INTERNAL PROJECT OF CLRA 695

RISK MINIMIZATION STRATAGIES IN THE USA, EU, JAPAN: HOW DEVELOPING

COUNTRIES MAY BENEFIT

SUBMITTED

TO

DR. IRWIN G. MARTIN PhD

COLLEGE OF HEALTH AND HUMAN SERVICES

EASTERN MICHIGAN UNIVERSITY

IN THE PARTIAL FULFILLMENT OF THE DEGREE

OF

MASTERS IN CLINICAL RESEARCH ADMINISTRATION

BY

UDAY K SINGATHI

(E00946891)
 DEDICATION

This research is completely dedicated to my parents, who gave me much support and

encouragement during the course of my studies. My life in the USA could never have been

possible without their love, affection, and support. I deeply express my love to my mother, Mrs.

Premalatha Prabhakar, for her unending support and motivation during tough times. I am

indebted to my brother, Mr. Rajesh Singathi, for his strong belief and hope in me and providing

me the necessary assistance in all ways. I would also thank my friends and colleagues (Priyanka

Tumuluru, Sunisha Chalasani, and Srikanth Maddali) who encouraged me during my stay at

Eastern.

1
 ACKNOWLEDGEMENTS

I would like to express my deep gratitude to my mentor Dr. Irwin G Martin for his

endless support, confidence, and the innovative thoughts throughout my master’s program.

I would like to thank Dr. Stephen Sonstein, our academic advisor, for his support

throughout my study at Eastern.

I would like to thank the teaching and non-teaching staff of College of Health and

Human Services especially, for their timely help during my learning experience at Eastern.

Also, I would like to thank the EMU Graduate School for providing me academic support.

2
 ABSTRACT

Risk management strategies are the most essential elements for the drug safety profile.

Developed countries like the USA, Europe, Canada and Japan are strengthening and updating

their risk management plan every now and then. These countries have a systematic and well

developed process of preventing drug risks in their respective markets. Developing countries like

India, Pakistan, Sri Lanka and Bangladesh need to work on the improvement of their risk

management processes. The risk management strategies in these countries are not as stringent

and organized as the developed countries. An informal survey was conducted in rural parts in

India to know the knowledge of risk management and drug risks among the pharmacists and

patients. The observations of the survey have been described in detail and suggestions to

improve the risk management have been proposed for developing counties and India in specific.

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 TABLE OF CONTENTS

DEDICATION .....................................................................................................................1

ACKNOWLEDGEMENTS .................................................................................................2

ABSTRACT.........................................................................................................................3

LIST OF FIGURES .............................................................................................................6

1. INTRODUCTION ...........................................................................................................7

2. BACKGROUND ...........................................................................................................10

2.1 Early Risk Management Strategy ..........................................................................10

3. METHODS ....................................................................................................................12

4. RESULTS ......................................................................................................................14

4.1 Summary of Risk Management Strategies in developed countries .......................14

4.1.1 US FDA .........................................................................................................14

4.1.1.1RiskMAPs ..............................................................................................15

4.1.1.2 Risk Evaluation and Mitigation Strategy (REMS) ...............................15

4.1.1.3 WHEN IS A REMS REQUIRED? .......................................................16

4.1.1.4 Different elements of REMS ................................................................16

4.1.1.4a Medication Guide .........................................................................17

4.1.1.4b Communication Plan....................................................................18

4.1.1.4c Elements To Assure Safe Use ......................................................18

4.1.1.4d Implementation Systems ..............................................................19

4.1.1.4e Timetable for the submission of assessments ..............................19

4.1.2 European Medical Agency (EMEA) ..............................................................19

4.1.2.1 Overview of EU-RMP Structure...........................................................20

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 4.1.3 Pharmaceutical and Medical Devices Agency (PMDA) ...............................23

4.1.3.1 Risk Minimization Plan ........................................................................24

4.1.3.2 Pharmacovigilance Plan ........................................................................25

4.2 Developing countries (India) .................................................................................26

4.2.1 Pharmacy Practice in India ............................................................................27

4.2.2 Lack of Risk managing Infrastructure ...........................................................27

4.2.3 Use of Medication guide (PPI) ......................................................................28

4.2.4 Communication Plan .....................................................................................28

4.2.5 Unqualified Pharmacists ................................................................................29

5. DISCUSSION ................................................................................................................31

5.1 US System ..............................................................................................................31

5.2 EU-RMP System ....................................................................................................31

5.3 India specific Issues ...............................................................................................32

5.3.1 Pharmacist’s Interaction/Knowledge .............................................................32

5.3.2 Patient Knowledge on Drug Risk ..................................................................34

5.3.3 Healthcare provider’s (Physician) Knowledge on Drug Risk........................35

5.3.4 Proposals ........................................................................................................36

5.3.4.1Proposal 1...............................................................................................36

5.3.4.2 Proposal 2..............................................................................................39

6. CONCLUSION ..............................................................................................................41

7. REFERENCES ..............................................................................................................42

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 LIST OF FIGURES

Figure Page

1 REMS Outline.......................................................................................................17

2 Pharmacist’s interaction with Patients/Medication guide .....................................33

3 Patient Knowledge Chart ......................................................................................34

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 1. INTRODUCTION

It is said that “No effective medicine is without risk but the benefits of a drug product

have to outweigh the known risks”1. Risk management is a process of estimating a drugs liability

of risks and benefits, taking keen steps to minimize the known risks and ensure that the benefits

of that drug outweigh the risks1. Different drug regulatory agencies are undertaking different

strategic programs to minimize the known risks through interventions such as medication guides,

specialized education, communication plans, special monitoring, prescribing only under certain

circumstances and assure the safe use of other elements1,2. There has been an increased trend

towards the establishment of risk minimization requirements for a class of drugs rather than an

individual drug. The misuse, abuse and accidental overdose of some drugs had led to the concern

to developing these strategies. The drug authorities have seriously started looking at the need to

balance access to those drugs with the need to reduce abuse and drug misuse2.

Usually, drugs or drug classes, which come under risk minimization requirements, are subject to

frequent changes. These strategies help in enhancing the communication with the patients about

risks and in some cases they require registration of patients and educating the pharmacists about

the risks of the drugs3.

Now, the question is, are all the drug authorities around the word following these Risk

Management Strategies? Are these Risk Management Strategies really necessary? Not all the

countries around the world are following these strategies though most of the developed countries

have their own risk minimization strategies and developed different procedures. There are many

7
developing countries and under developed countries who do not have risk minimization

strategies. These are mostly the non-ICH countries. The non-ICH countries include Australia,

Brazil, South Africa and most of the Asian countries such as China, India, Pakistan, Sri Lanka

and others.

Different countries have different means of managing or reducing the risk of marketed

pharmaceuticals. The United States has FDA which monitors the risk management through the

REMS program3. REMS have been effective from 2008 and since then there has been very good

risk management for the drugs approved by FDA. In Europe, the risk management strategies

have been monitored by European Medicines Agency (EMEA). In Europe, a program similar to

REMS has been into practice, known as Risk Management plans (RMP). This is a more

elaborated version of the REMS in USA. In Japan, the Pharmaceuticals and Medical Devices

Agency (PDMA) monitors the risk management strategies of their drugs and devices. Their

management plan is more or less similar to the above practices in United States and Europe. This

is known as Risk Minimization Plan (RMP). Other developed countries like Australia, Canada

have similar plans to reduce or avoid the risks of a drug comparing the benefits of it.

The risk management strategies followed in most of the developed countries is very

systematic and can be taken as an initiative to other developing countries. The outline of the

strategies vary from one country or organization to another, but the overall functionality of the

risk management strategies remain the same as to maintaining the benefit-risk balance.

Countries are trying to collaborate with each other to improve the risk management strategies

such as Europe and Japan. Other developing countries like China, India and Sri Lanka currently

do not have an organized or systematic risk management system to decide whether the benefits

of a drug outweigh the risks.

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During the past years, numerous drugs have been withdrawn from the market due to safety

concerns. Here, a question might arise to whether any of these drugs could have been rescued

following high standard REMS. Drugs like Posicor™ (Mibefradil, generic drug) and Seldane,
25
were removed from the market in 1998 . The reason for their withdrawal was other drug

interactions. Posicor, which was a blood pressure lowering drug, was found to be fatal with

interaction with 26 other drugs. These drugs could have been saved by following good risk

management strategies. Similarly, in Europe, an anti-diabetic drug known as Rosiglitazone has

been withdrawn from the market as the post marketing studies revealed that the benefits of this

drug no longer outweigh the risks. This drug was being used by thousands in Europe. This was

evaluated due to stringent risk management strategies followed by EMEA.

In developing countries like India, many drugs have been withdrawn from the market.

The reasons for the withdrawal are listed, but there aren’t any risk management performed to

justify the ban on these drugs. Phenformin, an anti-diabetic drug had been banned due to risk of

lactic acidosis. Similarly, drugs like Gatifloxacin, Astemizole and Seldane have been removed

from the market26.

There are many other drugs which are being pulled off from the market for some or the

other risk based reasons in India every year. These withdrawals are based on pharmacovigilance

studies that are conducted to evaluate these drugs. There are millions of dollars being invested in

research and development of these drugs which need to be handled systematically.

9
 2. BACKGROUND

The Risk Management Strategies are followed by all the drug authorities around the world

but different terminologies are used. In the United States, it is known as Risk Evaluation and

Mitigation Strategies (REMS). REMS were earlier known as Risk Minimization action plans

(Risk Maps) which was designed to minimize known risks for drug products4. The MHLW in

Japan deals with a similar concept with potential risks, important identified risks and missing

information known as Risk Management Plan (RMP) 6. The European Medical Agency (EMA)

has come up with a program known as European Risk Management Strategy (ERMS) which

aims at providing measures that help in early detection of risks, minimization of risks and

communication plans for drugs in the European countries throughout the lifecycle of the drug 7.

2.1 Early Risk management strategy

The process of identifying a risk, analyzing it, creating an action plan to manage or avoid the

risk is called risk management4. Risk management consists of four primary steps, risk detection,

risk assessment, risk minimization and ways for risk communication. We are aware of risk

management strategies in our day to day life. We experience this before we begin to do anything

daily. For example, when a person has to cross a busy road, he looks on both the sides to wait for

the vehicles to pass before he can cross the road to prevent the risk of being hit by a car. This is

simple risk management that we are mostly unaware of.

Risk Management Plans in pharmaceutical industry needs to include the pre-approval stages

of developing new medicines in submissions for approval5. This plan can be described as a set of

10
pharmacovigilance activities that characterize, identify, minimize or prevent the risks related to

the drug or medicine and to communicate the concerned risks to health care providers,

pharmacists and patients 5.

These risk strategies have been developed time and again by the concerned agencies

throughout the world. The economy and development of a country plays a key role in their drug

risk management. Many countries have learnt from the previous experiences of drug failures in

market and their impact on patients. These lessons led to strengthening the infrastructure of risk

management plans and upgrading their strategies. Today, most of the ICH following developed

countries such as USA, Europe, Japan and Canada has stringent rules and regulations 5. But,

developing countries like India, China, Sri Lanka and Pakistan have still a lot to work on their

risk management strategies. In most of these countries, there isn’t any department which

exclusively overlooks the risk strategies like those in the developed countries. Proposals will be

made to suggest risk minimization strategies for India keeping in mind the county’s economy

and this writer’s experience working in India as a pharmacist.

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 3. METHODS

This paper will contain brief review of the risk minimizing processes in developed and

developing countries. This will summary of the procedures and processes in the United States,

Europe, Japan and developing countries, India in specific.

A. Summary of Risk Management Strategies in developed countries:

a) USA- REMS

b) EMEA-RMP

c) Japan-RMP

B. India- Specific risk management and pharmacy practice issues

Later, an informal survey conducted by the writer and the observations in India will be

presented in detail. This informal survey was conducted in different pharmacy stores across

Adilabad district in Andhra Pradesh. In this survey, the writer had taken the opinion and

knowledge of nearly 45 pharmacists. These were either diploma holders (14) or holding a

bachelor’s degree in pharmacy (31). As a part of the survey, the writer had talks with

pharmacists and also spent time making observations while they were attending the

patients/customers. The writer had short talks with the patients/customers coming to these stores

to collect their prescribed drugs and also taken their opinion and knowledge on the drug effects

and medication guides. The observation from the interaction with pharmacists and

patients/customers has been elaborated below with their respective charts.

The writer will then provide suggestions for improving the risk management systems in

developing countries and India in particular. Two proposals will be made for this. The first

12
proposal will be suggestions for Indian risk management in particular and the second will be a

proposal in general for developing countries in Asia.

13
 4. RESULTS

4.1 Summary of Risk Management Strategies in developed countries:

4.1.1 US FDA

In 1960, FDA constituted a policy of complete disclosure, where the drug manufacturers

had to provide all the information of their product’s dose usage, effectiveness and side effects 8.

FDA also insisted on this mentioning these on the product labeling. Safety and effectiveness of a

product form a crucial part of the drug licensing procedure. Controlled Substances Act (CSA) of

1970 was known as the beginning of the modern day risk management. This US federal drug

policy CSA under which the prescribers, manufacturers, dispensers, product labeling, use,

warning and distribution of drug products is regulated, brought in a new era of risk management

by enforcing additional tools and risk indicators like letters to healthcare providers, pharmacists

and also included boxed warnings 8, 9.

Any drug approved by the FDA has to be marketed with a package insert along with the

product. This package insert is the means of communication of the risks associated with its

usage10, 11
. But, for some cases, the FDA and the manufacturers will have to go beyond the

product labeling process with REMS. REM is to manage the risks of a product and to ensure that

the benefits of the product outweigh the risks. FDA usually enforces REMS for a drug product or

biological product with a primary goal to educate or inform the healthcare providers such as

doctors and pharmacists as well as the patients. An applicant can also voluntarily submit a

proposed REMS, without even being notified by FDA along with an original application or it can

be a supplemental or amendment to original if it feels that REMS is necessary to ensure the

benefits outweigh the risks. It is finally FDA that decides if the proposed REMS are required for

that application. FDA can go ahead and also reject the proposed REMS application if it thinks

14
that is unnecessary and if it does not meet the FDAAA criteria. In such situations the applicant

can as well undertake the alternative risk management measures that are outside of REMS 11.

4.1.1.1 RiskMAPs

Before 2004, there were many drugs which were removed from market due to safety
8, 11
concerns, primarily; the risks of these drugs were outweighing their benefits . During this

period the government started to work on developing different risk management concepts and

their guidance. In March, 2005 RiskMAPs was outlined with three primary guidelines.

1) Developing a RiskMAP and its use

2) Risk assessment of a drug before marketing (Premarketing risk)

3) Reporting and communicating with the FDA to minimize the known risks10, 11.

RiskMAPs was designed with the primary goal to minimize the known risks of a product

while still preserving its benefits by following the guidance.

4.1.1.2 Risk Evaluation and Mitigation Strategy (REMS)

The Risk Evaluation and Mitigation Strategy has a primary goal to help the healthcare

providers and patients to be aware of the known potential risks associated with the drug product

and to work towards lessening the risk or eliminate the risk of a serious adverse reaction. The

FDA, in 2008 made it a rule that any drug with potential risks need to come with a REMS plan.

REMS are to make sure that the potential risks of a drug do not outweigh the benefits. The drug

companies should come up with a strategic plan to manage the risks of the drug throughout its

lifecycle8, 9.

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4.1.1.3 WHEN IS A REMS REQUIRED?

There may be numerous conditions to when REMS might be required. It can be a group

of drugs with similar risk factor or medications with from the same drug class. Today many drug

companies are submitting the REMS along with their NDA itself and allowing the FDA to

decide if REMS is required for that particular drug9. Usually when a new drug is approved and

there is a concern over the potential side effects or risks, FDA requires REMS to be submitted. It

can also be submitted later if the sponsor becomes aware of new safety information in the post

approval. FDA recommends REMS9, 11.

The drug companies should also describe how the proposed REMS will be working, the

objectives and goals from the time of drug approval to post marketing. But, from a sponsor’s

prospective; REMS implementation will be very expensive and time taking. The sponsor will

have to hire more resources that will have to devote more time and efforts on the risk

management, safety and regulatory activities of the drug. Usually the sponsors get very good

assistance from FDA through the draft guidance and other links in their website to prepare for

REMS12.

4.1.1.4 Different elements of REMS

There are different elements of REMS that can be used by a sponsor which need to be

appropriate. Below are elements proposed by the FDA based on the potential risk of the drug.

A) Medication Guide

B) Communication Plan

C) EASU ( Elements to Assure Safe Use)

D) Implementation Plan

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 E) Timetable for submission of assessments13, 16

Figure1: REMS outline taken from Ref 8.

4.1.1.4a Medication Guide

According to the Code of Federal Regulation, 21 CFR 208, medication guide is required

by law and draft guidance has been added to the FDA website to help the sponsors, healthcare

providers and patients understand its essence. Medication guide is the most commonly used

REMS tool for checking potential risks13.

Medication Guides are paper handouts that contain FDA approved information which is

helpful to the patient to understand the potential risks of a particular drug to prevent adverse

17
events. The medication guide has information like what the drug exactly is, how to use that drug

and what risks are involved in taking that drug. Along with the medication guides, we may also

find the consumer guides which contain even more detailed information of the drug usage

compare to medication guide14.

4.1.1.4b Communication Plan

It is a description of the company’s plan to educate healthcare professionals on the safe use

of the product to support implementation of the REMS14. The tools for a communication plan

include

a. Letters to health care providers

b. Information about serious hazard and risks of a potential drug passed on to the providers.

c. Seeking help of professional societies to disseminate the information.

d. Explain the healthcare providers about safety and management protocols and encourage

them to implement them16, 17.

4.1.1.4c Elements to Assure Safe Use (ETASU)

FDA requires these when the drug is inherently hazardous or is intentionally abused15.

This is required where PPI and communication plan are not expected to evaluate the risk factors

for the drug3. FDA needs to approve drugs only in presence of such elements. Attestations (legal

statement that one has met the thresholds and all of the requirements of an act), enrollment

forms, training materials, patient education, safety protocols, medical monitoring procedures,

and data collection forms may be included as ETASU 17.

18
 Training of prescribers/pharmacies/hospitals, patient monitoring, evidence of patient

safety, drug dispensary restrictions, periodic re-certification and re-enrollment may be also

included under ETASU16, 17

. Patient enrollment and collection of information like clinical

outcomes, compliance data safety information, clinical and lab data may be important.

4.1.1.4d Implementation systems

These systems monitor and evaluate the implementation of ETASU and suggest the

improvement methods for implementation. Process of distribution of applicable products by

certified distributors to certified pharmacies and appropriate patients may be included as a part of

these systems. A database with all certifications, conducting periodic audits to assure ETASU

compliance and trustworthiness of distribution systems are the elements of REMS17, 18.

4.1.1.4e Timetable for submission of assessment

Risk assessments for NDA’s and BLA’s should be submitted to FDA on a periodic basis

in REMS. Minimum frequency of 3 assessment submissions is required for every 18, 36 and 84
16
months but the frequency varies depending upon the risk factors . Three statements about

period of interval between submissions and the next approximate submittal date should be

notified not less than 60 days from each submission date. This periodic submission may be

amended upon request or only after a 36 month assessment16, 17.

4.1.2 European Medicines Agency (EMEA)

At the time of authorization, a product is authorized based on the positive indications

provided for the existing demographics keeping in mind the benefit and risk balance of the

19
product technically. A drug or product’s safety information during the time of authorization is

very limited due to numerous factors such as clinical trials done on relatively small population,

local ethnicity, restricted age group and other demographic issues that persist during that time 6

Though there are multiple risks attached to a product, there is a very small scope to identify the

potential risks of that product during initial authorization. The actual risks are identified with

necessary pharmacovigilance planning along with characterizing the safety profile of the drug

from the pre and post authorized study data. When the pre-authorization or initial authorization is

sought, not all potential or actual risks would have been identified. There may be other

demographic population such as pregnant, children, elderly people, lactating women, people of

different ethnicity with whom the drug risk is greater or the results of that drug are different6,7.

While assessing a drug’s profile there are a few important things to be kept in mind such

classification of known and unknown risks of a drug, pharmacovigilance planning to identify

new risk factors, implementation of risk mitigation strategies7, 19. A drug or a medicinal product

with a desired pharmacological activity will definitely have some undesired risk factors. But, its

difference on target population may vary with disease prevalence and its severity. Keeping these

strategies in mind a drug might have different versions of risk minimization procedures for a

particular region, though there will be core RMP overall regardless of where it is being used.19

4.1.2.1 Overview of the EU-RMP structure

According to the EU-RMP (Risk Management Plan) template, the following template is

categorized into Parts and Modules. The RMP consists of 7 standard parts and which are

subdivided into modules which are tailored in such a way that more modules can be added or

removed accordingly.20

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P1: Product information

This part of RMP contains the general information of a drug/medicinal product such as active

drug substance in the product and the therapeutic group that it belongs to. It also holds the

administrative RMP information of the parts and modules covered and the dosage, indication,

strength and the forms used and also the number of medicinal products in that application.19,20

P2: Safety specifications

This part of the template is again categorized into 8 different Modules. This part of RMP will

form the basis for future pharmacovigilance planning and also risk minimizing strategies. Safety

specifications provide the safety information of known

M1: Epidemiology of the drug indication and the target population

M2: Non-clinical section of safety specification

M3: Exposure to clinical trials

M4: Populations that were missed for clinical trials

M5: Post authorization studies

M6: Additional requirements from EMA for safety specifications

Under this module there are a few specific topics that are taken into consideration.

 Potential to be harmed with overdoses.

 Transmission of infectious diseases.

 Misuse for illegal purposes.

 Chances of medication errors or wrong medication/dose/patient.

 Possibility of off-label use.

 Particular pediatric issues21.

21
M7: Identified risks and potential risks

EU has categorized a few drug products as Advanced Therapy Medicinal Products (ATMPs) for

human use. These comprise of drug products related to gene therapy and somatic cell therapy.

Keeping in mind the importance and the risk factors of these kinds of drug products, the Module

7 in this case needs to be replaced with Identified and potential risks for ATMPs. Apart from

these, this module also highlights other possible risks like food-drug interaction and drug-drug

interaction, newly identified safety concerns from recent post authorization studies and safety

implications7, 21.

M8: Overall summary of the safety specifications.

This module deals with the safety concerns related to the active substance, formulations to be

used, route of administration, target population.

P3: Pharmacovigilance plan

This provides the structured plan for the identification of ne safety concerns of the drug product,

its risk factors and the importance of missing information that needs to be sought. This part of

RMP provides the information of routine and additional pharmacovigilance activities that need to

be done.

P4: Planning for post-authorization studies

P5: Evaluation of the need for risk minimization

P6: RMP

P7: Summary of the RMP

22
 Clinical and non-clinical brief overview and summary of all the above modules need to

be provided. The risk management plan should be treated as a scientific document and strictly

not used for promotional or commercial purposes19, 20.

European Medicines Agency sees benefits of interaction with Japanese regulators. There

has been an increase in the interaction between the developed countries for the betterment of

drug safety and to avoid duplication of the work done. Over the past 3 years there has been

constant increase in the interaction between Japan regulatory authorities and the European

Medicines Agency in information exchange, regulatory education and better awareness22.

4.1.3 PMDA (Pharmaceuticals and Medical Devices Agency)

Japan can be also listed as a developed country. Their risk minimization is not as specific

as EMEA or not as perfect as REMS by FDA. But, still they have implemented a different

method which is also effective as are the other developed countries. The risk management plan
22, 23
used in Japan is known as the Risk Minimization Plan (RMP) . RMP is the minimization

activities that are done to lessen the potential known risk of the drug and to maintain the

appropriate balance between the risks and benefits of the drug that were observed during the

approval process and also the post marketing. RMP guidelines deal with the identified risks,

important potential risks and other missing information which were identified during the

approval process and also the post marketing studies24.

In Japan, the sponsor is called a MAH (Marketing Authorization Holders). The MAH

should make sure to add new implementation plan of risk/benefit assessment. The RMP should

be developed at the time of approval following the E2E guidelines and the MAH is supposed to

23
outline the safety specifications at the time of application. If there are any safety issues that were

identified after the application, the MAH is supposed to update the RMP for the review 22, 24.

When can a RMP be applied?

 When a new dosage or additional indication is added to a new drug application at the

time of approval.

 When a new drug combination is proposed at the time of approval review.

 When safety specification is submitted newly for re-examination at the time of approval.

 When safety specification is submitted newly for re-examination at the time of post

marketing phase.

 When applying for a generic drug and its reference drug has already developed an

additional potential risk activity23.

According to the PMDA, keeping in mind the above conditions, before the sponsor submits

a PMS or a basic plan for post marketing surveillance, it will have to include RMP which will

contain the Pharmacovigilance Plan and the Risk Management Plan as recommended.

4.1.3.1 Risk Minimization Plan

Based on the identified Safety Specifications, MAHs should develop a Risk Management

Plan to promote the safe use of a drug and also check the risk to benefit balance. Keeping the

Safety Specifications in mind, additional actions should be developed and a clear description

should be provided of how these actions were taken and the methods used. The contents of the

Risk management Plan are assessed at the time of approval review process and any additional

actions are necessary are recommended 23, 24.

Below are a few considerations that a Risk Management Plan must follow:

24
  Identified risk population

 Demographics of patients being treated with the drug

 Potential risk of the drug

 Seriousness of the complications

 Seriousness of the disease

 Severity of the ADRs

 The impact of Adverse Drug Reactions on the benefit-risk balance.

 Safety measures and marketing strategies overseas.

 The differences in the safety profile of the drug in Japan compared to overseas.

 Effect of the Risk Minimization Plan (RMP).

All the above risk management activities need to be detailed considerably before reporting to

the PDMA. The Risk Management Plan has to be developed and kept updated depending on the

post marketing situations so that there is a good benefit-risk balance 22.

4.1.3.2 Pharmacovigilance Plan

Pharmacovigilance plan can be either routine pharmacovigilance plan or additional

pharmacovigilance plan. This is referred to as ICH E2E guidelines and these pharmacovigilance

activities are developed at the approval review and post marketing based on the Safety

Specifications which primarily include important identified risks, important potential risks and

important missing information23. The PDMA usually recommends this plan to generic drugs

which have additional pharmacological activities from the original drugs, follow on biologics

and new drugs at the time of approval submissions. This plan is also recommended when a new

safety concern has been identified during post marketing23, 24.

25
4.2 Developing countries (India)

The drug regulatory authority in India is Central Drugs Standard Control Organization

(CDSCO) which regulates the approval or new drugs to the marketing of any medicine in India.

CDSCO lays down the rules and regulations for the pharmaceutical industry in India. They have

subdivisions for every state which monitor the drug approval to marketing process for their

respective states. The Indian pharmaceutical industry is growing at the rate of 12-14% per

annum. More new drugs, vacancies and new routes of administration are coming up in the

market every year. It is estimated that every year around 20,000-30,000 applications for New

Chemical Entities (NCE) are being received by CDSCO. India is a country with a vast

population, different ethnic variations, different medicinal practices and various disease

prevalence patterns.

What could be the risk minimization strategies followed by India, a country with second

highest population and a large pharmaceutical market? After a lot of research and from the

writer’s knowledge of pharmacy, the writer noticed that the risk minimization strategies are at its

juvenile stage in this country. The risk management in India mainly concentrates on the adverse

reactions monitoring. As a part of the risk management program, CDSCO has coordinators at

different ADR monitoring centers (AMCs) in Zonal and sub-zonal offices. This is definitely an

excellent strategy for gathering adverse events from all parts. Adverse drug reporting is a strong

ICH procedure followed all throughout the world by both the developed and developing

countries27, 28.

In India, any person who has a either a diploma or a bachelor’s degree in pharmacy is

eligible to open up a pharmacy outlet. There are a few thousand pharmacists graduating every

26
year in India. This might be one of the reasons why you can find a pharmacy outlet almost every

few yards in a town. Every small clinic has an attached pharmacy with numerous generic non-

generic and other drugs. Nowadays even tiny villages with a population of a couple of hundreds

of people also have a pharmacy outlet.

4.2.1 Pharmacy practice in India

The literacy rate India is known to be 74.04% in 2011 but it is difficult for a layman to

understand the drug by its name and dosages or understand a medicine that he has been

prescribed. The issues that the writer feels that the pharmacy practice in India is facing include

the following.

4.2.2 Lack of Risk managing infrastructure

Unlike developed countries such as USA, Europe and Japan, India does not have a

planned and organized infrastructure that manages the risk minimizing strategies. Developed

countries have an organization exclusively monitoring this domain, which makes the

administration run smoothly with different checkpoints to monitor risk. Techniques like

medication guides, communication plans and post marketing studies do not exist in most of the

developing countries like India, Pakistan, Sri Lanka, etc. Processes such as REMS or RMP

which could lay rules and regulations for minimizing the risks of drugs could be more effective.

No pharmaceutical company in India or other developing countries would come forward

voluntarily to market their drugs with package inserts or medication guides. A process is

required to decide which medicine needs risk minimizing activities.

27
4.2.3 Use of Medication Guide (PPI)

Medication guides used in developed countries like USA and Japan have proved to be

the first and the best risk minimization strategy. They have been effective in carrying the risk

information of a drug and thus bringing awareness about that particular drug and so, minimizing

the risk. In India, only a few drug manufacturers follow the practice of using a medication guide,

mostly pediatric drugs. Sometimes, drugs in the form of gel or solution have medication guides

with minimal information of its therapeutic dosage, effects of over dosage and its side effects

which can be barely seen. Compact drugs like tablets and capsules are available in sheets which

have the therapeutic ingredients printed on it with minimal content of dosage information.

Pharmacists were trained to explain the use of a medication guide but hardly anyone follows it.

Most importantly, it is the patients who ignore the medication guide and treat it as an unwanted

waste paper 29.

4.2.4 Communication Plan

There is no such Communication Plan program in India. Here the manufacturer is least

bothered to give any detailed description of the risks of his product to the providers and the

providers are also least bothered. Everything here is done for commercial motive of give and

take. It is usually not the manufacturer that would directly communicate with providers but the

middlemen with a role ’Medical Representatives’ who would do knowledge transfer regarding

the new drugs in the market to the providers. These middlemen were not very qualified as

necessitated in law which affects the reliability of the information they provide. Providers in

countries like India would ignore the risk factors and risk assessment strategies in many

circumstances as they would treat their profession as a business but not a ‘Profession’ in its

28
virtual terms. These medical representatives are usually brokers who are basically behind

increasing the sales of the drug product without passing on the risk information. The

representatives preferentially request the providers to prescribe their drug in return for financial

favors. Even if a communication plan was set up between the manufacturers and providers in

one or the other way, the purpose was served in very rare circumstances.

4.2.5 Unqualified Pharmacists

As the writer mentioned earlier, in a small town in India, you will not be surprised to find

at least 20 pharmacy stores. But according to IPA (Indian Pharmaceutical Association) and

CDSCO, only a person with either a diploma or a bachelor’s degree is a qualified pharmacist.

But in most of the developing countries, you hardly see this happening. . Firstly about 70% of

pharmacists in countries like India were under qualified for their designations. These are students

who had just passed grade VIII or IX and are behind the counter selling medicines. Definitely,

these students will have no clue about a medication guide or can they explain the risks or side

effects of a drug. Prescription provided by the providers when taken to a pharmacy was handed

over an under qualified pharmacist who would only sometimes provide the medication

prescribed by the pharmacists. But, in most of the cases they would give the patients with drugs

with other brand names or different dosage forms 30. There would be some worst conditions of

patients being given expired drugs too which may be less efficacious with side effects.

Pharmacists lack knowledge on the benefits and side-effects of the drug due to which they fail to

explain its importance to patients. There were many instances of drug-poisoning due to improper

information provided by the pharmacists to the patients which wouldn’t come into lime light.

Pediatrics attain utmost importance in this scenario as the pharmacists would provide the patients

29
an over dosage/high potency medication which lead to child abnormalities31. Most of the

patients are also unaware of side effects of a medicine and the dosages leave alone the

medication guides. The so called pharmacists are at times reluctant to look into a prescription

and simply give a medication that they know. There is a drug controller for every zone who is

supposed to supervise these, but practically nothing has been done to change these situations.

Loopholes that the writer observed as a pharmacist:

 No higher authority or organizing infrastructure to manage the risk-benefit ratio of a new

drug in market.

 Risk management plan only concentrating on ADRs and not focusing on other strategies

to minimize risks of drugs.

 No proper communication plan program. Communication gap between the manufacturers

and the health care providers leading to primary focus on financial benefits rather than

treatment of patients.

 Prescription errors leading to pharmacists giving the wrong medicines.

 Unqualified pharmacists who do not know the principals of pharmacy leading to

administering wrong medicines.

 Pharmacists who are unaware of the risks and benefits of a drug.

 Pharmacists ignorant of knowing the risks of a new drug in market and reluctant to know

its facts through medication guide.

 Communication gap between the pharmacist and the patient.

 Medicines given to patients without prescription.

 Low literacy rate in suburban and rural areas.

30
 5. DISCUSSION

5.1 US System

The simplest and best risk minimization strategies followed throughout the world in my

opinion would be the REMS by FDA. REMS are to manage the risks of a product and to ensure

that the benefits of the product outweigh the risks. FDA usually enforces REMS for a drug

product or biological product with a primary goal to educate or inform the healthcare providers

such as doctors and pharmacists as well as the patients11. The primary elements of REMS are

A) Medication Guide

B) Communication Plan

C) EASU ( Elements to Assure Safe Use)

D) Implementation Plan

E) Timetable for submission of assessments13, 16

5.2 EU System

Out of all the risk management strategies discussed, EU-RMP is the most detailed

infrastructure. This would also mean that these strategies will be more effective to minimize the

risks of a drug. But keeping the economy and infrastructure of developing countries, I would not

suggest the EU-RMP system in these countries. For developing countries to implement this

infrastructure they need put in loads of funds initially and they will also need to hire more

number of employees. But, in my opinion EU-RMP would be the best risk management

organization which would prevent the risks of a drug to a great extent.

31
5.3 India specific issues

After working as a pharmacist and also doing a survey in India for 2 months (May & June,

2011) in a place called Bellampally in the state of Andhra Pradesh, India, the writer was able to

gather a little information regarding the knowledge of package inserts, medication guides and the

communication by doctors, pharmacists and patients. A detailed description of the below

mentioned issues is given in the results section.

 Lack of Risk managing infrastructure

 Use of Medication Guide (PPI)

 No Communication Plan

 Unqualified Pharmacists

Apart from these, author conducted informal surveys on the pharmacist’s knowledge of

medication guides, their interaction with the patients, their knowledge on the side effects of a

drug and the patient’s knowledge on package inserts and medication guides.

5.3.1 Pharmacist’s interaction/knowledge

Compared to other developed countries, Indian literacy rate is very low. Practically

speaking, most of the people find it difficult to understand English. Almost all the drugs in India,

be it generic or non-generic drugs are marketed and labeled in English, which cannot be

understood by a layman. The difficulty here is, there are nearly 30-40 regional languages in India

and it would be very impractical for the government to implement these languages in their

regions. So the easiest and practically possible method here would be to improve the

communication between the pharmacists and patients and also providers and patients. In

observations, author had the opportunity to interact with 45 pharmacists, most of whom own

32
pharmacies there. After spending considerable time with them, author had come to the below

conclusion.

Pharmacist's interaction with

Patients/Medication Guide

Responsible Pharmacists
Lack of knowledge
on medication
guide no interaction
with patients

Ignore the importance of

explaining medication
guide to patients

Figure 2: Pharmacist’s interaction with Patients/Medication guide

 It was only business that they were doing there and not really professional.

 Out of 45 pharmacists, 22 of them did not know what a medication guide was and they

did not do any interaction with the customers/patients.

 As they did not know what exactly a medication guide was they did not bother to read it

nor did they know the risk of that drug.

 Next, there were 12 of them who were aware of the medication guides or package inserts

knew the essence of them. But, unfortunately these neither read them nor could they

understand the medication guides of package guides. They ignored them and failed to

explain the risks of a drug to the patient/customer.

33
  Fortunately, there were 11 out of 45 pharmacists who followed the profession. They

spent ample time to know about a drug through package inserts or medication guides or

through internet. They were successfully able to convey the risk impacts of a drug and

also take a follow up of their experience. This was a great challenge for these pharmacists

as most of the patients or customers were village people who hardly knew how to read

and write.

5.3.2 Patient knowledge on drug risk

At the same time, I started doing an informal survey on patients who came to collect their

medicines at the pharmacies on their knowledge of drug risk, medication guides and package

inserts. Surprisingly, there were a few hundred people who did not want to know the drug risk or

side effects of a drug. Out of all, I could take the opinion of 184 patients/customers. The below

chart depicts the percentage of people in different categories.

Patient Knowledge Chart

patients
who follow
Patients understand
but never follow
Patients withno idea what a
medication guide is.
Patients witha basic idea
of a medication guide

Figure 3: Patient Knowledge Chart

34
  Out of the 184 people that I surveyed, nearly 55%, that is 101 people had no idea of

package inserts and what a medication guide in a drug were. Most of them thought that it

was a piece of advertisement for that drug. A few of them did not know that a drug would

have risks or side effects and most of them were not bothered to know what they were.

Unfortunately, most of them were hardly educated.

 Nearly 21%, that is 51 people had a basic idea that a drug could have risk factors and side

effects and knew what a package insert or medication guide contained. But,

unfortunately, they did not want to communicate with the pharmacists or the providers

about the risks. They just believed the drug would do whatever it is supposed to do.

 The next category was educated people which came up to 16% that are 23 out of 184

people. They knew that a medicine can have risk factors and side effects but did not

bother to know them. I requested them to read a medication guide and asked the

pharmacist to explain them the risks or side effects. They fortunately understood what

exactly was in the packages and medication guides and also were able to follow the

pharmacists.

 Finally, I had 13 people who were educated too and they did have lots of knowledge on

risks, side effects, package inserts and they did follow medication guides that they came

across. They were also curious to know more about the medicines that they were

prescribed and kept themselves updated.

5.3.3 Healthcare Provider’s (Physician) knowledge on drug risk

Below are few highlights and concerns of what I had observed. I would just like to compare

the communication plan that is been implemented in the US.

35
 In India, you will hardly find any Letters to health care providers, basically doctors

from the manufacturing companies to educate them about the risks of a new drug into

market.

There are no protocols set for the healthcare providers to learn about the safety

management.

No information about serious hazards or potential risk of drugs is passed on to the

providers.

If there are any hazards that come to the notice of a provider, it is hardly brought to the

notice of the manufacturer.

There are ‘medical representatives’ who are hired by the drug manufacturing companies

to market their product. These people seriously don’t have sufficient knowledge on the

drug they market and only lure the providers to prescribe their product with something

in return of the favor.

Overall, there is no communication plan, which would have helped to pass on the risk

information from the manufacturer to the providers to the patients. So, there is no

continuation in this chain.

5.3.4 Proposals

Based on the above research for the improvement of Risk minimizing strategies in

developing countries, India in particular, two proposals will be suggested.

5.3.4.1 Proposal 1:

 First and the foremost, India needs to develop an infrastructure exclusively for risk

minimization strategies in the country. Keeping in mind the economy of developing

countries such as India, Pakistan, Srilanka and Bangladesh, I suggest them to follow a

36
 FDA monitored REMS kind of system for risk minimization in their own countries. This

system is simpler and less sophisticated than EU-RMP and Japan-RMP as well as suits

the financial considerations of these countries. This way at least a few of the above

mentioned drugs could be protected if Indian drug authorities would follow few risk

management strategies similar to those of United States, Europe and Japan. This is an

easy step to implement in developing countries.

 This system should be given the authority to decide whether a New Drug Application

should be accompanied with a detailed risk minimization plan. This might take a little

while to implement but not hard.

 In this system, I would also like to suggest an element similar to medication guide to be

made available in English as well as the regional languages to improvise the patient

education. This is really necessary and easy to implement.

 Since the literacy rate in developing countries is comparatively low, strong rules should

be imposed such that it is the duty of the pharmacist as well as the provider to educate the

patients of the risk factors of a particular drug. This might be a hard task but can be

implemented up to certain extent.

 Pharmacists along with the providers should maintain the records of the patients who are

being administered with a drug that has a Risk minimization plan. This step can be a

great challenge, but if implemented, it would make a large difference.

 A follow-up of the adverse events for these drugs needs to be recorded and reported. This

is already being practiced in most places so easy to implement.

37
 Knowledge transfer sessions should be organized by the manufacturers to the providers

regarding the risk factors of any drug with risk minimization plan. This is a bit hard to

organize but not impossible to implement.

 A detailed description of the pharmacologic factors of the drug with an RMP should be

provided in a possibly efficient way to the providers to make them aware of all the risk

factors of a particular drug before being prescribed to the patients.

 Need for strong post marketing studies, especially for the drugs which have a RMP so

that the adverse effects can be effectively monitored. This is hard to implement but

should be implemented.

 Rules should be framed such that only eligible, qualified pharmacists work in a

pharmacy.

 Changes should be made in the education system of a pharmacist which should include

basic training on the understanding of a medication guide and package inserts which will

be practically helpful during their practice. This is easy to be implemented in the

education system of pharmacy practice.

 A pharmacist should be well trained to educate a patient about the potential risks and side

effects of a drug. This would thus decrease the communication gap between a pharmacist

and a patient and the betterment of risk minimization strategies.

 Government should bring in awareness programs among the people regarding the

importance of the risk minimization plans implemented. This will be the toughest plan for

the government, as it would be difficult to take pass the message to a common man.

38
5.3.4.2 Proposal 2

I would also like to propose another system which would suit the financial status of all the

developing countries especially Asian countries. Most of the Asian countries are developing

countries with Japan and Singapore being the notable exception. My suggestion would be that all

the Asian countries can plan to come on a single platform and develop a new risk minimization

system for all the Asian countries similar to the EU-RMP. The EU-RMP has all the European

countries under one system which monitors their risk management plan. Similarly, developing

countries like India, China, Pakistan, Sri Lanka, Korean countries, Bangladesh, Nepal and other

countries along with the developed countries like Japan and Singapore can plan for an Asian

Risk management Plan (ARMP). The benefits of the system can be,

 As most of the countries are still developing and a few still under developed this would

help them financially. They need not invest large amounts to start a new infrastructure.

 Developing countries will have a great opportunity to work with Japan which is far more

ahead in terms of risk management. The suggested Asian Risk Management Plan

(ARMP) can have its headquarters in Japan which will also help Japan and the

developing countries.

 The ARMP can be more detailed and a single organization can frame the rules and

regulations of the system.

 This will also improve the drug trade between these countries and this way the under

developed countries can benefit with new medicines coming to their market.

 There will also be a bigger scope for post marketing studies on larger population and with

different ethnic groups. This process would further reduce the risk properties of a drug.

39
 The 2nd proposal is very hard to be practically possible, but it can also be very effective if it

can be implemented. It might be time taking and needs lot of ground work to be done, but still it

all worth it.

40
 6. CONCLUSION

Developing countries along with India could improve their drug safety if the above

suggestions were implemented. These were just my opinion and not intending to criticize any

organization. The writer only thinks that the drug safety systems in these countries could

improve if there were less political interference. Most of the countries do not have a standard risk

management plan. The writer thinks that ICH should intervene and recommend the concerned

governments to start working on developing systems for risk minimization.

41
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46