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Competing Interests: Competing interests: Sukhy Mahl reports receiving organizational support from the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto, Ontario, Canada. MiCare is supported by a Canadian Institutes of Health Research (CIHR) Team Grant (CTP 87518) and the Ontario Ministry of Health. Joel Lexchin reports receiving royalties from the University of Toronto Press and James Lorimer & Co. Ltd. for books he has written. Dr. Lexchin has also received payments from the CIHR and payment for expert testimony from Goodmans LLP. He is a member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare. Brian Rowe’s research is supported by a Scientific Directors Operating Grant (SOP 168483) from CIHR. Dr. Rowe is the Scientific Director of the Institute of Circulatory and Respiratory Health, CIHR, and Professor and Director at the Emergency Medicine Research Group, Department of Emergency Medicine, Faculty of Medicine and Dentistry, College of Health Sciences. Shoo Lee reports receiving grant support for the MiCare team from CIHR. Dr. Lee is also the president of the Canadian Neonatal Foundation (a charity).

Objectives: This study examines the length of time between when a patent application is filed in Canada for a new drug and when it is available for patients (time to market) and various components of that time. It also looks at whether various factors explain the time between patent application to New Drug Submission (NDS) and compares Canadian and American times. Drugs approved between 1 January 2014 and 31 December 2018 are examined., Design: Descriptive study., Data Sources: Websites from Health Canada, Food and Drug Administration, Merck Index, United States Patent and Trademark Office, WHO and previously published articles., Interventions: None., Primary and Secondary Outcomes: The primary outcomes are time to market, time from patent application to NDS (pre-NDS time), review time, time from approval to availability (postapproval time) and factors that may influence the pre-NDS time. The secondary outcome is a comparison of Canadian and American review times and times between patent application and approval., Results: There were 113 drugs available for analysis. The median time to market was 11.80 years (IQR 9.40-14.05). The component median times were pre-NDS 10 years (IQR 8.05-12.80), review time 0.96 years (IQR 0.75-1.15) and postapproval time 0.15 years (IQR 0.08-0.28). Less than 8% of the pre-NDS time was explained by the factors that were analysed in a multiple linear regression equation. There was no statistically significant difference between Canadian and American pre-NDS times., Conclusion: Once a drug reaches the market, companies have a median of 8.2 years before the patent expires and generics can reach the market. Most of the time between the filing of a patent application and when a drug is marketed is determined by decisions that are largely under the control of the company., Competing Interests: Competing interests: From 2017 to 2020, JL received payments for being on a panel at the American Diabetes Association, for talks at the Toronto Reference Library, for writing a brief in an action for side effects of a drug for Michael F Smith, Lawyer, and a second brief on the role of promotion in generating prescriptions for Goodmans LLP and from the Canadian Institutes of Health Research for presenting at a workshop on conflict of interest in clinical practice guidelines. He is currently a member of research groups that are receiving money from the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council. He is a member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare. He receives royalties from University of Toronto Press and James Lorimer & Co Ltd for books he has written., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pharmaceutical companies engage heavily in promoting their products worldwide, and India is no exception. This article begins with an analysis of the therapeutic value of medications on the Indian market because, by definition, if a drug has no therapeutic value or has a negative benefit-to-harm ratio, then any promotion of that drug is inappropriate. It then examines 2 Indian case studies: drug promotion in Mumbai and the misuse of the World Health Organization logo in promotion. Next it describes specific types of promotion: advertisements in medical journals, brochures, and pamphlets; the actions of sales representatives; and the content of continuing medical education courses and medical conferences. The next sections examine medical students' and trainees' exposure to promotion and their attitudes about promotion; the attitudes of doctors about their interactions with the pharmaceutical industry; and whether promotion has an influence on prescribing. The article concludes with a critique of the existing industry, professional, and government regulatory regimes in India.

Background: Companies often defending their products when there are concerns about their safety and/or effectiveness., Objective: This study looks at drugs removed from the Canadian market from 1990 onward and examines how companies responded., Methods: This descriptive analysis used a previously published article and a hand search of a Government of Canada website to generate a list of drugs withdrawn from Canada from 1990 onwards. For each product the following information was extracted: brand name, generic name, company, date of withdrawal and evidence base for withdrawal. Google and Factiva searches were used to identify sources containing statements from the company about the withdrawal. Statements were independently graded by two people into the following categories: company agrees with the withdrawal; drug could be used safely with certain precautions; company may reintroduce the drug; company disagrees with the withdrawal. Searches were carried out between September 15-20, 2020., Results: There were 22 drugs for which there were company statements. In 10 statements, the companies disagreed with the decision to withdraw the drug and in 7 they agreed with the decision. In the other 5 cases they felt that the drug could have been kept on the market with restrictions (2 cases) or they might reintroduce the drug (3 cases). The level of evidence for the withdrawal did not seem to influence the companies' position., Conclusion: In 15 out of 22 cases, the company either disagreed with the decision to withdraw the drug or felt that the drug should continue to be available to Canadian patients.

Background: A previous study found that 2 of 29 (6.9%) meta-analyses published in high-impact journals in 2009 reported included drug trials' funding sources, and none reported trial authors' financial conflicts of interest (FCOIs) or industry employment. It is not known if reporting has improved since 2009. Our objectives were to (1) investigate the extent to which pharmaceutical industry funding and author-industry FCOIs and employment from included drug trials are reported in meta-analyses published in high-impact journals and (2) compare current reporting with results from 2009., Methods: We searched PubMed (January 2017-October 2018) for systematic reviews with meta-analyses including ≥ 2 randomized controlled trials (RCTs) of patented drugs. We included 3 meta-analyses published January 2017-October 2018 from each of 4 high-impact general medicine journals, high-impact journals from 5 specialty areas, and the Cochrane Database of Systematic Reviews, as in the previous study., Results: Among 29 meta-analyses reviewed, 13 of 29 (44.8%) reported the funding source of included trials compared to 2 of 29 (6.9%) in 2009, a difference of 37.9% (95% confidence interval, 15.7 to 56.3%); this included 7 of 11 (63.6%) from general medicine journals, 3 of 15 (20.0%) from specialty medicine journals, and 3 of 3 (100%) Cochrane reviews. Only 2 of 29 meta-analyses (6.9%) reported trial author FCOIs, and none reported trial author-industry employment., Protocol Publication: A protocol was uploaded to the Open Science Framework prior to initiating the study. https://osf.io/8xt5p/ LIMITATIONS: We examined only a relatively small number of meta-analyses from selected high-impact journals and compared results to a similarly small sample from an earlier time period., Conclusions: Reporting of drug trial sponsorship and author FCOIs in meta-analyses published in high-impact journals has increased since 2009 but is still suboptimal. Standards on reporting of trial funding described in the forthcoming revised PRISMA statement should be adapted and enforced by journals to improve reporting.

Background: Trade and investment agreements negotiated after the World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) have included increasingly elevated protection of intellectual property rights along with an expanding array of rules impacting many aspects of pharmaceutical policy. Despite the large body of literature on intellectual property and access to affordable medicines, the ways in which other provisions in trade agreements can affect pharmaceutical policy and, in turn, access to medicines have been little studied. There is a need for an analytical framework covering the full range of provisions, pathways, and potential impacts, on which to base future health and human rights impact assessment and research. A framework exploring the ways in which trade and investment agreements may affect pharmaceutical policy was developed, based on an analysis of four recently negotiated regional trade agreements. First a set of core pharmaceutical policy objectives based on international consensus was identified. A systematic comparative analysis of the publicly available legal texts of the four agreements was undertaken, and the potential impacts of the provisions in these agreements on the core pharmaceutical policy objectives were traced through an analysis of possible pathways., Results: An analytical framework is presented, linking ten types of provisions in the four trade agreements to potential impacts on four core pharmaceutical policy objectives (access and affordability; safety, efficacy, and quality; rational use of medicines; and local production capacity and health security) via various pathways., Conclusions: The analytical framework highlights provisions in trade and investment agreements that need to be examined, pathways that should be explored, and potential impacts that should be taken into consideration with respect to pharmaceutical policy. This may serve as a useful checklist or template for health and human rights impact assessments and research on the implications of trade agreements for pharmaceuticals.

Background: Patient groups represent the interest of their members when it comes to drug funding. Many patient groups receive grants from pharmaceutical companies that make products being considered for funding. This research examines whether there is an association between the positions that Canadian groups take about the products and conflicts of interest with the companies., Methods: The Common Drug Review (CDR) and panCanadian Oncology Drug Review (pCODR) make recommendations to Canadian provincial and federal drug plans about funding particular drug-indications. Both utilize input from patient groups in making their recommendations. Patient group submissions are available from both organizations and these submissions contain statements about conflicts of interest. Views of the patient groups, with and without a conflict with the company making the drug under consideration and without any conflicts at all, were assessed and then compared with the recommendations from CDR and pCODR., Results: There was a total of 222 reports for drug-indications. There were 372 submissions from 93 different patient groups. Groups declared a total of 1896 conflicts with drug companies in 324 (87.1%) individual submissions. There were 268 submissions where groups declared a conflict with the company making the product or said they had no conflict. Irrespective of whether there was a conflict, the views of patient groups about the drug-indications under consideration were the same. There was no statistically significant difference between views of patient groups and the recommendations from CDR and/or pCODR., Conclusions: The large majority of patient groups making submissions about funding of particular drug-indications had conflicts with the companies making the products and their views about the products were almost always positive. This association between funding and views needs to be further investigated to determine if a true cause and effect exists., Competing Interests: In 2015-2018, Joel Lexchin was a paid consultant on three projects: one looking at indication-based prescribing (United States Agency for Healthcare Research and Quality), a second to develop principles for conservative diagnosis (Gordon and Betty Moore Foundation) and a third deciding what drugs should be provided free of charge by general practitioners (Government of Canada, Ontario Supporting Patient Oriented Research Support Unit and the St Michael’s Hospital Foundation). He also received payment for being on a panel that discussed a pharmacare plan for Canada (Canadian Institute, a for-profit organization). He is currently a member of research groups that are receiving money from the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council. He is member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare. This does not alter my adherence to PLOS ONE policies on sharing data and materials.

Objectives: This study looks at market exclusivity time for the top selling originator drugs in Canada. Total sales for drugs without competition were also calculated., Methods: A list of the top selling originator drugs by dollar sales from 2009 to 2015 inclusive, except for 2010, was compiled along with their annual sales. Health Canada databases were used to extract the following information: generic name, date of Notice of Compliance (NOC, date of marketing authorization), whether the product was a small molecule drug or a biologic, and date of NOC for a generic or biosimilar. Market exclusivity time was calculated in days for drugs., Results: A total of 121 drugs were identified. There were 96 small molecule drugs (63 with a generic competitor and 33 with no generic competitor) and 25 biologics (none with a biosimilar competitor). The 63 drugs with a competitor had a mean market exclusivity time of 4478 days (12.3 years) (95% CI 4159-4798). The 58 drugs without competition had total annual sales of Can$8.59 billion and were on the market for a median of 5357 days (14.7 years) (interquartile range 3291-6679) as of January 31, 2017., Conclusions: Top selling originator drugs in Canada have a considerably longer period of market exclusivity than the 8 to 10 years that the research-based pharmaceutical industry claims., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

The Trans Pacific Partnership Agreement (TPP) is a large regional trade agreement involving 12 countries. It was signed in principle in February 2016 but has not yet been ratified in any of the participating countries. The TPP provisions place a range of constraints on how governments regulate the pharmaceutical sector and set prices for medicines. This article presents a prospective policy analysis of the possible effects of the TPP on these two points in Canada and Australia. Five chapters of relevance to pharmaceutical policy are analyzed: chapters on Technical Barriers to Trade (Chapter 8), Intellectual Property (Chapter 18), Investment (Chapter 9), Dispute Resolution (Chapter 28), and an annex of the chapter on Transparency and Anti-Corruption (Chapter 26, Annex 26-A). The article concludes that the TPP could have profound effects on the criteria these countries use to decide on drug safety and effectiveness, how new drugs are approved (or not) for marketing, post-market surveillance and inspection, the listing of drugs on public formularies, and how individual drugs are priced in the future. Furthermore, the TPP, if ratified and enforced, will reduce future policy flexibility to address the increasing challenge of rising drug prices., (© The Author(s) 2016.)

The Canadian constitution divides the responsibility for pharmaceuticals between the federal and provincial governments. While the provincial governments are responsible for establishing public formularies, the majority of the safety and efficacy information that the provinces use comes from the federal government. We interviewed drug plan officials from eight of the ten provinces and two of three territories regarding their views on the Canadian drug safety system. Here we report on the following categories: the federal drug approval system; the strengths and weaknesses of the federal system of postmarket pharmaceutical safety (i.e., pharmacosurveillance); resources available to support provincial formulary decision making; provincial roles in pharmacosurveillance; how the drug safety system could be improved; and the role of the Drug Safety and Effectiveness Network, a recently established virtual network designed to connect researchers throughout Canada who conduct postmarket drug research. Next, we place the Canadian system within an international context by comparing informational asymmetry between government institutions in the United States and the European Union and by looking at how institutions support each other's roles in sharing information and in jointly developing policy through the International Conference on Harmonization. Finally, we draw on international experiences and suggest potential solutions to the concerns that our key informants have identified.

Objectives: This paper investigates the pricing strategy (perfect flat pricing, perfect monotonic pricing, intermediate) used for multiple dosage medications listed in the Ontario Drug Benefit Formulary., Methods: All multiple dosage solid medications containing a single active ingredient newly listed in the Ontario Drug Benefit Formulary between 1996 and 2005 were identified. The relationship between price and dosage was calculated using a previously developed method., Results: Seventy-three multiple dosage medications were introduced. Where medications were equivalent to existing ones in most cases companies followed the pricing strategy used by therapeutically equivalent drugs already in the formulary. Where there were no equivalent products companies did not adopt any particular pricing strategy. There was no difference in the way that companies priced scored tablets versus unscored tablets and capsules or in the way that they priced drugs that had objective measurements of efficacy/effectiveness, for example blood pressure, versus those that did not have these measurements., Conclusions: When Monotonic pricing is used it leads to higher expenditures whereas flat pricing results in lower expenditures and offers more predictability in expenditures. Provincial governments should consider requiring flat pricing in return for formulary listing.

Background: Claims are made that new valuable drugs are not available in Canada at the time that they are marketed in the United States. This study uses a convenience sample of new drugs marketed in the United States and determines how many of these products are initially unavailable in Canada and their therapeutic value., Methods: Issues of the Canadian edition of The Medical Letter from May 12, 2003 to June 21, 2004 were hand searched for evaluations of new drugs and the following information was recorded: indication, availability in Canada and conclusions about therapeutic value. For drugs not available in Canada two clinical pharmacologists rated the therapeutic value of the products and the type of FDA review (standard or priority) was recorded. A database from the Therapeutic Products Directorate was searched to see if any of the drugs initially unavailable were subsequently marketed., Results: Thirty-two of 37 drugs were not available in Canada. Between 9 and 11 of these products were rated as offering moderate to significant therapeutic gains. Twelve of the 32 drugs eventually were marketed in Canada., Interpretation: Although the majority of new drugs marketed in the United States but not available in Canada do not offer any therapeutic advantage, between about a quarter and a third of may offer moderate to significant therapeutic gains. The reasons why these drugs are unavailable and how much their absence affects the treatment Canadians receive should be the subject of future research.

Background: Canada is strongly influenced by US cross-border direct-to-consumer advertising (DTCA) and has held consultations to discuss introduction of DTCA since 1996. This article describes a survey of Canadian drug policy experts carried out in 2001, during one such legislative review. The survey results are compared to more recent DTCA policy developments., Methods: We recruited key informants on pharmaceutical policy to complete a faxed questionnaire that queried their opinions on DTCA information quality, effects on drug and health care use, and regulatory issues. Respondents were asked about the evidence they had used to back their opinions. Analysis was descriptive., Results and Discussion: Of 79 identified potential participants, 60 (76%) participated, 40% of whom were from federal and provincial government; 3% were private insurers; 18%, 15%, and 8% were from health professional groups, consumer groups, and patient groups, respectively; 8% and 7% were from pharmaceutical and advertising industries, respectively. Opinions were highly polarized on the effects of DTCA on drug and health care use. Advertising and pharmaceutical industry respondents were generally positive, public sector, health professional and consumer groups generally negative. Over 80% believed DTCA leads to higher private and public drug costs and more frequent physician visits. Fewer judged billboards or television to be appropriate media for DTCA than magazines or the Internet, and most believed that children and adolescents should not be targeted., Conclusion: Given the polarization observed within this survey, we examined how DTCA policy has evolved in Canada since 2001. The federal government has legislative authority over DTCA, but bears few of the additional costs potentially incurred through policy change. These fall to the provinces, which provide an eroding patchwork of public coverage for prescription drugs in the face of rapidly increasing costs. No new federal legislation has been tabled since 2001. However, considerable shifts in administrative policy have occurred, all supportive of expanded advertising. Thus, the law continues to be restrictive but its application less so.

Objective: To examine how changes in outcomes are reported in drug advertisements in medical journals., Quality of Evidence: Advertisements from a convenience sample of 38 issues of Canadian Family Physician, Canadian Journal of Anaesthesia, Canadian Journal of Psychiatry, Canadian Medical Association Journal, and the New England Journal of Medicine., Main Message: Method of reporting changes in clinical outcomes (relative risk reduction [RRR], absolute risk reduction [ARR], number needed to treat [NNT]), name of product, and company marketing product were sought. In the 22 advertisements included in the analysis, 11 reported results as RRRs; two reported results as RRRs, but readers could calculate ARRs or NNTs from figures given in the advertisement; and nine gave no measure of results, but readers could calculate RRRs, ARRs, or NNTs from figures given., Conclusions: Most companies report changes in outcomes as RRRs, and this bias could influence the way physicians prescribe. Changes to the rules governing journal advertising and increased emphasis on critical appraisal skills would help mitigate this bias.