Report on the current status of the use of real-world data (RWD) and real-world evidence (RWE) in drug development and regulation.

Radically expanding use of real-world data (RWD) and real-world evidence (RWE) holds the potential to substantially impact drug development, pharmaceutical regulation, and payment within health care systems. Central to this is the reconfiguration of data gathering and transformation of data to information, which can be used as evidence for decision making. We discuss applications of this paradigm in the light of recent developments in both the United States and Europe on RWD and RWE.

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

BACKGROUND: Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. MATERIALS AND METHODS: We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). RESULTS: Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). CONCLUSION: Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. IMPLICATIONS FOR PRACTICE: Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies.

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.

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.

Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials.

BACKGROUND: Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. METHODS: We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHO's Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. FINDINGS: The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30.3% (95% CI 19.8-39.4, p<0.0001) against clinical malaria, 21.3% (8.2-32.5, p=0.002) against the risk of anaemia, 38.1% (12.5-56.2, p=0.007) against hospital admissions associated with malaria parasitaemia, and 22.9% (10.0-34.0, p=0.001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1.05, 95% CI 0.72-1.54, p=0.79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. INTERPRETATION: IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. FUNDING: Bill & Melinda Gates Foundation.

A Proposed Framework for a Globally Applicable Pragmatic Approach to Using Facilitated Regulatory Pathways.

BACKGROUND: As regulatory agencies come under increased pressure to review medicines of critical importance through efficient regulatory systems to provide equitable access, the benefits of using expedited review pathways are being explored. These facilitated regulatory pathways (FRPs) provide a variety of review strategies that can also expedite assessments. Stringent regulatory authorities (SRAs) use primary FRPs to accelerate development or to shorten review time. Some emerging national regulatory authorities can implement primary FRPs but are more likely to use secondary FRPs that rely on or recognize an SRA or reference agency decision, the World Health Organization Collaborative Prequalification of Medicines Programme, "altruistic" reviews, or collaborative work sharing. Despite their availability, there are no formal guidelines or consensus for the definition, basic elements, or best practices for FRPs. METHODS: Herein, we present a 4-step pragmatic approach to a framework designed to help agencies determine how best to use FRPs. Each step is based on characteristics identified through research, surveys, literature assessments, regulatory capacity categorization analyses, and practical experience. RESULTS: Step 1 assesses 4 domains of the environment preparedness, step 2 offers process criteria that should be in place to effectively use an FRP, step 3 tiers agencies through a self-assessment of readiness and capacity, and step 4 provides a pathway for agencies to determine the most relevant FRP for their use. Target timelines are proposed for FRPs. CONCLUSIONS: This framework represents the first endeavor to holistically address the multifaceted aspects that should be considered for the effective use of an FRP.

Regulatory Frameworks in Times of Uncertainty.

Patient and public expectations on access to new types of medicines has changed the role of the regulator in granting marketing authorizations. Whether current regulatory frameworks can accommodate further advances in biomedical science remains a challenge, but suggestions are made as to how this may be possible.

Overcoming the legal and regulatory barriers to drug repurposing.

Drug repurposing has been proposed as a strategy to develop new therapies that has fewer risks, lower costs and shorter timelines than developing completely new drugs. However, the potential of this strategy has not been as widely realized as hoped, in part owing to legal and regulatory barriers. Here, we highlight these barriers and consider how they could be overcome.

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.

Monitoring the safety of licensed medicines.

The withdrawal of the selective cyclooxygenase 2 inhibitor rofecoxib owing to cardiovascular side effects ignited debate about the need for major changes to current mechanisms for post-marketing surveillance (PMS) of drug safety. Here, we discuss the current mechanisms, whether they are being used appropriately, and consider the need for changes to regulatory systems.

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.