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.

Accelerated approval of medicines: fit for purpose?

The uptake of a new medicine represents a balance between benefit-risk assessment and value considerations. In the case of products approved via accelerated pathways, the increased uncertainty adds to the challenge. Here, we suggest solutions so that regulators, companies, payers and patients can align around management of the uncertainties and expectations.

Factors related to drug approvals: predictors of outcome?

There is growing interest in characterising factors associated with positive regulatory outcomes for drug marketing authorisations. We assessed empirical studies published over the past 15 years seeking to identify predictive factors. Factors were classified to one of four 'factor clusters': evidentiary support; product or indication characteristics; company experience or strategy; social and regulatory factors. We observed a heterogeneous mix of technical factors (e.g., study designs, clinical evidence of efficacy) and less studied social factors (e.g., company-regulator interactions). We confirmed factors known to be of relevance to drug approval decisions (imperative) and a cohort of less understood (compensatory) social factors. Having robust supportive clinical evidence, addressing rare or serious illness, following scientific advice and prior company experience were associated with positive outcomes, which illustrated the multifactorial nature of regulatory decision making and factors need to be considered holistically while having varying, context-dependent importance.

Precision medicine and the changing role of regulatory agencies.

The growth of precision medicine presents challenges for the regulators of medicines, related to aspects that include the basis of evidence generation, patient involvement in the regulatory process, cost of new medicines and the need for new regulatory models. It also raises questions about the tolerance of risk, especially with early interventions for life-threatening diseases.

The burden of adverse drug events.

Drug safety should be considered as part of the balance between benefit and risk, and represents a burden to the patient, the healthcare professional, the regulator and industry. Each of these has a different view on adverse drug reactions and these are discussed in this article.

New horizons in pharmaceutical regulation.

A life cycle approach to pharmaceutical regulation, in which the benefit-risk balance of new drugs continues to be robustly assessed following market approval, is emerging in both the United States and Europe.

Development and delivery of clinical pharmacology in regulatory agencies.

Medicines regulation is based on a foundation of science, policy and judgement. It operates within several frameworks (scientific, legal and public health), which are interdependent. While safety, quality and efficacy remain the criteria by which medicines are assessed, the benefit-to-harm balance for any medicine or medical device is of paramount importance. While the regulator was hitherto the gatekeeper who allowed a medicine on to the market, payers now require, in addition, assessment of cost and clinical effectiveness before use. As regulatory frameworks develop, several changes will occur, as follows: (i) formal benefit-harm assessment will become an integral part of submission for marketing authorizations; (ii) there will be greater use of surveillance for adverse reactions to new medicines using methods other than voluntary reporting; (iii) risk management plans will become benefit-risk management plans; (iv) life-saving medicines will be approved earlier; and (v) regulation and health technology assessment will take place simultaneously. Clinical pharmacologists will play important roles in these developments.

Pharmacogenomics: a new clinical or regulatory paradigm? European experiences of pharmacogenomics in drug regulation and regulatory initiatives.

Are regulatory agencies and processes up to speed? This is an often asked question. Recent advances in science and the improved knowledge of the human genome have a considerable influence on drug development and their impact on the regulatory aspect is also significant for several reasons, including changing stakeholder expectations and treatment paradigms. One of the challenges faced by the regulators is the need to adapt regulatory processes to accommodate the newer methodologies and techniques while ensuring that the biomarkers, tests and/or diagnostics, and the clinical trials are appropriate and fit for purpose. The change in emphasis in pharmacological treatment from a phenotype-based approach to newer methods is attractive but is it ready for universal adoption? This paper details some of the regulatory responses to the developments in this area.

New approaches to drug safety: a pharmacovigilance tool kit.

The importance of pharmacovigilance - the ongoing assessment of the safety of a marketed medicine - has been increasingly appreciated in recent years, owing in part to high-profile safety issues with widely used drugs. In response, strategies to improve the collection, integration and analysis of data related to post-marketing drug safety are being initiated or enhanced. In this article, we summarize the key tools that are available for pharmacovigilance, discuss which might be the most appropriate to use in different situations and consider the future directions of the field.

Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma.

Drug regulatory agencies are increasingly pressed by the challenge of finding the appropriate balance between the need for rapid access to new drugs and the need to ensure comprehensive data on their benefits and risks. This dilemma is not new, but has been made more prominent by recent high-profile drug withdrawals and conflicting demands, including the need to improve the efficiency of drug development on one hand, and the need to avoid exposing patients to unnecessary risks or possibly ineffective treatments on the other. Here, we summarize the current demands by stakeholders and the scientific and regulatory issues at stake, describe existing and emerging regulatory approaches, and speculate on future directions, such as evolution of the current regulatory model from a one-off marketing authorization to a life-cycle approach.

Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients.

OBJECTIVE: To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. DESIGN: Prospective observational study. SETTING: Two large general hospitals in Merseyside, England. PARTICIPANTS: 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. MAIN OUTCOME MEASURES: Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. RESULTS: There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is 466m pounds sterling (706m Euros, 847m dollars). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. CONCLUSION: The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.