Courtney Davis

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

Deficits, Expectations and Paradigms in British and American Drug Safety Assessments Prising Open the Black Box of Regulatory Science

This article examines the regulation of nonsteroidal anti-inflammatory drugs (NSAIDs), with particular focus on products approved for marketing in the United Kingdom, while denied marketing approval in the United States on safety grounds, and then subsequently withdrawn from the UK market on those grounds. Using international comparison of regulatory data never before accessed outside government and companies, together with interviews with relevant industry scientists and regulators, the article demonstrates the importance of regulatory expectations, deficits and paradigms. It is argued both that these sociological concepts can be enriched by their application to detailed comparative case study of regulatory science, and that they provide an important policy-relevant framework with which to understand discrepant drug regulatory processes in a sociohistorical context. It is found that regulatory expectations and paradigms may be regarded as mediating factors between political culture and structural interests, on the one hand, and the outcomes of regulatory science (including deficits), on the other.

Interpellative Sociology of Pharmaceuticals: Problems and Challenges for Innovation and Regulation in the 21st Century

Abstract This paper develops a framework with which to interrogate how well pharmaceutical innovation and regulation are performing to produce drugs that improve health. That framework comprises five key dimensions: therapeutic advance of drug product innovations; safety standards in drug testing; use of surrogate measures of clinical benefit; independence of regulatory agencies; and public access to regulatory science. It is concluded that: more demanding regulatory intervention is required in order to increase the proportion of drug innovation that actually offers therapeutic benefits over existing products; drug regulatory agencies need much greater independence from the pharmaceutical industry; the erosion of safety standards since 1990 needs to be reversed; accelerated approvals of drugs based on surrogate, rather than clinical endpoints, require much greater critical attention; and much more extensive public access to regulatory science is required in order for regulatory decision-making to be thoroughly accountable to the public and the wider scientific community.

“Adaptive pathways” to drug authorisation: adapting to industry?

Evidence for benefits to patients and public health of adaptive pathways is lacking or contradictory, say Courtney Davis and colleagues

Is there a cure for corporate crime in the drug industry

Effective enforcement of regulations requires more resources and determination to impose robust sanctions

Rethinking Innovation Accounting in Pharmaceutical Regulation: A Case Study in the Deconstruction of Therapeutic Advance and Therapeutic Breakthrough

The controversy over the prescription drug, alosetron, is examined in order to investigate what is permitted to count as ‘therapeutic advance’ and ‘therapeutic breakthrough’ within pharmaceutical innovation and regulation. It is argued that those official accounting categories can mask very modest efficacy of some drugs by reference to the official techno-scientific evidence, thus leading to questionable acceptance of risks to public health. This is explained by: the drug availability options set by the commercial interests of manufacturers; the FDA managements need to demonstrate rapid approval of therapeutic advances to their budgetary masters, especially in the context of patient demands for access to new drugs; and the increasing capacity of patient groups, sometimes in collaboration with pharmaceutical manufacturers, to challenge techno-scientific expertise and evidence with experiential testimony. It is concluded that regulatory policy-makers need much more sophisticated accounting systems for differentiating between drugs defined as significant therapeutic advances, and between drugs (‘therapeutic breakthroughs’ fast-tracked to treat serious or life-threatening conditions. Contrary to some STS analyses, the desirability of an ascendancy of patients’ anecdotal evidence in regulatory decisions for public health is questioned.

Do patient access schemes for high-cost cancer drugs deliver value to society?-lessons from the NHS Cancer Drugs Fund.

Abstract Background The NHS Cancer Drugs Fund (CDF) was established in 2010 to reduce delays and improve access to cancer drugs, including those that had been previously appraised but not approved by NICE (National Institute for Health and Care Excellence). After 1.3 billion GBP expenditure, a UK parliamentary review in 2016 rationalized the CDF back into NICE. Methods This paper analyses the potential value delivered by the CDF according to six value criteria. This includes validated clinical benefits scales, cost-effectiveness criteria as defined by NICE and an assessment of real-world data. The analysis focuses on 29 cancer drugs approved for 47 indications that could be prescribed through the CDF in January 2015. Results Of the 47 CDF approved indications, only 18 (38%) reported a statistically significant OS benefit, with an overall median survival of 3.1 months (1.4–15.7 months). When assessed according to clinical benefit scales, only 23 (48%) and 9 (18%) of the 47 drug indications met ASCO and ESMO criteria, respectively. NICE had previously rejected 26 (55%) of the CDF approved indications because they did not meet cost-effectiveness thresholds. Four drugs—bevacizumab, cetuximab, everolimus and lapatinib—represented the bulk of CDF applications and were approved for a total of 18 separate indications. Thirteen of these indications were subsequently delisted by the CDF in January 2015 due to insufficient evidence for clinical benefit—data which were unchanged since their initial approval. Conclusions We conclude the CDF has not delivered meaningful value to patients or society. There is no empirical evidence to support a ‘drug only’ ring fenced cancer fund relative to concomitant investments in other cancer domains such as surgery and radiotherapy, or other noncancer medicines. Reimbursement decisions for all drugs and interventions within cancer care should be made through appropriate health technology appraisal processes.

Risking public safety: Experts, the medical profession and ‘acceptable’ drug injury

Abstract By locating expertise within an institutional framework, this paper examines the roles of regulators, the pharmaceutical industry and the medical profession in drug risk assessment and in the construction of ‘acceptable’ drug injury in particular. It is suggested that, while public perceptions of risks are important, they may be extremely limited due to relative secrecy surrounding some risk-generating activities, such as pharmaceutical development and regulation. Under these circumstances, a necessary starting point is the investigation of the formation of expert risk assessments. Taking the case of the anaesthetic drug, Althesin, the article explains how drug risks, largely unknown to the public, came to be defined as acceptable by expert and regulatory interpretation for over a decade. The reasons for and drivers of the regulatory route taken, together with alternative regulatory approaches are identified in relation to the salient risk – benefit problems: extrapolation of animal toxicology to humans, construction of therapeutic benefit, comparative risk assessment, unpredictability of risk and risk – benefit evaluation. It is argued that professional closure between expert regulators, the manufacturer and sections of the anaesthesiology profession led to passive decision-making and a regulatory approach towards acceptable drug injury unlikely to have been sustainable if it had been subjected to public accountability. The Althesin experience also suggests that regulators, the medical profession and other stakeholders concerned about drug risks should focus their attention not only on improving the evidence-base of risk assessment, but also on more robust interpretation and informative communication of the evidence already available at any particular time. Finally, the Althesin case demonstrates that, contrary to popular claims, major drug risks have not necessarily only been discovered upon widespread use after marketing approval and that, even after discovery of life-threatening risks, drugs have not necessarily been withdrawn quickly by the UK regulatory authorities despite the availability of safer alternatives.

Pharmaceutical Industry Off-label Promotion and Self-regulation: A Document Analysis of Off-label Promotion Rulings by the United Kingdom Prescription Medicines Code of Practice Authority 2003-2012

Background European Union law prohibits companies from marketing drugs off-label. In the United Kingdom—as in some other European countries, but unlike the United States—industry self-regulatory bodies are tasked with supervising compliance with marketing rules. The objectives of this study were to (1) characterize off-label promotion rulings in the UK compared to the whistleblower-initiated cases in the US and (2) shed light on the UK self-regulatory mechanism for detecting, deterring, and sanctioning off-label promotion. Methods and Findings We conducted structured reviews of rulings by the UK self-regulatory authority, the Prescription Medicines Code of Practice Authority (PMCPA), between 2003 and 2012. There were 74 off-label promotion rulings involving 43 companies and 65 drugs. Nineteen companies were ruled in breach more than once, and ten companies were ruled in breach three or more times over the 10-y period. Drawing on a typology previously developed to analyse US whistleblower complaints, we coded and analysed the apparent strategic goals of each off-label marketing scheme and the practices consistent with those alleged goals. 50% of rulings cited efforts to expand drug use to unapproved indications, and 39% and 38% cited efforts to expand beyond approved disease entities and dosing strategies, respectively. The most frequently described promotional tactic was attempts to influence prescribers (n = 72, 97%), using print material (70/72, 97%), for example, advertisements (21/70, 30%). Although rulings cited prescribers as the prime target of off-label promotion, competing companies lodged the majority of complaints (prescriber: n = 16, 22%, versus companies: n = 42, 57%). Unlike US whistleblower complaints, few UK rulings described practices targeting consumers (n = 3, 4%), payers (n = 2, 3%), or company staff (n = 2, 3%). Eight UK rulings (11%) pertaining to six drugs described promotion of the same drug for the same off-label use as was alleged by whistleblowers in the US. However, while the UK cases typically related to only one or a few claims made in printed material, several complaints in the US alleged multifaceted and covert marketing activities. Because this study is limited to PMCPA rulings and whistleblower-initiated federal cases, it may offer a partial view of exposed off-label marketing. Conclusion The UK self-regulatory system for exposing marketing violations relies largely on complaints from company outsiders, which may explain why most off-label promotion rulings relate to plainly visible promotional activities such as advertising. This contrasts with the US, where Department of Justice investigations and whistleblower testimony have alleged complex off-label marketing campaigns that remain concealed to company outsiders. UK authorities should consider introducing increased incentives and protections for whistleblowers combined with US-style governmental investigations and meaningful sanctions. UK prescribers should be attentive to, and increasingly report, off-label promotion.

A comparative analysis of risk management strategies in European Union and United States pharmaceutical regulation

Analyses of risk management within prescription pharmaceutical regulation are rare. We present the first comparison of pharmaceutical risk regulation between the EUs centralised supranational ‘state’ and another country, the US. Drawing on documentary and interview-based research on case-study drugs and risk management, we argue that ‘risk colonisation’, neo-liberal governmentality, and pressure from powerful industry interests have combined to produce permissive, rather than precautionary, risk management within pharmaceutical regulation, though more so in the US than Europe. Product labelling is central to pharmaceutical risk management by communicating risks to doctors and patients, but can also legitimate permissive regulatory approval, especially when new drugs offer no therapeutic advance. Such neo-liberal risk management was practised by both the American and European regulatory agencies. However, the FDA, more willingly than EU regulators, used risk communication, warnings, and patient monitoring to maintain on the market pharmaceuticals with severe/life-threatening risks, such as liver and cardiac toxicity, despite growing evidence of their incapacity to prevent harm. Senior EU regulators were sceptical about risk-managing toxic drugs during post-marketing, rather than simply removing them from the market. EU regulators’ more precautionary application of pharmaceutical risk management than the FDA offers some support for the ‘flip-flop’ hypothesis, which asserts that US environmental and consumer product risk regulation was more precautionary during the 1970s and early 1980s, but since then Europe has become more precautionary. However, such support does not necessarily apply to drug regulation overall. The supranational EU regulatory system has been more resistant to neo-liberal governmentality, ‘risk colonisation’, and the pressure of industry interests. We suggest that this is because EU regulators’ practice of regulatory science has greater autonomy from political ideology and institutional interests than its American counterpart.