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.

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.

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.

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.

FDA Facilitated Regulatory Pathways: Visualizing Their Characteristics, Development, and Authorization Timelines.

The US Food and Drug Administration (FDA) has four facilitated regulatory pathways (FRPs): Fast Track (FT), Breakthrough Therapy (BTD), Priority Review (PR), and Accelerated Approval (AA). Only PR specifies an expedited review timeline (6 months). We sought to determine to what extent the combination of two or more FRPs influenced development and approval times. We developed a "metro map" to illustrate FRP elements and their influence on review times. We assessed 125 new active substances (approved January 2013 to December 2015) 74 of which used one or more FRPs. For these 74, development times ranged from 1,458 (BTD + PR + AA) to 3,515 days (PR). PR alone had a median approval time of 242 days. The most common combination was FT + PR (median approval 292 days, n = 21). The fastest approval times were for PR + FT + BTD + AA (145 days) and PR + BTD + AA (166 days). Our findings support the combination of FRPs for shortening development and review times beyond that provided by PR alone.

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.

Poor medication adherence in clinical trials: consequences and solutions.

Poor adherence to medicines in clinical trials can undermine the value of the trials; for example, by compromising estimates of the benefits and risks of a medicine. In this article, we highlight such consequences and also discuss approaches to tackle this problem.

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.

Accelerating access to new medicines: Current status of facilitated regulatory pathways used by emerging regulatory authorities.

OBJECTIVES: We assessed the characteristics of currently implemented expedited (facilitated) regulatory pathways (FRPs) used by national regulatory authorities (NRAs) in emerging economies to speed access to important new medicines. METHODS: We identified NRAs with FRPs through Thomson Reuters Cortellis Regulatory Intelligence and through agency Websites. We developed a list of 27 FRP characteristics. We categorised characteristics as procedural or substantive and based them on five sequential regulatory activities. FINDINGS: We assessed 29 countries with 33 FRPs. The regions with the characteristics described most extensively by their FRPs were the Middle East/North Africa and Eastern Europe. The Sub-Saharan African region included the FRPs that were least specific in describing characteristics. Overall, FRPs presented at least twice as many procedural as substantive characteristics. CONCLUSIONS: We observed diversity by region in FRP characteristics, suggesting a role for further engagement with emerging NRAs in their design and implementation. Common processes could advance regulatory alignment initiatives and help the WHO inform the development of novel, globally aligned accelerated development and regulatory pathways for products that fulfil serious unmet public health needs.Journal of Public Health Policy advance online publication, 10 March 2016; doi:10.1057/jphp.2016.8.

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.

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 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.