Courtney Davis

Courtney Davis and colleagues argue that drug regulatory agencies should improve their oversight and direct provision of relevant, useful, and trustworthy information on new drugs

Objective To evaluate the frequency with which relevant and accurate information about the benefits and related uncertainties of anticancer drugs are communicated to patients and clinicians in regulated information sources in Europe. Design Document content analysis. Setting European Medicines Agency. Participants Anticancer drugs granted a first marketing authorisation by the European Medicines Agency, 2017-19. Main outcome measures Whether written information on a product addressed patients’ commonly asked questions about: who and what the drug is used for; how the drug was studied; types of drug benefit expected; and the extent of weak, uncertain, or missing evidence for drug benefits. Information on drug benefits in written sources for clinicians (summaries of product characteristics), patients (patient information leaflets), and the public (public summaries) was compared with information reported in regulatory assessment documents (European public assessment reports). Results 29 anticancer drugs that received a first marketing authorisation for 32 separate cancer indications in 2017-19 were included. General information about the drug (including information on approved indications and how the drug works) was frequently reported across regulated information sources aimed at both clinicians and patients. Nearly all summaries of product characteristics communicated full information to clinicians about the number and design of the main studies, the control arm (if any), study sample size, and primary measures of drug benefit. None of the patient information leaflets communicated information to patients about how drugs were studied. 31 (97%) summaries of product characteristics and 25 (78%) public summaries contained information about drug benefits that was accurate and consistent with information in regulatory assessment documents. The presence or absence of evidence that a drug extended survival was reported in 23 (72%) summaries of product characteristics and four (13%) public summaries. None of the patient information leaflets communicated information about the drug benefits that patients might expect based on study findings. Scientific concerns about the reliability of evidence on drug benefits, which were raised by European regulatory assessors for almost all drugs in the study sample, were rarely communicated to clinicians, patients, or the public. Conclusions The findings of this study highlight the need to improve the communication of the benefits and related uncertainties of anticancer drugs in regulated information sources in Europe to support evidence informed decision making by patients and their clinicians.

The Swedish Medical Products Agency (MPA) objects to the fact that we occasionally refer to one of its senior ex-employees by name. However, names of individual MPA assessors, Food and Drug Administration (FDA) reviewers, and European Medicines Agency rapporteurs and co-rapporteurs are cited in regulatory documents and are a matter of public record. In our paper (Health Res Policy Syst 15:93, 2017), we in no way suggest that regulatory decisions were left to individual reviewers or assessors, although we do emphasise that individual MPA and FDA employees’ scientific assessments and benefit–risk evaluations are critical to the decision-making process. In this response to the MPA, we raise a further issue – one in which the question of personal identification of individuals is relevant – and this pertains to the accountability of influential scientists and experts who contribute to public policy decisions with important ramifications for public health. In our view, it is important that interested observers are able to identify those influential individuals, and entirely appropriate that their work should be open to public scrutiny.

Relenza represents the first neuraminidase inhibitor (NI), a class of drugs that also includes the drug Tamiflu. Although heralded as breakthrough treatments in influenza, NI efficacy has remained highly controversial. A key unsettled question is why the United States Food and Drug Administration (FDA) has approved more cautious efficacy statements in labelling than European regulators for both drugs. We conducted a qualitative analysis of United States and European Union regulatory appraisals for Relenza to investigate the reasons for divergent regulatory interpretations, pertaining to Relenza’s capacity to alleviate symptoms and reduce frequency of complications of influenza. In Europe, Relenza was evaluated via the so-called national procedure with Sweden as the reference country. We show that FDA reviewers, unlike their European (i.e. Swedish) counterpart, (1) rejected the manufacturer’s insistence on pooling efficacy data, (2) remained wary of subgroup analyses, and (3) insisted on stringent statistical analyses. These differences meant that the FDA was less likely to depart from prevailing regulatory and scientific standards in interpreting trial results. We argue that the differences are explained largely by divergent institutionalised review methodologies, i.e. the European regulator’s reliance on manufacturer-compiled summaries compared to the FDA’s examination of original data and documentation from trials. The FDA’s more probing and meticulous evaluative methodology allowed its reviewers to develop ‘deep’ knowledge concerning the clinical and statistical facets of trials, and more informed opinions regarding suitable methods for analysing trial results. These findings challenge the current emphasis on evaluating regulatory performance mainly in terms of speed of review. We propose that persistent uncertainty and knowledge deficits regarding NIs could have been ameliorated had regulators engaged in the public debates over the drugs’ efficacy and explained their contrasting methodologies and judgments. Regulators use major resources to evaluate drugs, but if regulators’ assessments are not effectively disseminated and used, resources are used inefficiently.

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.

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

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. 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. 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. Before a pharmaceutical company can market a new prescription drug, the drug has to go through a long approval process. After extensive studies in the laboratory and in animals, the company must test the drug’s safety and efficacy in series of clinical trials in which patients with specific diseases receive the drug under carefully controlled conditions. Regulatory bodies such as the US FDA, the UK MHRA and the European Medicines Agency (EMA) then review the results of these trials and, when they are satisfied that the drug is safe and effective for the conditions in which it was tested, give the pharmaceutical company approval to market the drug in the relevant country. An important part of the approval process is the creation of the “drug label,” a detailed report that specifies the exact diseases and patient groups in which the drug can be used and the drug’s approved doses. Physicians can use approved drugs “off-label.” That is, they can prescribe drugs for a different disease, in a different group of patients, or at a different dose to that specified in the label. However, in the UK, the US, and other countries, national law prohibits the promotion of off-label uses of prescription drugs by pharmaceutical companies, which stand to benefit financially from off-label use through increased drugs sales. The primary rationale for banning off-label promotion is that it might encourage the widespread use of drugs in settings where they have not been rigorously tested, thereby exposing patients to uncertain benefits and possible adverse effects. In the US, the FDA regulates and prosecutes off-label promotion, but enforcement actions against companies can also be brought by federal and state prosecutors and private citizens. In the UK, the MHRA has delegated an important part of its responsibility for supervising off-label marketing to a self-regulatory body set up by the pharmaceutical industry—the PMCPA. Here, by reviewing off-label promotion rulings made by the PMCPA between 2003 and 2012, the researchers compare off-label promotion cases ruled on in the UK with whistleblower (company insider)-initiated cases from the US and shed light on the UK self-regulatory mechanism for detecting, deterring, and sanctioning off-label promotion. The researchers identified 74 UK off-label promotion rulings over the ten-year study period involving 43 companies (including 19 that were ruled in breach more than once) and 65 drugs. They coded and analyzed each off-label promotion ruling using a typology (a classification according to general type) previously developed to analyze US whistleblower-initiated off-label promotion cases. Half of the rulings cited efforts to expand drug use to unapproved indications (for example, using a drug to treat all patients with MS rather than only patients with recent relapses); 39% and 38% of the rulings cited efforts to expand drug use beyond approved diseases and dosing strategies, respectively. The most commonly cited off-label promotional tactic was attempts to influence prescribers using advertisements and other print material; competing companies lodged 57% of complaints whereas prescribers (the prime target of off-label promotion) lodged only 22% of the complaints. Unlike US whistleblower complaints, which often alleged promotional tactics targeting consumers, payers and company staff, few UK rulings described practices targeting these classes of individuals. Finally, although several US whistleblower-initiated cases alleged multifaceted and covert marketing activities, the UK cases typically related to one or a few claims made in printed material. Because this study only describes PMCPA rulings and whistleblower-initiated US cases of off-label promotion, these findings provide an incomplete view of off-label marketing violations (some of which may not be deliberate) in the UK and US. The findings suggest that the UK self-regulatory approach, which relies mainly on complaints from company outsiders, is capable of detecting and dealing with instances of off-label promotion with high visibility (for example, advertisements). However, the UK self-regulatory approach may be less capable of uncovering complex marketing campaigns than the US government-led approach. The researchers suggest, therefore, that the UK authorities should consider the introduction of increased incentives and protections for whistleblowers and of US-style governmental investigation (the PMCPA rulings are based on complainant and company submissions alone) and that both the MHRA and PMCPA should strengthen their regulatory oversight of promotional material. Finally, prescribers—the main target of off-label promotion in the UK—should be encouraged to identify and report off-label promotion. This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001945.

This chapter is a case study of the controversy surrounding a thalassaemia drug, known as deferiprone. The approval of the drug for the EU market was appealed, to what was then the European Court of Justice (now the Court of Justice of the European Union), by one of the key clinical investigators of the drug, on the grounds of safety and efficacy. This case study explores some of the interactions between law, science, and the ‘medical-industrial complex’, at various stages of controversy about drug technology. In particular, it highlights the role of the law in constraining professional autonomy. In so doing, it also facilitates an examination of the roles of drug risks in clinical trials, the rights of stakeholders during the drug development process, and the interaction between ethics and markets.