluency were completed by community-dwelling, cognitively normal seniors (n = 635), and by individuals diagnosed with dementia of the Alzheimer type (DAT) (n = 155), or with vascular dementia (n = 39). Among normal seniors, category, but not letter fluency, declined with age, females performed better than males on letter but not on category fluency, and performance increased with education on both tasks. Among participants with DAT, letter fluency was influenced by level of education, whereas category fluency was education-, age-, and gender-invariant. Both measures differentiated normal seniors from those with dementia. Category fluency was more impaired than letter fluency at both mild and moderate stages of dementia, but neither task differentiated DAT from vascular dementia.

Objective: To determine the validity of data pertaining to hysterectomy in the Saskatchewan health care utilisation datafiles., Design: Retrospective analysis of routinely collected data covering hospital discharge records and practitioner claims for reimbursement of services, together with a review of clinical charts., Setting: Province of Saskatchewan, Canada., Sample: All 1905 cases of hysterectomy in one calendar year for analysis of datafiles and a random sample of 227 clinical charts for review., Method: Information in the hospitalisation datafile was validated through an external comparison with data extracted from a review of clinical charts, as well as an internal comparison with independent data from the practitioner claims file. Corresponding context data on drug use and performance of related procedures were also analysed., Results: Concordance between hospital data and clinical charts was greater than 95% for those items of an administrative nature as well as type of hysterectomy and was around 85% for the diagnoses. When hospitalisation and practitioner claims data were compared, the concordance was 98% for type of hysterectomy but only 56% for diagnoses., Conclusions: The agreement between hospital data and clinical charts was excellent. The concordance between hospitalisation and practitioner claims data was almost exact for type of hysterectomy, while discrepancies in diagnoses between these files were mostly explainable on the basis of accepted clinical practice. Saskatchewan health care utilisation datafiles provide a source of valid data for research and evaluation studies.

The internal validity of the recording of information about ischaemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) in the administrative health care datafiles of the Canadian province of Saskatchewan is investigated. Comparisons between hospital data and medical charts for acute myocardial infarction and chronic airways obstruction patients showed excellent diagnostic agreement: 97 per cent and 94 per cent, respectively. Appropriate physician service claims were identified for 89 per cent of hospitalizations for IHD and COPD and exact concordance between diagnoses in the two datafiles varied between 15 per cent for acute/sub-acute IHD and 80 per cent for asthma; including any physician diagnosis within the same broad category (IHD or COPD) increased concordance to 79-94 per cent for IHD and 64-88 per cent for COPD. Contextual information related to the hospitalizations was clinically and epidemiologically realistic.