Vittorio Bertele

Non-inferiority trials are unethical because they disregard patients' interests

1have been widely used to assess new drugs, but have recently lost ground to a non-inferiority design. This type of trial is usually accepted by regulatory authorities for approval of new drugs or new indications, although the US Food and Drugs Administration has raised some concerns. 2 In this paper, we argue that the scientifi c community should ban non-inferiority and equivalence trials because they are unethical, whatever measures are taken to prevent their methodological pitfalls and inappropriate interpretation of results. 3–8

Recent national and regional drug reforms in Sweden: implications for pharmaceutical companies in Europe.

With an aging population and increased prevalence of chronic diseases, such as obesity and diabetes mellitus, drug reforms are needed across Europe to ensure the continued provision of comprehensive healthcare. It is also a challenge, with the limited resources available, to fund new innovative drugs that significantly improve patient health.Recent national and regional reforms in Sweden have moderated the rate of increase in drug expenditure, despite increased volumes of drug use and the launch of new, expensive drugs. National reforms include the adoption of economic principles when assessing the value and subsequent reimbursement of new and existing drugs, as well as reforms to obtain low prices for generic drugs. Regional reforms aim to encourage the rational use of medicines through the establishment of drug and therapeutic committees, development of guidelines, academic detailing, continuous benchmarking of prescribing patterns, and financial incentives.Some of these reforms provide examples to other European countries, whilst others duplicate existing measures. As such, we believe other European countries can benefit from an analysis of the Swedish reforms. We believe the pharmaceutical industry can also benefit from this analysis by working with key regional payers involved with developing and implementing the reforms as they moderate and refine their future activities, including finding acceptable ways of introducing new expensive drugs.

Enhancing the rational use of new medicines across European health care systems

How do we maintain the ideals underlying socially funded and equal health services under demanding conditions of the twenty-first century? Expenditure on health care throughout Europe has been rising more rapidly than any other public service, and pharmaceutical expenditure more rapidly than other components of healthcare [1]. The reasons underlying this tendency are well known: demographic changes, rising patient expectations, stricter clinical targets, and expensive new technologies [2]. To what extent is such pressure compatible with the aim of financing a comprehensive and equitable health service in Europe that is largely free at the point of delivery? In addition, what can be done to address these pressures? A two-day meeting involving 33 leading health care professionals from nine European Union (EU) countries was recently convened in Stockholm to address these issues. A deliberate decision was made not to seek external funding in order to ensure a free exchange of ideas from independent academics, regulators, and clinicians. Each delegate is actively involved either in registration, reimbursement, formulary listing, and/ or enhancing the rational use of drugs in his or her country. The meeting was hosted by the Karolinska Institute and Stockholm County Council together with leaders from the ‘Mario Negri’ Institute of Pharmacological Research in Milan and the universities of Heidelberg, Liverpool, and Marseilles. The meeting identified that optimizing the use of new expensive technologies represented the major challenge faced by health care services throughout Europe, especially with pharmaceutical companies seeking to overcome lost revenues from patent expiry estimated at over

Adjusting Europe's drug regulation to public health needs

100 bn USD per year over the next 4 years [3]. Whereas increasing the proportion of health care expenditure allocated to drugs is not intrinsically regrettable, ongoing pressure reinforces the need to ensure optimum stewardship of national pharmaceutical expenditure. This was encapsulated in the agreed vision which was “to ensure robust systems are in place in Europe to enhance the rational use of drugs, including new, expensive drugs, to improve health.” The delegates believed these objectives could be achieved by collaborating and developing pan-European strategies to shared problems and pressures that can be adapted locally. Guidelines and incentives are seen as beneficial to enhance rational use in line with an approach that has became known as the “five E’s,” namely: Evaluation, Economics, Enforcement, Education, and Engineering. Rational use of new, expensive drugs would also be enhanced through obtaining greater transparency in the information provided by pharmaceutical companies to regulators and national reimbursement agencies [4, 5]. Ensuring a basic infrastrucEur J Clin Pharmacol (2008) 64:1137–1138 DOI 10.1007/s00228-008-0537-z

Orphan drug development is not taking off

The inauguration of the European Medicines Evaluation Agency (EMEA) 5 years ago, revolutionised the European pharmaceutical system. The new system saves member states of the European Union time and effort in assessing marketing authorisation applications, and ensures a homogeneous regulatory policy throughout the European Union. Pharmaceutical companies apply only once for marketing authorisations, extensions, and variations; thus they avoid the uncertainty caused in the past by different procedures and bureaucracies in the 15 member states. However, harmonisation is far from complete because prices and reimbursability of products are left to individual member states, which have different health systems. CPMP (Committee for Proprietary Medicinal Products), the scientific advisory committee, and EMEA’s technical and administrative staff have made the new system efficient and reliable: 126 products (98 active ingredients) have been positively assessed and released for marketing by the European Commission. EMEA’s merits are undisputed and its effect on the pharmaceutical area rightly acknowledged. However, some aspects of the system need to be reviewed to ensure that patients derive maximum advantage. Institutional location of EMEA EMEA is located in an industrial institution of the European Commission (initially called Directorate General [DG] III, now called DG Enterprise) despite the fact that its mission is “to promote the protection of human health . . . and of consumers of medicinal products”. 1 Public health should be the fundamental concern of EMEA because it is the final outcome of improved availability of medicines. The pharmaceutical industry aims to enlarge its market to maximise profits. Consumers, who are frequently anxious to have access to drugs even while they are still in an early stage of assessment, can be biased in assessing the merit of therapies. If public health issues were paramount, EMEA approval of new drugs would depend on their benefit to patients, and would be granted only for well defined indications after extensive research. Removal of EMEA from its industrial location would therefore indicate political willingness to think of patients as more important than the interests attached to the production of medicines.

How can research ethics committees protect patients better

Although, by definition, rare diseases involve few patients, there are so many – about 7000 (http://www.orpha.net/testor/cgi-bin/OTmain.php?&UserCell=publications) – that their epidemiological impact is impressive: 6–8% of the population is affected worldwide, with 30–40 million patients in the European Union (EU). This makes rare diseases a major public health issue [1]. However, the fragmented market means it is an area of little commercial interest for pharmaceutical companies, and the high price of orphan drugs tends to put them out of reach for the National Health Service [2].

Evidence-based clinical practice: Overview of threats to the validity of evidence and how to minimise them

The duties of research ethics committees are becoming increasingly difficult—what skills and knowledge do their members need to evaluate protocols that contain elements that are not in the patients interests?

Approvals of drugs with uncertain benefit–risk profiles in Europe

Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.

Potentiation by dazoxiben, a thromboxane synthetase inhibitor, of platelet aggregation inhibitory activity of a thromboxane receptor antagonist and of prostacyclin

PURPOSE This paper examines conditional approvals that allow the marketing of medicines with unsettled benefit-risk profiles in the European Union. METHODS We identified medicines that had received conditional approval from the European Medicines Agency in the period January 2006-June 2015. We searched the reasons and bases for approvals, the median time to address the specific obligations imposed in order to cover the information gap and allow regular authorisations, and their extent of fulfilment. RESULTS Of the 26 products conditionally authorised two were withdrawn for commercial reasons, ten were switched to regular approval, and 14 are still under conditional approval. Conditional approval was granted mainly to medicinal products intended for seriously debilitating disease or life-threatening disease. The median time to address the specific obligations was four years (range 0.2 to 7.7). There were delays or discrepancies in the fulfilment of these obligations in more than one third of the authorisation procedures. CONCLUSIONS In most cases there was limited evidence supporting the positive benefit-risk balance at the time of approval. Delays or discrepancies in the fulfilment of obligations allow medicinal products with unsettled benefit-risk profiles onto the market for several years. This should be taken into account when further early or step-wise licensing strategies are considered.

Europe’s opportunity to open up drug regulation

Dazoxiben, a thromboxane (Tx)-synthetase inhibitor, completely prevented platelet TxB2 synthesis, but not the platelet aggregation induced by arachidonic acid (AA) or ADP. It was also ineffective against platelet aggregation brought about by a prostaglandin (PG) endoperoxide analogue, which does not trigger platelet TxA2 synthesis. The association of dazoxiben with a Tx receptor antagonist or with PGI2 resulted in marked potentiation of the latter compounds as inhibitors of platelet aggregation induced by AA or ADP (second wave), but not by U-46619 (a stable analogue of prostaglandin endoperoxides). It therefore appears that inhibition of Tx synthesis does not modify the platelet response to aggregating stimuli but renders platelets more susceptible to inhibition induced by other compounds.