On what basis did Health Canada approve OxyContin in 1996? A retrospective analysis of regulatory data.

The marketing and sale of oxycodone (OxyContin) by Purdue Pharma has commanded a great deal of legal and policy attention due to the drug's central role in the ongoing overdose crisis. However, little is known about the basis for OxyContin's approval by regulators, such as Health Canada in 1996. Taking advantage of a recently created online database containing information pertaining to the safety and effectiveness of drugs, we conducted a retrospective analysis of Purdue Pharma's submission to Health Canada, including both published and unpublished clinical trials. None of the trials sponsored by Purdue Pharma sought to meaningfully assess the risks of misuse or addiction associated with OxyContin. The trials were short in duration (maximum length was 24 days) and only assessed safety and efficacy of a 12-h dosing interval. Also, the two trial reports that explicitly mentioned (but did not formally evaluate) the risk of misuse were not published, making it unclear how Health Canada concluded that there was no risk of misuse. In our view, these findings underscore the need for transparency of not only of clinical trial data, but also the regulator's interpretation of such data, which is currently lacking in Canada. Furthermore, they call into question why Health Canada's role in precipitating the overdose crisis has not received greater scrutiny, including in the context of recent litigation surrounding OxyContin.

Pharmaceutical Drugs of Uncertain Value, Lifecycle Regulation at the US Food and Drug Administration, and Institutional Incumbency.

Policy Points The US Food and Drug Administration (FDA) has in recent years allowed onto the market several drugs with limited evidence of safety and effectiveness, provided that manufacturers agree to carry out additional studies while the drugs are in clinical use. Studies suggest that these postmarketing requirements (PMRs) frequently lack transparency, are subject to delays, and fail to answer the questions of greatest clinical importance. Yet, none of the literature speaks directly to the challenges that the FDA-as a regulatory institution-encounters in enforcing PMRs. Through a series of interviews with FDA leadership, this article analyzes and situates those challenges in the midst of political threats to the FDA's public health mandate. CONTEXT: Modern pharmaceutical regulation is premised on a rigorous examination of a drug's safety and effectiveness prior to its lawful sale. However, since the 1990s, the US Food and Drug Administration (FDA) has gradually shifted to a model of "lifecycle" regulation that increasingly relies on postmarketing requirements (PMRs) to encourage studies of drug safety and effectiveness following regulatory approval. This article examines the range of legal, institutional, and political challenges that FDA faces in the context of lifecycle regulation. METHODS: Document-based legal and policy analysis was combined with a set of semistructured interviews of current and former FDA officials (n = 23) in order to explore the implications of the FDA's use of PMRs. The median interview time per official was 61 minutes, with a range of 24 to 227 minutes. All of the officials interviewed occupied positions of leadership and influence within the FDA, such as directors of an FDA center or office, key legal counsel on agency-wide policy initiatives, and the commissioner of the FDA. FINDINGS: Insufficient resources and coordination within the FDA, inadequate legal authorities, and the political economy of withdrawing an approved indication in the face of opposition from companies and patients all contribute to the observed shortcomings in the FDA's use and enforcement of PMRs. Further, the FDA is fully aware of these challenges, yet is seemingly resigned to and resistant to criticism of its use of PMRs. CONCLUSIONS: This study of the FDA's shift toward lifecycle regulation reveals not simply an agency in transition, but rather an agency on guard against a set of larger political threats to its mandate. This can be characterized as a state of institutional incumbency in which the agency is engaged in an effort to reproduce key features of the regulatory system-in concert with regulated industries and others-while simultaneously sanctioning significant changes to the regulatory standards the FDA has long applied, to the detriment of public health.

What Is the Purpose of the Orphan Drug Act?

Matthew Herder suggests it may be time to re-examine the purpose of the U.S. Orphan Drug Act.

'Our project, your problem?' A case study of the WHO's mRNA technology transfer programme in South Africa.

In June 2021 the World Health Organization (WHO) and the Medicines Patent Pool (MPP) launched an mRNA technology transfer programme. With a South African consortium serving as the hub, the programme aimed to increase vaccine manufacturing capacity in low- and middle-income countries (LMICs) in view of the "vaccine apartheid" that was observed during COVID-19. Following Clarke's "situational analysis," the present study assessed whether the mRNA programme differs from the approach and practices that comprise current biopharmaceutical production. Numerous documentary sources, including legal agreements underpinning the programme, funding agreements, and patent filings, were reviewed. Semi-structured interviews with 35 individuals, ranging from the programme's architects and university scientists to representatives from LMIC vaccine manufacturers taking part in the programme were also conducted. While the mRNA programme may improve the sharing of knowledge, other design features, in particular, weak conditionalities around product affordability, participants' freedom to contract with third parties, and acceptance of market-based competition, are in line with the status quo. Further, WHO and MPP's tight control over the programme evokes the dynamics that are often in play in global health, to the detriment of empowering LMIC-based manufacturers to generate mRNA products in response to local health needs.

"A Most Equitable Drug": How the Clinical Studies of Convalescent Plasma as a Treatment for SARS-CoV-2 Might Usefully Inform Post-Pandemic Public Sector Approaches to Drug Development.

Interventional clinical studies of convalescent plasma to treat COVID-19 were predominantly funded and led by public sector actors, including blood services operators. We aimed to analyze the processes of clinical studies of convalescent plasma to understand alternatives to pharmaceutical industry biopharmaceutical research and development, particularly where public sector actors play a dominant role. We conducted a qualitative, critical case study of purposively sampled prominent and impactful clinical studies of convalescent plasma during 2020-2021.

Aducanumab, Accelerated Approvals & the Agency: Why the FDA Needs Structural Reform.

The US Food and Drug Administration's controversial decision to grant accelerated approval to aducanumab (Aduhelm), a therapy for Alzheimer's disease, has motivated multiple policy reforms. Drawing a case series of other drugs granted accelerated approval and interviews of senior FDA officials, I argue that reform should be informed but not defined by aducanumab. Rather, structural reforms are needed to reshape FDA's core priorities and restore the regulatory system's commitment to scientific rigor.

How to use the regulatory data from Health Canada for secondary analyses on new drugs, biologics and vaccines.

Incorporating clinical data held by national health product regulatory authorities into secondary analyses such as systematic reviews can help combat publication bias and selective outcome reporting, in turn, supporting more evidence-based decisions regarding the prescribing of drugs, biologics and vaccines. Owing to recent changes in Canadian law, Health Canada has begun to make clinical information-whether it has been previously published or not-publicly available through its 'Public Release of Clinical Information' (PRCI) online database. We provide guidance about how to access and use regulatory data obtained through the PRCI database for the purpose of conducting drug and biologic secondary analyses.

'More of the same, but worse than before': A qualitative study of the challenges encountered by people who use drugs in Nova Scotia, Canada during COVID-19.

BACKGROUND: To learn about the experiences of people who use drugs, specifically opioids, in the Halifax Regional Municipality (HRM), in Nova Scotia, Canada during the COVID-19 pandemic through qualitative interviews with people who use drugs and healthcare providers (HCP). This study took place within the HRM, a municipality of 448,500 people [1]. During the pandemic many critical services were interrupted while overdose events increased. We wanted to understand the experiences of people who use drugs as well as their HCPs during the first year of the pandemic. METHODOLOGY: We conducted a qualitative study using semi-structured interviews with 13 people who use drugs and 6 HCPs, including physicians who work in addiction medicine (3), a pharmacist, a nurse, and a community-based opioid agonist therapy (OAT) program staff member. Participants were recruited within HRM. Interviews were held via phone or videoconference due to social distancing directives. Interviews focused on the challenges people who use drugs and HCPs faced during the pandemic as well as elicited perspectives on a safe supply of drugs and the associated barriers and facilitators to the provision of a safe supply. RESULTS: Of the 13 people who use drugs who participated in this study, ages ranged from 21-55 years (mean 40). Individuals had spent on average 17 years in HRM. Most people who use drugs (85%, n = 11) utilized income assistance, the Canadian Emergency Response Benefit, or disability support. Many had experienced homelessness (85%, n = 11) and almost half (46%, n = 6) were currently precariously housed in the shelter system. The main themes among interviews (people who use drugs and HCPs) were housing, accessing healthcare and community services, shifts in the drug supply, and perspectives on safe supply. CONCLUSIONS: We identified several challenges that people who use drugs face in general, but especially during the COVID-19 pandemic. Access to services, housing support, and interventions to use safely at home were limited. As many challenges faced by people who use drugs exist outside of COVID-19, we concluded that the formal and informal interventions and changes in practice that were made to support people who use drugs should be sustained well past the end of the pandemic. The need for enhanced community supports and a safe supply of drugs, despite its complicated nature, is essential for the health and safety of people who use drugs in HRM, especially during COVID-19.

Biopharmaceutical Financialization and Public Funding of Medical Countermeasures (MCMs) in Canada During the COVID-19 Pandemic.

BACKGROUND: Analysing the Canadian government's efforts to support the development of COVID-19 "medical countermeasures" (MCMs), this article seeks insights into political economy as a driver of pandemic response. We explore whether Canadian public funding policy during the pandemic involved departures from established practices of financialisation in biopharmaceutical research and development (R&D), including the dominance of private sector involvement in an intellectual property (IP) intensive approach to innovation underscoring profit, and governance opacity. METHODS: We interrogate public funding for MCMs by analyzing how much the Government of Canada (GoC) spent, how those funds were allocated, on what terms, and to whom. We identify the funding institutions, and the funds awarded between February 10, 2020, and March 31, 2021, to support the research, development, and manufacturing of MCMs, including diagnostics, vaccines, therapeutics, and information about clinical management and virus transmission. To collect these data, we conducted searches on the Internet, public data repositories, and filed several requests under the Access to Information Act (1985). Subsequently, we carried out a document-based analysis of electronically accessible research contracts, proposals, grant calls, and policy announcements. RESULTS: The GoC announced CAD$ 1.4 billion for research, development and manufacturing of COVID-19 MCMs. Fully 68% (CAD$ 959 million) of the announced public funding was channelled to investment in private sector firms. Canadian public funding showed a consistent focus on early and late stage development of COVID-19 MCMs and the expansion of biopharmaceutical manufacturing capacity. Assessing whether Canada's investments into developing COVID-19 MCMs safeguard affordable and transparent access to the products of publicly funded research, we found that access policies on IP management, sharing of clinical data, affordability and availability were not systematic, consistent, or transparent, and few, if any, mechanisms ensured long-term sustainability. CONCLUSION: Beyond incremental change in policy goals, such as public investment in domestic biomanufacturing, the features of Canadian public policies endorsing financialization in the biopharmaceutical sector remained largely unchanged during the pandemic.

US Food and Drug Administration regulatory reviewer disagreements and postmarket safety actions among new therapeutics.

OBJECTIVES: To examine the association between regulatory reviewer disagreements and postmarket safety actions among novel therapeutics approved by the US Food and Drug Administration (FDA) between 2011 and 2015. Disagreements among FDA reviewers regarding the recommendation for a novel therapeutic's approval, its safety, the indicated patient population and/or other parameters of the drug's approval are common. However, the implications of such disagreements-particularly with respect to postmarket safety actions-are poorly understood. DESIGN: Cross-sectional study. SETTING: All novel therapeutics approved by the FDA between January 2011 and December 2015. PARTICIPANTS: None. MAIN OUTCOME MEASURES: Postmarket safety actions defined as new label warnings/increased warning severity, FDA safety communications and safety-related therapeutic withdrawals after the original regulatory approval. RESULTS: Among 174 novel therapeutics approved by the FDA between 2011 and 2015, 42 (24%) had at least one regulatory reviewer disagreement. Altogether, 156 instances of disagreement were observed. Following market approval, a total of 253 postmarket safety actions were taken by the FDA among all new therapeutics, with at least one postmarket safety action identified for 98 (56.3%) of the 174 novel therapeutic approvals. Overall, therapeutics that were the subject of disagreement during the FDA's review had fewer safety actions following approval compared with therapeutics in which no disagreement was observed (38.1% vs 62.1%; RR 0.61, 95% CI 0.41 to 0.92; p=0.006). Therapeutic approvals containing at least one reviewer disagreement also more often carried a black box warning at the point of approval (47.7% vs 31.1%; RR 1.53, 95% CI 1.02 to 2.30; p=0.05). CONCLUSIONS: This investigation of regulatory reviewer disagreements and postmarket safety actions among new therapeutics suggests that disagreements among regulatory reviewers may lead to important pre-emptive actions, potentially mitigating the need for postmarket safety actions to be taken.

Extending the US Food and Drug Administration's Postmarket Authorities.

Importance: The US Food and Drug Administration (FDA) has expansive regulatory flexibility regarding the quality and quantity of evidence it deems sufficient to approve new drugs, which has been increasingly used to grant approval based on less certain evidence of benefit. However, the FDA's regulatory flexibility with respect to standards for approval has not been matched by sufficient stringency in its exercise of postmarket safeguards, including the FDA's authority and willingness to require confirmation of benefit through postmarket efficacy studies or to withdraw approval when benefit is not confirmed. Objective: To identify and evaluate opportunities for the FDA to extend its authority to require postmarket efficacy studies and use expedited withdrawal procedures for drugs approved despite substantial residual uncertainty outside the accelerated approval pathway. Evidence: The FDA's current approaches to regulatory flexibility with respect to standards for drug approval; examples of shortcomings in the postmarket period; existing statutes and regulations governing the scope of the FDA's authority to impose and enforce postmarket study requirements; and recent legislative reform and agency action regarding the accelerated approval pathway. Findings: Drawing on the broad language of the federal Food, Drug, and Cosmetic Act, the FDA could independently extend its core accelerated approval authorities-required postmarket efficacy studies and expedited withdrawal procedures-to any drug approved with substantial residual uncertainty regarding benefit, such as those supported by a single pivotal trial. To avoid exacerbating existing problems that have become evident during the past 3 decades of experience using the accelerated approval pathway, however, the FDA must ensure that postmarket studies are well designed and completed quickly, while compelling expedited withdrawal when needed. Conclusions and Relevance: Under current FDA approaches to drug approval, patients, clinicians, and payers may be left with little confidence about a drug's benefit not only when it first enters the market but also for an extended period thereafter. If policy makers continue to favor earlier market access over evidentiary certainty, flexible approvals must be matched by more expansive use of postmarket safeguards, an approach possible within the FDA's existing legal authorities.

Permissive regulation: A critical review of the regulatory history of buprenorphine formulations in Canada.

Suboxone (buprenorphine-naloxone) is an opioid product approved in the US and Canada for the treatment of opioid use disorder. The drug is considered an important response to the opioid overdose epidemic with consistent calls for wider prescribing and deregulation. The history of Suboxone regulation in Canada has not been critically examined. Part of the rationale for doing so stems from the US regulatory experience, with documented irregularities, or what some have called abuses, that support profit-making by Suboxone's manufacturers. This regulatory analysis allows us to determine how opportunities to address health crises through drug innovation are managed at a federal level. We used public drug and patent registries to critically examine Suboxone's Canadian history. First, we investigated Suboxone's entry into the Canadian market to understand how it achieved market exclusivity. Second, we examined Health Canada's risk mitigation process to address extramedical use and diversion to understand the intersection of regulation and brand promotion. Insights from these two analyses were then extended to the recent approval of two related buprenorphine-containing products and their specific pathways to Canadian market exclusivity. We identified inconsistencies in Suboxone's regulatory history that suggest Health Canada's functions of health protection and promotion were compromised in favour of an "innovations" agenda that supports profit-making. Despite six years of market exclusivity in Canada, there was no evidence suggesting Suboxone achieved formal exclusivity (i.e., through patent or data protection). Health Canada's process to address safety concerns of Suboxone were compromised by reliance on the manufacturer to carry out post-market education, allowing the manufacturer to create and market a branded "education" program for its product. Similar inconsistencies have afforded market exclusivity for two related products despite marginal innovation. These analyses reveal a case of permissive regulation, where principles of health protection are compromised by economic imperatives. Such a regulatory approach has the potential to adversely impact public health due to unnecessarily high costs for medicines deemed essential to stem a major health crisis. Alternative pharmaceutical policies are urgently needed to safely and efficiently expand treatment access for opioid use disorder.