Impact of Brexit on UK and EU Drug Regulation and Patient Access.

The chronology of the United Kingdom (UK) leaving the European Union (EU) is presented together with its implications for medicines regulation, including the move of the European Medicines Agency from London (UK) to Amsterdam (the Netherlands). The legal and political options for the UK and the EU are discussed, which at the time of writing (October 2018) are both uncertain. Of importance is the response of the pharmaceutical industry and the possible consequences for UK patients, including delays in access to innovative medicines and an increase in drug costs. Although there may be some possible advantages for UK medicines regulation, these will depend on the outcome of the ongoing negotiations.

After thalidomide - do we have the right balance between public health and intellectual property.

The current European regulatory and consumer protection legal framework is the legacy of Thalidomide. The disaster led to the introduction of systematic biological and clinical data to endorse the safety and efficacy of new medicines. The European Medicines Directive outlined the pre-clinical, clinical data and product information to evaluate an appropriate benefit. Risk profile of new medicines and also allowed innovative companies to extend patent protection and data/marketing exclusivity periods to compensate for the cost for research and development. However in recent years it has become apparent that the costs and time for research and development are becoming increasingly burdensome, particularly for new drugs with recently discovered mechanisms of action for cancers and neurodegenerative disorders. The costs of development and the commercial uncertainty of such products is reducing commercialisation of these medicines. There is now considerable debate in the regulatory community as to how this regulatory burden may be eased by making earlier review of benefit risk and hence earlier access to authorised medicines. The Courts are moving away from the wide definition of medicinal product to a more nuanced view of the biological and clinical therapeutic mechanisms to satisfy the 'functional' limb definition in the Directive. This may be a move away from the rigorous scientific methodology generated after thalidomide. We discuss the ethical and public health implications of this shift in policy and the implications for intellectual property mechanisms currently available to protect the commercial needs of companies.

The medico-legal aspects of prescribing vitamin D.

Vitamin D is a particularly important sterol hormone and its effects beyond bone are increasingly recognized. Over the last decade clinical interest has grown in vitamin D, with increased recognition of deficiency and hence increased prescribing of vitamin D products. However, the increased prescription of vitamin D has generally been met with unlicensed vitamin D products which potentially expose the patient to clinical risk. This review discusses the issues relating to the clinical use of unlicensed vitamin D products, safety concerns that may arise from this, as well as discussing the medico-legal responsibilities of the prescriber and dispenser.

Proposal for new European pharmaceutical legislation to permit access to custom-made anti-sense oligonucleotide medicinal products.

Current European pharmaceutical legislation is not adequate to meet advances in science and technologies that will lead to rapid development of custom-made medicines. Using existing legislation for custom-made medical devices as a template and anti-sense oligonucleotides as model medicinal products, we propose new European pharmaceutical legislation to permit timely access to custom-made anti-sense oligonucleotide medicinal products. The proposals may be more widely applicable to other medicinal products.

Challenges posed to the European pharmaceutical regulatory system by highly personalized medicines.

The European pharmaceutical regulatory system has not yet been challenged by issues related to highly personalized medicines such as those to be found with active substances that affect RNA biochemistry. We review the current status of RNA-based pharmacology and present three possible case histories. The implications for the European pharmaceutical regulatory system are discussed.

The Imperfect Intellectual Bridge Between a Master Medicinal Product and Its Associated Custom-Made Medicinal Products.

To obtain a license to be placed on the marketplace, a medicinal product must be accompanied by data on quality and data from preclinical studies and studies of clinical safety and efficacy. At the time of first production, a custom-made medicinal product will have data on quality but will not be accompanied by data from preclinical studies or from studies of clinical safety and efficacy. To span the gap in data, an "imperfect intellectual bridge" between data for a custom-made medicinal product and data for its master medicinal product is described. The imperfect intellectual bridge will allow the custom-made medicinal product to draw on data associated with its master medicinal product. In time, it may be possible for a custom-made medicinal product to transfer to an independent license after collection of data on clinical safety and efficacy by means of a pharmacovigilance exercise.

Symmetrical analysis of risk-benefit.

To quantify the value of a medical therapy the benefits are weighed against the risks. Effectiveness is defined by objective evidence from predefined endpoints. This benefit is offset against the disadvantage of adverse events. The safety assessment is usually a subjective summary of concerns that can often be neither confirmed nor dismissed. But sometimes a clinical database is so large that a parameter common to both efficacy and safety can be quantified with reasonable certainty: myocardial infarction (MI) is used here as an example. Recently the Food and Drug Administration (FDA) proposed set limits for the incidence of MI as a safety threshold for diabetes treatment. Setting a threshold before something is considered as a safety concern opens the possibility of setting a threshold for clinically important efficacy. When a parameter is common to both safety and efficacy, then logically a unit change in either direction should be of equal weight in the risk and benefit analysis. For example, a doubling in the incidence of myocardial infarction as a safety signal should be given equal weight to the halving of the incidence of myocardial infarction as an efficacy signal. Similarly, if FDA guidance suggests that a less than a 30% increase in the incidence of MI as a safety parameter is considered acceptable, for example for diabetes treatment, when there is no other major toxicity, this opens a debate about a possible inverse threshold for clinical benefit for drugs that reduce a risk factor, such as antihypertensives.

The European Medicines Agency review of eltrombopag (Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

On 11(th) March 2010, the European Commission issued a marketing authorization valid throughout the European Union for Revolade for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura. Revolade is an orphan medicinal product indicated for splenectomized patients with immune (idiopathic) thrombocytopenic purpura who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) and as second-line treatment for non-splenectomized patients where surgery is contraindicated. The active substance of Revolade is eltrombopag (ATC code B02BX05). Eltrombopag increases platelet production through activation of the thrombopoietin receptor. The recommended oral dose is 50 mg once daily to achieve and maintain a platelet count of the 50×10(9)/L or more necessary to reduce or prevent the risk of bleeding. The benefit of Revolade is a durable response in maintaining platelet levels. The most common side effects include headache, nausea, hepatobiliary toxicity, diarrhea, fatigue, paresthesia, constipation, rash, pruritus, cataract, arthralgia and myalgia. The decision to grant the marketing authorization was based on the favorable recommendation of the Committee for Medicinal Products for Human Use of the European Medicines Agency. The objective of this paper is to describe the data submitted to the European Medicines Agency and to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (www.ema.europa.eu).