Inappropriate use of clinical practices in Canada: a systematic review.

BACKGROUND: Inappropriate health care leads to negative patient experiences, poor health outcomes and inefficient use of resources. We aimed to conduct a systematic review of inappropriately used clinical practices in Canada. METHODS: We searched multiple bibliometric databases and grey literature to identify inappropriately used clinical practices in Canada between 2007 and 2021. Two team members independently screened citations, extracted data and assessed methodological quality. Findings were synthesized in 2 categories: diagnostics and therapeutics. We reported ranges of proportions of inappropriate use for all practices. Medians and interquartile ranges (IQRs), based on the percentage of patients not receiving recommended practices (underuse) or receiving practices not recommended (overuse), were calculated. All statistics are at the study summary level. RESULTS: We included 174 studies, representing 228 clinical practices and 28 900 762 patients. The median proportion of inappropriate care, as assessed in the studies, was 30.0% (IQR 12.0%-56.6%). Underuse (median 43.9%, IQR 23.8%-66.3%) was more frequent than overuse (median 13.6%, IQR 3.2%-30.7%). The most frequently investigated diagnostics were glycated hemoglobin (underused, range 18.0%-85.7%, n = 9) and thyroid-stimulating hormone (overused, range 3.0%-35.1%, n = 5). The most frequently investigated therapeutics were statin medications (underused, range 18.5%-71.0%, n = 6) and potentially inappropriate medications (overused, range 13.5%-97.3%, n = 9). INTERPRETATION: We have provided a summary of inappropriately used clinical practices in Canadian health care systems. Our findings can be used to support health care professionals and quality agencies to improve patient care and safety in Canada.

Emergency Medical Services Provider Self-Reported Occupational Safety.

BACKGROUND: Emergency medical services (EMS) providers are at high risk for occupational violence, and some tactical EMS providers carry weapons. METHODS: Anonymous surveys were administered to tactical and nontactical prehospital providers at 180 prehospital agencies in northeast Ohio between September 2018 and March 2019. Demographics were collected, and survey questions asked about workplace violence and comfort level with tactical EMS carrying weapons. RESULTS: Of 432 respondents, 404 EMS providers (94%) reported a history of verbal or physical assault on scene, and 395 (91%) reported working in a setting with a direct active threat at least rarely. Of those reporting a history of assault on scene, 46.5% reported that it occurred at least sometimes. Higher rates of assault on scene were associated with being younger, white, or an emergency medical technician-paramedic, working in an urban environment, having more frequent direct active threats, and having more comfort with tactical EMS carrying firearms (p ≤ .03). Most respondents (306; 71%) reported that they were prepared to defend themselves from someone who originally called for help. Most (303; 70%) reported a comfort level of 8 or higher (from 1, not comfortable to 10, completely comfortable) with tactical EMS providers carrying weapons. Comfort with tactical EMS providers carrying weapons was associated with being white, not having a bachelor's degree, and feeling prepared to defend oneself from a patient (p ≤ .02). CONCLUSION: EMS providers in the survey report high rates of verbal and physical violence while on scene and are comfortable with tactical EMS providers carrying weapons.

Accurate neonatal heart rate monitoring using a new wireless, cap mounted device.

AIM: A device for newborn heart rate (HR) monitoring at birth that is compatible with delayed cord clamping and minimises hypothermia risk could have advantages over current approaches. We evaluated a wireless, cap mounted device (fhPPG) for monitoring neonatal HR. METHODS: A total of 52 infants on the neonatal intensive care unit (NICU) and immediately following birth by elective caesarean section (ECS) were recruited. HR was monitored by electrocardiogram (ECG), pulse oximetry (PO) and the fhPPG device. Success rate, accuracy and time to output HR were compared with ECG as the gold standard. Standardised simulated data assessed the fhPPG algorithm accuracy. RESULTS: Compared to ECG HR, the median bias (and 95% limits of agreement) for the NICU was fhPPG -0.6 (-5.6, 4.9) vs PO -0.3 (-6.3, 6.2) bpm, and ECS phase fhPPG -0.5 (-8.7, 7.7) vs PO -0.1 (-7.6, 7.1) bpm. In both settings, fhPPG and PO correlated with paired ECG HRs (both R2  = 0.89). The fhPPG HR algorithm during simulations demonstrated a near-linear correlation (n = 1266, R2  = 0.99). CONCLUSION: Monitoring infants in the NICU and following ECS using a wireless, cap mounted device provides accurate HR measurements. This alternative approach could confer advantages compared with current methods of HR assessment and warrants further evaluation at birth.

Inappropriateness of health care in Canada: a systematic review protocol.

BACKGROUND: There is increasing recognition in Canada and globally that a substantial proportion of health care delivered is inappropriate as evidenced by (1) harmful and/or ineffective practices being overused, (2) effective clinical practices being underused, and (3) other clinical practices being misused. Inappropriate health care leads to negative patient experiences, poor health outcomes, and inefficient use of scarce health care resources. The purpose of this study is to conduct a systematic review of inappropriate health care in Canada. Our specific objectives are to (1) systematically search and critically review published and grey literature for studies on inappropriate health care in Canada; (2) estimate the nature and magnitude of inappropriate health care in Canada and its provincial and territorial jurisdictions. METHODS: We will include all quantitative study designs reporting objective or subjective measurements of inappropriate health care in Canada over the last 10 years. We will search the following online databases: MEDLINE, Cochrane Central Register of Controlled Trials, EconLit, and ISI-Web of Knowledge, which contains Web of Science Core Collection-Citation Indexes, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and Conference Proceedings Citation Index-Social Science & Humanities. We will also search grey literature sources to identify provincial and national audits of inappropriate health care. Two authors will independently screen, assess data quality, and extract data for synthesis. Study findings will be synthesized narratively. We will organize our data into three care categorizations: preventive care, acute care, and chronic care. We will provide a compendium of inappropriate health care for each care category for Canada and each Canadian province and territory, where sufficient data exists, by calculating (1) overall medians of underuse, overuse, and misuse of clinical practices and (2) the range of medians of underuse, overuse, and misuse for each clinical practice investigated. DISCUSSION: This review will result in the first-ever evidence-based compendium of inappropriate health care in Canada. We will also develop detailed reports of inappropriate health care for each Canadian province and territory. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018093495.

Mucosal injury following short-term tracheal intubation: A novel animal model and composite tracheal injury score.

OBJECTIVES: Postintubation laryngotracheal injury is common. Assessment of histopathological changes currently requires animal models. We set about developing a viable, resource effective animal model to study these effects and to develop a detailed tissue injury score. METHODS: Six pigs were anesthetized using a standard regimen. We intubated the tracheas using a standard endotracheal tube modified to include optical sensors. Animals were anesthetized for a duration of two to four hours, and their lungs were ventilated using a normoxic gas mixture. Following euthanasia, the tracheas were removed and underwent histological assessment by two independent veterinary pathologists. The histological lesions, including controls, were described and quantified, and two pathologists classified tissues according to a novel injury score. RESULTS: Mean duration of tracheal intubation was 191 minutes (SD ± 41.6). In all except one animal, cuff pressures were maintained in the range of 25-45 cmH20. Histopathological findings in all study animals showed more extensive changes than previously described with short-term intubation. Changes were seen in all mucosal layers consistent with acute, suppurative, and ulcerative tracheitis. The range of scores of the developed composite scoring system among the animals was wider than in earlier descriptions. There was a high percentage of agreement between both pathologists. CONCLUSIONS: We have described a novel tracheal injury score to assess pathological changes following short term intubation in a viable animal model. The scoring system distinguished between the test animals as well as controls and may be appropriate for continuing study of intubation injury. LEVEL OF EVIDENCE: 3.

Is cardiovascular risk reduction therapy effective in South Asian, Chinese and other patients with diabetes? A population-based cohort study from Canada.

OBJECTIVES: Guidelines recommend ACE inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs) and diuretics in all patients with diabetes mellitus. However, the effectiveness of these agents in South Asian and Chinese populations is unknown. We sought to determine whether ACEi, ARB, CCB and diuretics are associated with reduced mortality in South Asian, Chinese and other patients with diabetes. DESIGN: Population-based cohort study using administrative health databases. SETTING: Province of British Columbia, Canada (2006-2013). PARTICIPANTS: Patients aged ≥35 years with incident diabetes. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was all-cause mortality for each medication class compared with untreated patients within each ethnicity. Treatment effect was assessed using inverse probability of treatment weighted Cox proportional hazards models. Medication adherence effect on mortality was also evaluated. RESULTS: 208 870 patients (13 755 South Asian, 22 871 Chinese, 172 244 other Canadian) were included. ACEi reduced mortality in other patients (HR=0.88, 0.84-0.91), but power was insufficient to evaluate for benefit in Chinese and South Asian patients. ARB and diuretics reduced mortality in Chinese (ARB HR=0.64, 0.50-0.82; diuretics HR=0.77, 0.62-0.96) and other patients (ARB HR=0.69, 0.64-0.74; diuretics HR=0.66, 0.63-0.69) compared with untreated patients. No mortality benefit was observed among South Asians for any drug class or for CCB among all ethnicities. Higher medication adherence was associated with lower mortality for other patients only (HR=0.79, 0.72-0.86). CONCLUSIONS: Effectiveness of cardiovascular risk reduction therapy on mortality varies considerably by ethnicity. Further study is needed to evaluate the mortality benefit of antihypertensive agents in South Asians. Inclusion of these ethnic groups in future clinical trials is essential to examine for differential responses.

Protocol for a randomised controlled trial evaluating the effects of providing essential medicines at no charge: the Carefully seLected and Easily Accessible at No Charge Medicines (CLEAN Meds) trial.

INTRODUCTION: Cost-related non-adherence to medicines is common in low-income, middle-income and high-income countries such as Canada. Medicine non-adherence is associated with poor health outcomes and increased mortality. This randomised trial will test the impact of a carefully selected list of essential medicines at no charge (compared with usual medicine access) in primary care patients reporting cost-related non-adherence. METHODS AND ANALYSIS: This is an open-label, parallel two-arm, superiority, individually randomised controlled trial conducted in three primary care sites (one urban, two rural) in Ontario, Canada, that was codesigned by a community guidance panel. Adult patients (≥18 years) who report cost-related non-adherence to medicines are eligible to participate in the study. Participants will be randomised to receive free and convenient access to a carefully selected list of 125 essential medicines (based on the WHO's Model List of Essential Medicines) or usual means of medicine access. Care for patients in both groups will otherwise be unchanged. The primary outcome of this trial is adherence to appropriately prescribed medicines. Secondary outcomes include medicine adherence, appropriate prescribing, blood pressure, haemoglobin A1c, low-density lipoprotein cholesterol, patient-oriented outcomes and healthcare costs. All participants will be followed for at least 12 months. ETHICS AND DISSEMINATION: Ethics approval was obtained in all three participating sites. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal and discussed with members of the public and decision makers. TRIAL REGISTRATION NUMBER: NCT02744963.

Cost-related nonadherence to prescribed medicines among older Canadians in 2014: a cross-sectional analysis of a telephone survey.

BACKGROUND: Canadians receive universal coverage for medically necessary hospital and physician services, but pharmaceutical coverage is incomplete. We sought to assess the effects of cost on access to medicines among older Canadians using data from a large survey conducted in 2014. METHODS: This is a cross-sectional analysis of data from the Commonwealth Fund's 2014 International Health Policy Survey of Older Adults. Our primary outcome variable was self-reported cost-related nonadherence in the form of either not filling a prescription or skipping doses within the last 12 months because of out-of-pocket costs. We computed sample-weighted estimates of the population prevalence of cost-related nonadherence and conducted logistic regression analyses to determine associated factors. RESULTS: We estimate that the prevalence of cost-related nonadherence in 2014 among Canadians aged 55 years and older was 8.3% (about 1 in 12). The population prevalence and adjusted odds of cost-related nonadherence was significantly higher among Canadians who were younger, in worse health, poorer or without private health insurance. Regional differences in population prevalence of cost-related nonadherence were not significant. The only provincial or regional difference in the adjusted odds of cost-related nonadherence was that residents of Quebec aged 55-64 years were about half as likely to report nonadherence as similarly aged residents of Ontario, our reference province (adjusted odds ratio 0.49, 95% confidence interval 0.29-0.82). INTERPRETATION: The financial accessibility of prescription medicines still is a substantial public health issue in Canada that affects 1 in 12 Canadians older than 55 years of age. Older Canadians at greatest risk of cost-related nonadherence to prescribed treatments are those with low incomes and those without private insurance to cover costs not covered by public programs.

An Ecological Approach to Reducing Potentially Inappropriate Medication Use: Canadian Deprescribing Network.

Polypharmacy is growing in Canada, along with adverse drug events and drug-related costs. Part of the solution may be deprescribing, the planned and supervised process of dose reduction or stopping of medications that may be causing harm or are no longer providing benefit. Deprescribing can be a complex process, involving the intersection of patients, health care providers, and organizational and policy factors serving as enablers or barriers. This article describes the justification, theoretical foundation, and process for developing a Canadian Deprescribing Network (CaDeN), a network of individuals, organizations, and decision-makers committed to promoting the appropriate use of medications and non-pharmacological approaches to care, especially among older people in Canada. CaDeN will deploy multiple levels of action across multiple stakeholder groups simultaneously in an ecological approach to health system change. CaDeN proposes a unique model that might be applied both in national settings and for different transformational challenges in health care.

Mortality and Cardiovascular Risk of Sulfonylureas in South Asian, Chinese and Other Canadians with Diabetes.

OBJECTIVES: Sulfonylureas have been inconsistently associated with increased cardiovascular mortality in patients with type 2 diabetes mellitus. However, there are no existing studies of long-term risk in South Asian and Chinese populations. Our objective was to determine whether sulfonylureas are associated with increased mortality or cardiovascular disease in a population cohort of South Asian, Chinese and other Canadian patients with incident diabetes. METHODS: We studied a population-based cohort of adults 35 years of age or older who had diabetes and had been diagnosed between April 2004 and March 2014 by using administrative databases from British Columbia. The primary outcome was time to death from any cause or from a major cardiovascular event (MACE) with sulfonylurea treatment within each ethnicity. Propensity score modelling was applied using inverse probability of treatment weights. Results were stratified by agent and adjusted for age, sex, comorbidities, income and other medications. RESULTS: We included 208 870 patients: 13 755 South Asians, 22 871 Chinese, 172 244 other Canadians. Mortality and MACEs were higher in other Canadian patients for whom sulfonylureas had been prescribed (adjusted HR = 2.0; 95% confidence interval 1.9 to 2.2; and HR = 1.9, 1.7 to 2.2). Among Chinese and South Asian patients who had been prescribed sulfonylureas, mortality (HR = 2.6, 2.0 to 3.5; and HR = 2.4, 1.7 to 3.4, respectively) and MACEs (HR = 2.3; 1.4 to 4.0; and HR = 2.0, 1.2 to 3.2, respectively) were elevated. CONCLUSIONS: Considering the widespread use of sulfonylureas, there is a significant signal for increased mortality in all patients. In particular, increased mortality and MACEs were observed in South Asian and Chinese patients. These results should be confirmed in other studies, and patients of Asian descent should be included in clinical trials concerning diabetes.

Clinical implementation of photon beam flatness measurements to verify beam quality.

This work describes the replacement of Tissue Phantom Ratio (TPR) measurements with beam profile flatness measurements to determine photon beam quality during routine quality assurance (QA) measurements. To achieve this, a relationship was derived between the existing TPR15/5 energy metric and beam flatness, to provide baseline values and clinically relevant tolerances. The beam quality was varied around two nominal beam energy values for four matched Elekta linear accelerators (linacs) by varying the bending magnet currents and reoptimizing the beam. For each adjusted beam quality the TPR15/5 was measured using an ionization chamber and Solid Water phantom. Two metrics of beam flatness were evaluated using two identical commercial ionization chamber arrays. A linear relationship was found between TPR15/5 and both metrics of flatness, for both nominal energies and on all linacs. Baseline diagonal flatness (FDN) values were measured to be 103.0% (ranging from 102.5% to 103.8%) for 6 MV and 102.7% (ranging from 102.6% to 102.8%) for 10 MV across all four linacs. Clinically acceptable tolerances of ± 2% for 6 MV, and ± 3% for 10 MV, were derived to equate to the current TPR15/5 clinical tolerance of ± 0.5%. Small variations in the baseline diagonal flatness values were observed between ionization chamber arrays; however, the rate of change of TPR15/5 with diagonal flatness was found to remain within experimental uncertainty. Measurements of beam flatness were shown to display an increased sensitivity to variations in the beam quality when compared to TPR measurements. This effect is amplified for higher nominal energy photons. The derivation of clinical baselines and associated tolerances has allowed this method to be incorporated into routine QA, streamlining the process whilst also increasing versatility. In addition, the effect of beam adjustment can be observed in real time, allowing increased practicality during corrective and preventive maintenance interventions.

Trends and Determinants of Prescription Drug Use during Pregnancy and Postpartum in British Columbia, 2002-2011: A Population-Based Cohort Study.

PURPOSE: To describe trends, patterns, and determinants of prescription drug use during pregnancy and postpartum. METHODS: This is a retrospective, population-based study of all women who gave birth between January 2002 and 31 December 2011 in British Columbia, Canada. Study population consisted of 225,973 women who had 322,219 pregnancies. We examined administrative datasets containing person-specific information on filled prescriptions, hospitalizations, and medical services. Main outcome measures were filled prescriptions during pregnancy and postpartum. We used logistic regressions to examine associations between prescription drug use and maternal characteristics. RESULTS: Approximately two thirds of women filled a prescription during pregnancy, increasing from 60% in 2002 to 66% in 2011. The proportion of pregnant women using medicines in all three trimesters of pregnancy increased from 20% in 2002 to 27% in 2011. Use of four or more different types of prescription drug during at least one trimester increased from 8.4% in 2002 to 11.7% in 2011. Higher BMI, smoking during pregnancy, age under 25, carrying multiples, and being diagnosed with a chronic condition all significantly increased the odds of prescription drug use during pregnancy. CONCLUSIONS: The observed increase in the number of prescriptions and number of different drugs being dispensed suggests a trend in prescribing practices with potentially important implications for mothers, their neonates, and caregivers. Monitoring of prescribing practices and further research into the safety of most commonly prescribed medications is crucial in better understanding risks and benefits to the fetus and the mother.

Technical note: a method for improving the calibration reproducibility of an ionization chamber detector array.

PURPOSE: This paper describes an extension to a wide field calibration method implemented on a commercial detector array in order to improve the reproducibility of the calibration procedure. METHODS: Following the standard array calibration procedure, two additional 10×10 cm exposures were acquired for each array axis with the detector array shifted by ±10 cm in the transverse or axial axes, or by ±10√2 cm in the positive or negative diagonal axes. These exposures were compared with a final baseline 10×10 cm exposure captured with the detector repositioned at the isocenter. The measurements were used to calculate a linear off-axis correction gradient which was then applied to the stored calibration factors. RESULTS: The mean coefficient of variation between five repeat calibrations was reduced from 4.17% to 0.48% and the maximum percentage error in individual calibration factors was reduced from 6.46% to 0.77%. CONCLUSIONS: The reproducibility of the calibration factors of an ionization chamber array was increased by capturing a baseline exposure and two further off-axis readings per calibration axis.

The drivers of overspending on prescription drugs in Quebec.

According to data from the most recent edition of the Canadian Rx Atlas, Quebec was the province with the highest total spending per capita on prescription drugs. The difference between Quebec and the rest of Canada was 35%, which translates into $1.5 billion dollars of extra spending. This analysis explores the economic cost drivers of the higher level of pharmaceutical spending in Quebec. While much of the additional spending was driven by a higher volume of drugs being prescribed overall, the factors contributing to higher spending differed greatly within particular therapeutic categories. The results and their implications are discussed in the context of pharmaceutical policy environment.

Information behaviour of Canadian pharmaceutical policy makers.

OBJECTIVES: Understanding the information behaviour of policy makers targeted by knowledge translation efforts is key to improving policy research impact. This study explores the reported information behaviour of pharmaceutical policy decision-makers in Canada, a country highly associated with evidence-based practice yet still facing substantial barriers to evidence-informed health policy. METHODS: We conducted semi-structured telephone interviews with a purposive sample of 15 Canadian pharmaceutical policy decision-makers. Results of the descriptive, qualitative analysis were compared with the General Model of Information Seeking of Professionals (GMISP) proposed by Leckie, Pettigrew and Sylvain in 1996. RESULTS: Characteristics of information needs included topic, depth/breadth of questions and time sensitivity. Approaches to information seeking were variously scattershot, systematic and delegated, depending on the characteristics as well as respondent resources. Major source types were human experts, electronic sources and trusted organisations. Affective (emotion-related) outcomes were common, including frustration and desire for better information systems and sources. CONCLUSIONS: The GMISP model may be adapted to model information behaviour of Canadian pharmaceutical policy makers. In the absence of a dedicated, independent source for rapid-response policy research, these policy makers will likely continue to satisfice (make do) with available resources, and barriers to evidence-informed policy will persist.

Income-related inequity in initiation of evidence-based therapies among patients with acute myocardial infarction.

BACKGROUND: Previous research has shown a socioeconomic status (SES) gradient in the receipt of cardiac services following acute myocardial infarction (AMI), but much less is known about SES and the use of secondary preventive medicines following AMI. OBJECTIVES: To examine the role of income in initiation of treatment with ACE-inhibitors, beta-blockers and statins in the 120 days following discharge from hospital for first AMI. DESIGN: A cross-sectional study with a population-based cohort. PARTICIPANTS: First-time AMI patients between age 40 and 100 discharged alive from the hospital and surviving at least 120 days following discharge between January 1, 1999 and September 3, 2006. MAIN MEASURES: Binary variables indicating whether the patient had filled at least one prescription for each of the medicines of interest. KEY RESULTS: Our results reveal a significant and positive income gradient with initiation of the guideline-recommended medicines among male AMI patients. Men in the third income quintile and above were significantly more likely to initiate treatment with any of the medicines than those in the first quintile, with those in the fifth income quintile having 37%, 50% and 71% higher odds of initiating ACE-inhibitors, beta-blockers and statins, respectively, than men in the lowest income quintile [OR = 1.37 95% CI (1.24, 1.51); OR = 1.50 95% CI (1.35, 1.68); and OR = 1.71 95% CI (1.53, 190)]. The gradient was not present among women, although women in the fifth income quintile were more likely to initiate beta-blockers and statins than women in the lowest income quintile [OR = 1.25 95% CI (1.06, 1.47) and OR = 1.32 95% CI (1.12, 1.54)]. CONCLUSIONS: There were inequities in treatment following AMI in the form of a clear and often significant gradient between income and initiation of evidence-based pharmacologic therapies among male patients. This gradient persisted despite significant changes in coverage levels for the costs of these medicines.

The redistributive effect of the move from age-based to income-based prescription drug coverage in British Columbia, Canada.

OBJECTIVES: To explore the redistributive impact of two different pharmaceutical financing policies (age-based versus income-based pharmacare) on the distribution of income in British Columbia (B.C.), Canada. METHODS: Using household-level data on all payments that are used to finance prescription drugs in B.C. (including taxation and private payments), we performed a redistributive analysis to indicate how much income inequality in the province changed as a result of payments made for prescription drugs. We also illustrated changes in vertical equity (different treatment according to ability-to-pay) and horizontal equity (equals, according to ability-to-pay, being treated equally) between the two years separately through a pre-post policy examination. RESULTS: We found that payments made to finance prescription drugs increased overall income inequality in the province. This negative impact was larger after the move to income-based pharmacare. Our results also show increasing horizontal inequity after the policy change, and suggest that the increased reliance on out-of-pocket payments was a major source of the negative impact on the B.C.'s overall income distribution. We also show that the consequences of the move to income-based pharmacare would have been less severe had the level of public financing not decreased substantially between the two years. CONCLUSIONS: The increase in income inequality in B.C. following the policy change was an unintended consequence of the move to income-based pharmacare. This finding is worth consideration as countries and jurisdictions weigh pharmaceutical policy alternatives.

The cost of drug development: a systematic review.

OBJECTIVES: We aimed to systematically review and assess published estimates of the cost of developing new drugs. METHODS: We sought English language research articles containing original estimates of the cost of drug development that were published from 1980 to 2009, inclusive. We searched seven databases and used citation tracing and expert referral to identify studies. We abstracted qualifying studies for information about methods, data sources, study samples, and key results. RESULTS: Thirteen articles were found to meet our inclusion criteria. Estimates of the cost of drug development ranged more than 9-fold, from USD$92 million cash (USD$161 million capitalized) to USD$883.6 million cash (USD$1.8 billion capitalized). Differences in methods, data sources, and time periods explain some of the variation in estimates. Lack of transparency limits many studies. Confidential information provided by unnamed companies about unspecified products forms all or part of the data underlying 10 of the 13 studies. CONCLUSIONS: Despite three decades of research in this area, no published estimate of the cost of developing a drug can be considered a gold standard. Studies on this topic should be subjected to reasonable audit and disclosure of - at the very least - the drugs which authors purport to provide development cost estimates for.