Are the European Medicines Agency, US Food and Drug Administration, and Other International Regulators Talking to Each Other?

There is talk of regulatory collaboration worldwide to protect public health and allow patients timely access to medicines. Here, we present the reality of the collaboration between the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). This takes the form of near daily interactions, which may be less known outside of regulatory agencies. We present a review of what we call clusters, which involve the EMA, the FDA, and many other agencies under the umbrella of confidentiality arrangements. Through a survey of participants, we identified about 30 clusters of variable composition; these allow for the exchange of information and discussion among experts of applying regulatory science to common challenges in global drug development at every phase of its lifecycle and facilitate global medicines development.

A Comparison of EMA and FDA Decisions for New Drug Marketing Applications 2014-2016: Concordance, Discordance, and Why.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have robust scientific and technical collaborations. As a window to the impact of these activities we compared the agencies' decisions on drug marketing applications. Decisions were compared for 107 new drug applications with a regulatory outcome at both agencies in the period 2014-2016. Further analysis addressed individual applications for which the agencies had differing outcomes in terms of marketing approval, type of approval, and approved indication, including reasons underlying differences. The EMA and the FDA had high concordance (91-98%) in decisions on marketing approvals. Divergence in approval decisions, type of approval, and approved indication were primarily due to differences in agencies' conclusions about efficacy based on review of the same data or differing clinical data submitted to support the application. This high rate of concordance suggests that engagement and collaboration on regulatory science has a positive impact.

Regional Approaches to Expedited Drug Development and Review: Can Regulatory Harmonization Improve Outcomes?

Drug regulatory agencies around the world have implemented programs to expedite drug development and review for promising new products for serious diseases. These programs are all intended to minimize delays in patient access to innovative medicines, and have used broadly similar strategies to shorten drug development and review timelines. However, they differ in many key respects, and some stakeholders have suggested that these differences create unnecessary barriers in the development and approval process, possibly leading to delays in access. In collaboration with FDA, the Duke-Margolis Center for Health Policy convened an expert workshop to elicit feedback from a broad range of stakeholders as to whether a lack of harmonization across expedited programs is interfering with the efficient development of new products and, if so, to explore strategies for addressing these challenges. This report provides a summary of key themes and major findings from that discussion.

Can we ensure the safe use of known human teratogens?: The iPLEDGE test case.

Minimising the public health burden of isotretinoin-induced teratogenicity has been a challenge for 24 years, the duration of availability of isotretinoin in the US for the treatment of severe, recalcitrant nodular acne. Although the teratogenicity of this drug is well known and risk-management programmes had been implemented, preventable fetal exposures continued to occur, largely as a result of the lack of sufficient controls within the programmes themselves. The manufacturers of isotretinoin implemented a new risk-management programme, iPLEDGE, in March 2006. iPLEDGE is a comprehensive distribution system that includes mandatory registration of patients, healthcare providers, pharmacies, and wholesalers. It allows real-time linkage of pregnancy-test results for verification prior to the dispensing of isotretinoin. Although the challenges of implementing a closed distribution system for a very widely used medication have been extensive, the potential public health benefits from preventing fetal exposure to isotretinoin are substantial.

Pregnancy exposure registries.

Scientifically valid data on the safety of drug use during pregnancy are a significant public health need. Data are rarely available on the fetal effects of in utero exposure in human pregnancies, particularly when a drug is first marketed. Data from animal reproductive toxicology studies, which function as a screen for potential human teratogenicity, are usually all that is available in a product's labelling. For practising clinicians, translating known animal risks into an accurate assessment of teratogenic risks in their patients is very difficult, if not impossible. Without human data on the effects of in utero drug exposure, it is difficult for physicians and other healthcare providers (e.g. genetic counsellors) to adequately counsel patients about fetal risks. Therefore, a pregnant woman may decide to unnecessarily terminate a wanted pregnancy or forego needed drug therapy. In spite of the lack of data on the safety of drug use during human pregnancies, pregnant women are exposed to drugs either as prescribed therapy or inadvertently before pregnancy is known (over one-half of pregnancies are unplanned). Because little is known about the teratogenic potential of a drug in humans before marketing, post-marketing surveillance of drug use in pregnancy is critical to the detection of drug-induced fetal effects. The existing passive mechanism of spontaneous reporting of adverse drug effects is inadequate to routinely detect drug-induced fetal risks or lack of such risks. Therefore, post-marketing pregnancy exposure registries are being increasingly used to proactively monitor for major fetal effects and to describe margins of safety associated with drug exposure during pregnancy. However, differing methodological rigour has been applied to the development of pregnancy exposure registries. It is important that all pregnancy registries develop epidemiologically sound written study protocols a priori. It is only through the use of rigorous methodology and procedures that data from pregnancy exposure registries will withstand scientific scrutiny. Successful recruitment of an adequate number of exposed pregnancies, aggressive follow-up, and complete and accurate ascertainment of pregnancy outcome are critical attributes of a well-designed registry.

Risk management strategies in the Physicians' Desk Reference product labels for pregnancy category X drugs.

BACKGROUND: Drugs that carry a concern for teratogenicity are often classified as pregnancy category X in the drug label and contraindicated for use during pregnancy. Many drug labels can be found in the Physicians' Desk Reference (PDR), a widely used source of drug information by American clinicians and patients. OBJECTIVE: To review product labelling in the electronic PDR for the pregnancy category X products for pregnancy prevention risk management components in labelling. METHODS: The electronic version of the 2001 and 2002 PDR was searched for 'pregnancy category X' products using the full text search feature. All product labels identified were retrieved and reviewed for trade name, generic name, manufacturer and indication. Product labels were manually searched for any pregnancy prevention risk management strategies included in labelling. Those labels that had specific pregnancy prevention risk management strategies were further evaluated. RESULTS: One hundred and seventeen pregnancy category X products were obtained from 2249 products searched in the 2001 PDR database and 124 pregnancy category X products were obtained from the 2150 products in the 2002 PDR database. All pregnancy category X products identified were drug products. The label/package insert for each drug was reviewed to identify risk management strategies for pregnancy prevention. The majority of the labels include as the sole risk management strategy either a black box warning and/or a contraindication for use in women who are or may become pregnant. Only 13 drugs contained specific pregnancy prevention risk management strategies in the label directing the clinician and/or patient, e.g. frequency of pregnancy testing, number and type of contraception methods. Two drugs, bexarotene capsules and gel, were only included in the 2001 PDR. Three drugs, isotretinoin, acitretin, and thalidomide, have formal pregnancy prevention risk management programmes. CONCLUSION: This study demonstrates the varied risk management approaches in labelling for pregnancy prevention for pregnancy category X drugs. There is a need for consistency in the classification of pregnancy category X products and the pregnancy prevention risk management strategies utilised in the labelling for them.