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Regional Variation

Terri Madison at Xcenda gives her views on how manufacturers can overcome the issues of regional variation and better predict non-routine risk minimisation requirements for new products at the point of regulatory authorisation

Although it’s been more than five years since the EMA established the EU RMP requirements, and a similar timeframe since the FDA established RiskMap followed by REMS requirements, manufacturers often still approach their application submissions with uncertainty as to whether additional risk minimisation activities beyond routine will be required. One factor contributing to this uncertainty is regional variation in both requirements and philosophical approach to risk management. Moreover, the question as to whether additional risk minimisation activities will be required is complicated by the fact that there are differences in country-specific regulations as well as in healthcare delivery systems. These differences not only infl uence the feasibility of implementing various types of risk minimisation approach across regions, but ultimately can infl uence whether a product will be authorised (or remain authorised) in a specific region. Together, these factors lead to uncertainty as to what regulators will require and prove to be the source of much deliberation both internally at manufacturers and externally with regulators.


US Approach

The US FDA defines risk management as an iterative process of:

  • Assessing a product’s risk-benefit balance
  • Developing and implementing tools to minimise its risk while preserving its benefits
  • Evaluating tool effectiveness and re-assessing the benefitrisk balance
  • Making adjustments, as appropriate, to the risk minimisation tools to further improve the benefit-risk balance

This lifecycle approach to risk management, where results of ongoing risk assessment iteratively inform risk minimisation activities, is described in the FDA’s risk management and REMS guidance documents and is governed by Section 505-1 of the Federal Food Drug and Cosmetic Act (FDCA) (1-4).

The regulatory framework and timeline for risk minimisation in the US is illustrated in Figure 1. The FDA released its RiskMap guidance in March 2005, defining risk minimisation as actions designed to minimise known risks of a product while preserving its benefits. The passage of the 2007 FDA Amendments Act (FDAAA) put legislation in place to provide the FDA with legal authority to require risk evaluation and mitigation strategies (REMS) for both authorised products and products submitted for marketing authorisation. With the passage of the FDAAA, for products without existing RiskMaps, REMS will be used instead of RiskMaps. Additionally, 16 of the products with approved RiskMaps were deemed to have in effect an approved REMS because their RiskMaps in place at the time the FDAAA went into effect had the more restrictive Elements to Assure Safe Use (ETASU) (5).

In the US, product labelling and routine pharmacovigilance reporting remain as the cornerstone of risk communication and risk minimisation for most authorised products. REMS are only required for a subset of products if the FDA determines that a REMS is required to ensure that the benefits of the product outweigh the risks. Components of a REMS can include any of the elements described in Table 1; an approved REMS can require different components in different combinations.

EU Approach

The regulatory framework for risk management in the EU is laid down in Article 8(3)(ia) of Directive 2001/83/EC, which requires inclusion of “a detailed description of the pharmacovigilance and, where appropriate, of the risk management system which the applicant will introduce”, and Article 9 (4) of Regulation (EC) No 726/2004, which states that for centrally authorised products, if the opinion is favourable, details of conditions or restrictions which should be imposed on the supply or use of the product, including conditions under which the product may be made available to patients, and recommended conditions or restrictions with regard to the safe and effective use of the product, should be included (7). EMA’s 2005 Guideline on Risk Management Systems is based on this regulatory framework. Volume 9A, issued in January 2007, provides instruction on all aspects of pharmacovigilance and risk management, and incorporates the 2005 risk management guidance.

The EMA defines a risk management system as “a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products including the assessment of the effectiveness of those interventions” (7). In contrast to the US, an EU-RMP is generally required with all applications for marketing authorisation. The EU-RMP is a two-part document, where Part 1 includes the safety specification and pharmacovigilance plan, and Part 2 evaluates the need for risk minimisation. In the EU-RMP guidelines, risk minimisation is defined as a set of activities used to reduce the probability of an adverse event occurring, or its severity should it occur (7). For Part 2, if any risk minimisation beyond routine safety reporting and product labeling is needed, then a risk minimisation plan should be included to describe the additional activities. Table 2 summarises methods for risk minimisation in the EU.

Approach Outside the US and EU

Requirements and associated legislation for risk management and risk minimisation continue to evolve in other regions of the world, with several countries now requiring submission of a local RMP or an RMP in EU RMP format.


This section is based on information from the FDA REMS website (8). From 1 January 2008 through to 31 December 2010, 40.8 per cent of all new molecules/new biologics approved by FDA were approved with a REMS requirement, where 80 per cent of new biologics required a REMS compared with only 30.4 per cent of new drugs requiring a REMS.

REMS are generally considered to fall into three basic tiers: with medication guide-only REMS as the least restrictive type; REMS with ETASU as the most restrictive type; and REMS with communication plans falling in the middle. Figure 2 shows trends in types of approved REMS from the time FDAAA went into effect until 1 March 2011. To account for all currently marketed products in the US with REMS that include ETASU, the percentages provided in Figure 2 include products still under a deemed REMS as of 1 March 2011. Until 1 March 2011, the majority of approved REMS (63.3 per cent) were the least restrictive medication guide-only type; only a minority of approved REMS (16 per cent) were the most restrictive types with ETASU.

In late February 2011, the FDA issued a new guidance to modify its approach regarding when medication guides will be required as part of a REMS (9). Since the enactment of the FDAAA, the FDA had considered any new medication guide (or safety-related changes made to existing medication guides) to be part of a REMS. The February 2011 guidance clarified the FDA’s authority to require a medication guide outside of a REMS, stating that, “In most cases, (the) FDA expects to include a medication guide as part of a REMS only when the REMS include elements to assure safe use” (9). As of 1 July 2011, 43 medication guide-only REMS have been released from their REMS requirement based on this guidance. This substantially affects trends in types of approved REMS; therefore, updated trends post-release of this guidance until 1 July 2011 are provided in Figure 3. As the FDA continues to work with marketing authorisation holders to release medication guide-only REMS from their REMS requirement, we can anticipate these proportions will continue to change, with higher proportions of REMS being in the communication plan or ETASU REMS.

Figure 4 shows trends in types of approved REMS, by the year of initial REMS approval, from the time REMS became effective until 1 July 2011. Temporal trends through 2011 show a clear increase in the proportion of REMS requiring communication plans. Temporal trends in REMS requiring ETASU are less clear and are also influenced by the total number of REMS approved in each calendar year. For example, in both 2008 and 2009, three products had an initial REMS with ETASU requirements. However, the total number of approved REMS in 2009 almost tripled from 2008, so the proportion of approved REMS with ETASU are very different. In 2010, although seven products had an initial REMS with ETASU, six of these products required REMS to mitigate class risks (four opioids and two erythropoiesis-stimulating agents). For 2011 year-to-date, six products have had an initial REMS requiring ETASU.


From 1 January 2008 through to 31 December 2010, 36.1 per cent of all new molecules/new biologics authorised by EMA required non-routine risk minimisation as a condition or restriction with regard to the safe and effective use of the product (10).

Figure 5 provides a summary of the non-routine risk minimisation requirements for new active substances, excluding vaccines, authorised by the EMA and posted on the EPAR website from 1 January 2008 through to 1 July 2011. In general, the majority of non-routine risk minimisation requirements were additional healthcare provider (HCP) education programmes beyond information included in the summary of product characteristics (SmPC). A small number of products also had a requirement for patientdirected risk communication beyond the patient information leaflet (PIL), usually either a patient information kit or a patient alert card. Few products required restrictive elements analogous to ETASU in the US. One important trend in the EU was a frequent requirement for additional non-routine pharmacovigilance requirements (for instance, post-authorisation safety study), even when no non-routine risk minimisation activities were required.


For the US, Section 505-1 of the FDCA lists the following factors to be considered in the FDA’s determination of a REMS and its required components (11):

  • Estimated size of the population likely to use the product
  • Seriousness of the disease or condition that the product is intended to treat
  • Expected benefit of the product for that disease or condition
  • Expected or actual duration of treatment with the product
  • Seriousness of any known or potential adverse events that may be related to the product and the background incidence of these events in the underlying population intended to use the product
  • Whether the product is a NME

In reviewing US REMS required to date, several trends emerge as likely predictors of FDA requiring a REMS (8). Since the majority of new biologics approved since 2008 (80 per cent) have had a REMS requirement at the time of initial approval, a new biologic is more likely to require a REMS. In addition, the majority of REMS required to date target the mitigation of risks that apply to an entire product class (for example, bisphosphonates and atypical fracture, long-acting beta agonists and increased risk of asthmarelated death) or are variations on a product class-level risk (for example, anti-epileptic drugs and suicidal thoughts or behaviour). Thus, one of the most reliable predictors of a new product having a REMS is if similar products with similar risks already have a REMS requirement.

The factors that the FDA uses to determine a REMS and its required components, in practice, are used in combination. For example, a product intended to treat a condition with a large patient population may be more likely to require ETASU if the product is administered in a less controlled setting or the risk is serious. For example, isotretinoin, which can be dispensed in a retail pharmacy setting, is selfadministered and has a teratogenic risk, has more restrictions than telavancin, which has a potential risk for adverse developmental outcomes if administered to pregnant women, but is dispensed and administered in a healthcare setting, and there is a smaller population with potential to use telavancin. In addition, benefit-risk plays a strong role in the FDA’s determination where, in general, products used to treat more severe underlying disease have been less likely to require a REMS with ETASU. Medications used to treat cancer illustrate this well, where despite substantial toxicities associated with many cancer treatments, less than five per cent of products ever required to have a REMS are cancerdirected treatments, and three of the eight REMS required for cancer-directed treatments have recently been released from their REMS requirement.

The EU appears to rely frequently on routine risk communication materials (PIL and SmPC) to communicate important risks, but as shown in Figure 5 (see page 93), EMA is trending to require non-routine risk communication strategies to supplement the routine materials more often than previously. From 2008 through 2010, with the US requiring a REMS for 40.8 per cent of new moleculesbiologics approved, and the EMA requiring non-routine risk minimisation for 36.1 per cent of new active substances authorised, the proportions of products approved with non-routine risk minimisation requirements overall are similar, although there are differences on a product-specific basis.


Regional variation in risk management requirements and feasibility constraints to implement certain risk minimisation measures in different regions lead to uncertainty for manufacturers in predicting risk minimisation requirements at the time of product authorisation. The level of uncertainty can be reduced through examining trends in risk minimisation requirements for several authorised products. By examining these trends, triggers that lead to requirements for nonroutine risk minimisation activities can be identified to help inform manufacturers in predicting non-routine risk minimisation requirements for a specific product.


  1. FDA, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Guidance for Industry: Development and Use of Risk Minimization Action Plans, 2005
  2. FDA, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, 2005
  3. FDA, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Guidance for Industry: Premarketing Risk Assessment, 2005
  4. FDA, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications, 2009
  5. Visit
  6. European Medicines Agency, Guideline on Risk Management Systems for Medicinal Products for Human Use (EMEA/ CHMP/96268/2005), 2005
  7. European Commission, Volume 9A of The Rules Governing Medicinal Products in the European Union, Guidelines on Pharmacovigilance for Medicinal Products for Human Use, 2008
  8. Visit PostmarketDrugSafetyInformationforPatientsandProviders/ ucm111350.htm
  9. FDA, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Guidance for Industry: Medication Guides – Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS), 2011
  10. Visit medicines/landing/epar_search.jsp&murl=menus/medicines/ medicines.jsp&mid=WC0b01ac058001d125
  11. Visit Legislation/FederalFoodDrugandCosmeticActFDCAct/ FDCActChapterVDrugsandDevices/ucm109090.htm

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Terri Madison leads the Epidemiology and Risk Management consulting practice at Xcenda. Terri received her PhD and MPH in Epidemiology from the University of Michigan, and was the recipient of a NIH predoctoral fellowship in Cancer Training and Prevention. With 25 years’ experience and an in-depth understanding of global safety regulations, Terri is an industry expert in epidemiology, drug safety, and risk management. Prior to joining Xcenda, she was the President of i3 Drug Safety, where she provided scientific and operational leadership for the pharmacoepidemiology and pharmacovigilance teams, and was also active in FDA-funded safety studies including the FDA’s Sentinel Initiative. She has been a presenter and panelist at various workshops and public forums on risk minimisation. Terri’s experience also includes several years at STATPROBE, Inc and Parke-Davis. Email:
Terri Madison
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