Virgilio Vinas., MD, PhD, MPH

UPDATES ON EMA-FDA PROCEDURES & GVP

EU RISK MANAGEMENT PLANS (RMPS)- US FDA ELEMENTS TO ENSURE SAFE USE (ETASUS)

Module VIII (PASS)- In April 2013 ( systematic literature review or a meta-analysis may be considered s PASS if their aims fulfil the criteria in the PASS definition; details of PASS conducted outside the EU should also be included in the EU PAS Register.

GVP Module X (Additional Monitoring) published in April 2013. MAH granted before 1 September 2013 which concern products subject to additional monitoring should have included the black symbol and in SmPC and PIL

Changes GVP Module VI (Management & reporting of Adverse reactions)- For non interventional studies with data collection directly from Health Care Professionals, non-academic sponsors should specify in the protocol any adverse events to be actively sought and reported. Death and fatal outcomes need to be actively collected, unless good justification (e.g. study with high mortality)

Actively valid adverse reactions should be reported. Serious and non serious, which are not actively sought should only be summarized in the interim or final study report

GVP Module XVI (Risk Minimization measures): selection of tools and effectiveness indicators

GVP Module XI (Public participation in pharmacovigilance) GVP Module XII (Continuous pharmacovigilance), ongoing benefit-risk evaluation,

regulatory action and planning of public communication.

EU RISK MANAGEMENT PLANS (RMPS)- US FDA ELEMENTS TO ENSURE SAFE USE (ETASUS)EMA GVP Practices Module XVI on Risk Minimization

Measures: Selection of tools and effectives indicators, discuss risk minimization measures in RMP, and covers the same things that the US FDA has in ETASUs, to use in conjunction with Module V on risk management systems.

Risk Minimization Plan include measures for public health interventions intended to prevent or reduce the occurrence of adverse reactions associated with exposure to medicine, or reduce their severity or impact on the patient should occur.

Goal of all routine and special measure is to optimize the safe and effective use of product throughout its life-cycle:Reducing AR burden – Optimize the benefits – Target appropriate patient population

The standard procedures for pharmacovigilance include the labelling, summary of product characteristics (SmPC) [EMA], package leaflet [FDA], package size and design and legal prescription status of the product

Each measure should be linked to specific safety concern in the RMP:

Rationale, proposed additional measures including objectives Description of measures, and tools that will be used Implementation plan, setting and timing or frequency of intervention, details target

audience). Evaluation plan, milestone for evaluating the effectiveness of the measured ( reduction

of the risk).Customize Risk Minimization Measures, in purpose, design, target

audience, to assure appropriate patient selection, can include educational programs, controlled access, and other measures.

Educational Programs, by teaching or training. In any format paper, audio, video, web, in person, avoiding promotional elements and aligned with SmPC (EMA), package leaflet (FDA)

Controlled Access Programs: Specific testing & examination Prescriber, dispenser & patient documenting their receipt and understanding of

information Systematic patient follow-up through enrolment in a patient registry Dispensing in registered & approved pharmacies.Pregnancy Prevention Programs (PPP), minimize pregnancy

when starting or during treatment with known or potential teratogenic effects, apply to females and males, where use would have a negative effect on pregnancy outcome:

Educational measures Controlled access to ensure pregnancy test is carried out and is negative Prescription limited to maximum 30 days supply Counseling in event inadvertent pregnancyDirect Health Care Professional Communication

Effectiveness measurement of risk minimization measure, to determine whether they are working and if not, why not. Should be qualitative but should include quantitative metrics:

Process itself (implementation going as planes) The impact on knowledge and behavior of target audience (health care

professionals and patients). Outcome (achieving objective)

Process indicators /metrics: Appropriateness of the tool for audience (language, pictures, diagrams) & assess. Assess clinical knowledge acquire from the tool, using survey methods. Assess clinical actions such as prescribing behavior.

Outcome indicators: Safety outcomes should me measure (incidence rates of adverse reactions in post

aproval safety study

Frequency before and after implementation Spontaneous reporting frequency are NOT acceptable as a rule for outcome

indicators.

EMA via PRAC will monitor RMPs, evaluating protocols and outcomes

PSURs/PBRERs and RMPs, effectiveness evaluation must be done:

Describe implemented risks minimization measures: objectives, selected process and outcome indicators

Analyze nature of the adverse reactions including severity and preventability Examine the delivery of the risk minimization measures in routine clinical

practice and deviation Include outcome indicators. Proposal for changes

SUMMARYThe EMA RMP and FDA ETASUs or minimization measures look very similar, the

application of the tools and measures can be consistent for both regions.Given the differences in medical practices in EU and USA, and the way products are

sold and distributed, some additional activities, specific for each region will be necessary.