Risk management plan

A STUDY ON REGULATORY REQUIREMENTS OF RISK
MANAGEMENT PLAN FOR PHARMACEUTICALS IN
EUROPE, US AND BRAZIL
Prepared By:
Ravindra Trivedi
Enroll No:142270815008
Guided By:
Mr. Darshil Shah
Assistant Professor
L J INSTITUTE OF PHARMACY, AHMEDABAD
Introduction to Dissertation
M.Pharm (QARA) Sem-3
on
Enroll no:142270815008 L J Institute of Pharmacy,Ahmedebad

CONTENTS
2
Pharmacovigilance
History of Pharmacovigilance
Need of Pharmacovigilance
Risk Management
Benefit /Risk profile of drug
Risk Management Plan
Need of Risk Management Plan
Aim of Risk Management Plan
Objective of Risk Management Plan
Enroll no:142270815008 L J Institute of Pharmacy,Ahmedebad

CONT..
Risk Management Plan In Europe
Risk Management Plan In US
Risk Management Plan In Brazil
Review of Literature
Patent Search & Analysis Report
Enroll no:142270815008 L J Institute of Pharmacy,Ahmedebad 3

CONT..
Rationale of Work
Aim & Objective of Work
Plan of Work
References
4Enroll no:142270815008 L J Institute of Pharmacy,Ahmedebad

PHARMACOVIGILANCE[1-3]
According to World Health organization Pharmacovigilance means The
science and activities relating to the detection, evaluation, understanding
and prevention of adverse drug reactions or any other drug-related
problems.

HISTORY OF PHARMACOVIGILANCE[4]

NEED OF PHARMACOVIGILANCE[5-6]
• It is widely accepted that clinical development of medicines is
a complex process which require huge amount of time for its
completion.
• Once a drug is marketed, it leaves the secure and protected
scientific environment of clinical trials and is free for
consumption by the general public.
• At this point, most medicines will only have been tested for
short-term safety and efficacy on a limited number of carefully
selected individuals.

CONT..
• Hence, need of Pharmacovigilance arises which include,
securing the early detection of new adverse reactions or
patients subgroups of exceptional sensitivity; and introducing
certain measures in order to manage such risks.
• Moreover, it is essential that new and medically still evolving
treatments are monitored for their effectiveness and safety
under real-life conditions after being marketed.

RISK MANAGEMENT[7]
• Risk management in general is a proactive approach to
assessing and reducing risks.
RISK MANAGEMENT = RISK ASSESSMENT + RISK MINIMIZATION

CONT..
• Risk/ benefit profile of drug:
When drug is marketed it may be used in patient population
that were not studied during clinical trials and a different set of
warnings, precaution or contradictions for the product’s
labeling may be necessary in order to maintain positive risk/
benefit profile in all known population.

CONT..
• Other key activities with in the area of risk management are
Risk Management Plan and aggregate repot such as PSUR,
PBER and The DSUR.

RISK MANAGEMENT PLAN[8-10]
• A Risk Management Plan (RMP) is a documented plan that
describes the risks (adverse drug reactions and potential
adverse reactions) associated with the use of a drug and how
they are being handled (warning on drug label or on packet
inserts of possible side effects which if observed should cause
the patient to inform/see his physician and/or pharmacist
and/or the manufacturer of the drug)

CONT..
• Risk management activities include in risk management plan
fall into two categories. Routine activities- which would
generally be conducted for any medicine at the same stage of
development where no special safety concerns have arisen.
Additional activities- designed to address identified safety
concerns.

NEED OF RISK MANAGEMENT PLAN
At the time of authorization, information on the safety of a
medicine is relatively limited. This is due to the limitations
of clinical trials, including:
 relatively small numbers of subjects in clinical trials
compared with the intended treatment population
 restricted population in terms of age, gender or ethnicity

CONT..
 Restricted co morbidity
 Restricted co medication
 Restricted conditions of use
 Relatively short duration of exposure and follow-up
 Statistical problems associated with assessing many
different outcomes

AIM OF RISK MANAGEMENT PLAN
• The overall aim of risk management is to ensure that the
benefits of a particular medicinal product exceed the risks by
the greatest achievable margin for the individual patient and
for the target population as a whole.

OBJECTIVE OF RISK MANAGEMENT PLAN
• Identify or characterize the safety profile of the medicinal
product(s) concerned;
• indicate how to characterize further the safety profile of the
medicinal product(s) concerned;
• Document measures to prevent or minimize the risks
associated with the medicinal product including an assessment
of the effectiveness of those interventions;
• Document post-authorization obligations that have been
imposed as a condition of the marketing authorization

RISK MANAGEMENT PLAN IN EUROPE[11-12]
• In the EU, the concept of a risk management plan was
formally crystallized in an amendment to Directive
2001/83/EC on the Community code relating to medicinal
products for human use (Code for Human Medicines
Directive) by Directive 2004/27/EC on the Community code
relating to medicinal products for human use.
• In Europe, Risk Management Plans (RMPs) are routinely
required by EMA as part of the medicine approval process.
• The Module V of Pharmacovigilance Describes about the Risk
Management Plan.

CONTENTS OF EU RMP
PART I PRODUCT OVERVIEW
PART II SAFETY SPECIFICATION
PART III PHARMACOVIGILANCE PLAN
PART IV PLAN OF POST AUTHORIZATION EFFICACY STUDY
PART V RISK MINIMIZATION MEASURE
PART VI SUMMARY OF RISK MANAGEMENT PLAN
PARTS OF RISK MANAGEMENT PLAN

US RISK EVALUATION AND MITIGATION
STRATEGY[13-14]
• The Risk Evaluation and mitigation strategy is the risk
management plan for the US.
• The FDAAA (Food and Drug Administration Amendments
Act) of September 27, 2007 gave FDA the authority to require
a REMS (Risk Evaluation and Mitigation Strategy) from
manufacturers to ensure that the benefits of a drug or
biological product outweigh its risks.

ELEMENTS OF REMS
1. Medication Guides
2. Elements to Assure Safe Use (ETASU)
3. Communication Plan
4. Implementation System

BRAZIL RISK MANAGEMENT PLAN[15]
• The Agência Nacional de Vigilância Sanitária (ANVISA) is
the regulatory authority in Brazil. It has published a regulatory
guide to pharmacovigilance plans and risk minimization plans
in English (ANVISA, 2009a). This guidance was developed
based on the ICH E2E, EMA Volume 9A and FDA Risk MAP
guidelines, as well as the relevant legal requirements defined
in Articles 11 and 12 of Resolution RDC 04/2009.

PARTS OF BRAZIL RMP
1. Pharmacovigilance Plan
2. Risk Minimization Plan

LITERATURE REVIEW
o Thijs J. Giezen et.al , “Evaluation of Post-Authorization Safety Studies in the First
Cohort of EU Risk Management Plans at Time of Regulatory Approval”, 2009
EU Risk Management Plan (EU-RMP) has had to be submitted as part of a marketing
application for all new chemical entities in the EU. In the EU-RMP, the safety profile of the
medicine has to be described and pharmacovigilance activities should be proposed to study
further safety concerns during use of the drug in the real-world setting.
o Serena Frau et.al, “Risk Management Plans: are they a tool for improving drug
safety?” , 2010
Risk Management Plans could bring added value to Pharmacovigilance provided that the
main safety concerns are not deferred until the post-marketing phase that additional
Pharmacovigilance activities are adequate for the proposed safety concerns and that post-
marketing studies become mandatory for marketing authorization holders.
o Pfizer, “What Is a Risk Management Plan?” , 2011
Pharmaceutical companies recognizing that clinical studies do not necessarily represent
real-world experience often designed Risk Management Plans in the pre-approval stages of
developing new medicines and have included them in submissions for approval

CONT..
o Zomerdijk IM et.al, “Risk minimization activities of centrally authorized products in the
EU: a descriptive study” ,2012
New legislation on risk management, which came into force in November 2005, an EU Risk
Management Plan (EU-RMP), is a required part of the authorization dossier of innovative
drugs licensed in the EU. The EU-RMP can include additional risk minimization activities
(RMAs) to strengthen the benefit-risk balance of a drug.
o Steven Gabardi, “Understanding Risk Evaluation and Mitigation Strategies in Organ
Transplantation”, 2012
The United States Food and Drug Administration (FDA) Amendments Act of 2007 mandated
that Risk Evaluation and Mitigation Strategies (REMS) be required of manufacturers. These
REMS are strategies implemented to manage known or potential risks associated with drugs
and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product,
including once the product becomes available as generic

CONT..
o Nicholson S et.al, “Pharmaceutical industry perspective on risk evaluation and
mitigation strategies: manufacturer take heed”, 2012
Enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA)
authorized the FDA to require manufacturers to submit Risk Evaluation and Mitigation
Strategy (REMS) when it was deemed necessary to ensure that a drug's benefit outweigh its
risk.
o Stella C. F. et.al “Benefit Risk Management Plans?” , 2012
A medicinal product is authorized on the basis that in the specified indication(s), at the time
of authorization, the benefit–risk balance is positive for the target population. risk
management plan describing the risk management system which the applicant will introduce
for the medicinal product concerned, together with a summary.
o Stephen J. Mayall et.al , “Development risk management plans” ,2014
The key Pharmacovigilance documents during clinical development are the DRMP and the
DSUR. The DRMP should document the risks of a product and plans to address them, which
comprise developmental PV and/or risk minimization activities. It is usually initially
developed early in clinical development and then updated iteratively during the clinical trial
Programme, before evolving into an RMP suitable for filing.

CONT…
o Lisa Chamberlain James et.al “Risk management plans –New challenges for a new
era”2014
The risk management plan (RMP) is currently a hot topic and the focus of much discussion
in industry due to the recent overhaul of the RMP guidance template. The complexity of the
new RMP has introduced many challenges in preparing a high quality document compliant
with all requirements
o Garlapati S et.al, “Risk Management Plan Its Importance and Emphasys on
Pharmacovigilance Activities”, 2015
Risk management plan (RMP) is the complete description of risk management system.
Main aim of RMP is to ensure safety of the patient using the drug. Pharmacovigilance and
Risk management plan are life time processes they do not stop once a drug released or well
established in the market for any number of years, nor when a patent simply dies

PATENT SEARCH ANALYSIS REPORT
SR
NO
PATENT
APPLICATION
NUMBER
TITLE OF PATENT
1 US 8,626,529 B1 System and method for identifying risk evaluation and
mitigation strategy compliance
2 US7306562 B1 Medical risk assessment method and program product
3 EP 1 760 616 A2 Method and apparatus for collecting patient data for risk
management
4 US 8,595,029 B2 Methods for managing infection risk incident to surgical
procedures in health care provider environments
5 US 20060281997 A1 Arrythmogenic risk management tools and
methods of use

PSAR SUMMARY
• First patent gives a description about determination of whether
the risk evaluation and mitigation strategy condition is
associated with the product.
• Second patent give details about that medical risk assessment
method and computer programme product is resident on
computer or hand held device and that allows physician to
determine best strategy for primary and secondary
cardiovascular disease prevention.
• Thirds paten gives information about steps of identifying
parameter, searching database to identify member of
population appropriate for population, group consisting
medication, medical procedure and population of patient
receiving, being treated according to, and or using one of the
group.

CONT..
• Fourth patent provides details about method for managing
occurrence or surgical site infection incident to surgical
procedure, the method comprising of identifying a plurality of
stage operative care, identifying one or more points of care
within each identified stages of operative care.
• Fifth patent gives idea about to identifying and managing
cardiac Arrythmogenic risk associated with prolongation and
dispersion of ventricular repolarization, torsadogenic risks and
QT prolongation risk.

CONT..
• From the study of above patents, it gives ideas about the
method of risk management but none of the above patent gives
ideas about regulation of risk management plan in different
countries So Dissertation topic To study the regulatory
requirement of risk management plan for pharmaceuticals in
Different countries is novel and necessary.

RATIONALE OF WORK
• Every Effective Medicines are associated with Risk
• Due to strict Medicinal Regulation throughout the life
cycle of Product, Pharmaceutical Companies have to
provide evidence that product is effective ,safe and out
of risk.

CONT..
So, now a days Pharmaceutical companies as well as regulatory
authorities have placed increasing emphasis how to detect, manage, and
communicate risk, as not everything is known about the safety of newly
approved product because clinical trial is not able to detect rare drug
induced adverse event at the time of approval.
Different countries have different Risk Management Plan and it is
require by regulatory authorities to submit risk management plan along
with dossier for marketing authorization.

• Regulatory Authorities require submitting certain applications
(applicants of NDAs, ANDAs and BLAs) along with Risk
Management Plan as core dossier elements.
• Submission of RMP can lead to a faster assessment by the
regulatory authority and potentially will accelerate the overall
approval process & it will beneficial for Pharmaceutical
companies to apply faster for approval of Drug.
CONT..

AIM OF WORK
• To study regulatory requirements of risk management plan for
pharmaceuticals in Europe, US and Brazil.

OBJECTIVE OF WORK
• To Study regulation of risk management plan for
Pharmaceuticals.
Pharmaceuticals in Europe.
Pharmaceuticals in US.

CONT..
Pharmaceuticals in Brazil.
• Comparison of Regulation of Risk Management Plan for
Pharmaceuticals in Europe, US and Brazil.

PLAN OF WORK
Study regulatory of risk management plan for pharmaceuticals
in Europe, US and Brazil
Literature Review
Comparison of Regulatory requirement of risk management
plan for pharmaceuticals for risk management plan in Europe,
US and Brazil.
Compile the all guidance data and document
Analyze the document

PAPER PUBLICATION
• Journal:
Journal of global trends in pharmaceutical science
• Title:
Pharmaceutical Risk management Plan: A Tool for
Pharmaceutical Industry
• Author:
Ravindra Trivedi, Darshil Shah*, Dr. Dilip Maheshwari
• Publication:
JGTPS, 2015, vol. 6(3): 2789 - 2793

REFERENCES
1. Mann RD and Andrews EB. Pharmacovigilance; 2nd Edn; John Wiley & Sons Ltd,
England,2007, pp 3-5
2. Rohilla A et.al, “Pharmacovigilance: An Overview” IJPBA.2012,3(6),1342-1345
3. Tragulpiankit P et.al, “Pharmacovigilance: An Overview.” MUJPS. 2011, 38(1-2),
1-7
4. Fentel Bara et.al. “The thalidomide tragedy: lessons for drug safety and
regulation” , 2010,
https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-
regulation,
5. WHO, “Need of Pharmacovigilance” , November 2009,
http://www.who.int/hiv/topics/pharmacovigilance/2a_why_pv.pdf
6. Rohilla A et.al, “Pharmacovigilance: Needs and Objectives.” JAPER.2014, 2(4),
201-205.
7. Vargo JJ, “Risk Management in Medicine: A Primer”
http://www.cwru.edu/med/epidbio/mphp439/Risk_Management.htm

CONT..
8. Pfizer, “Risk management plan” , October 2011
https://www.pfizer.com/files/health/medicine_safety/22_What_is_a_Risk_Manage
ment_Plan.pdf
9. Eli Lilly, “Risk management plan”
http://www.lilly.com/products/patient-safety/lillys-role/risk
10. Hpra, “Risk ManagementPlan”,
http://www.hpra.ie/homepage/medicines/regulatory
information/pharmacovigilance-and post authorization-safety/risk-management
plans-(rmps)
11. EMEA, “Risk management plan” , November 2012
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/
document_listing_000360.jsp
12 EMEA, “Guideline on good Pharmacovigilance practices (GVP) Module V – Risk
management systems”,April 2014,
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/20
12/06/WC500129134.pdf

CONT..
13. Paragnorx, “Risk Evaluation and Mitigation Strategies (REMS) - A Brief History”
,September 2009 ,
http://www.paragonrx.com/rems-hub/rems-history
14. USFDA, “A Brief Overview of Risk Evaluation & Mitigation Strategies”
http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM328784.pdf
15. ANVISA, “Regulatory Guide - Anvisa Pharmacovigilance Plan and Risk
Minimization Plan PVP/RMP” , August 2009,
http://portal.anvisa.gov.br/wps/wcm/connect/2546be8047458cdb95fcd53fbc4c673
5/Pharmacovigilance_Plan_and_Risk_Minimization_Plan.pdf?MOD=AJPERES

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