Introduction to Pharmacovigilance

UReachclincare
(ClinoLife Clinical Research Pvt Ltd)
nd
Corporate Office: #4/3,2 Floor,Opp FORUM Mall,Behind @ HOME Furniture,Hosur Road,Bangalore-
560029,INDIA
nd
Local Office: Bhabanagar-2 Lane (Near New Bus stand), Dandapat Road, Berhampur (Gm), Orissa-760004
Mail-www.clinolife.com
 Contents

1. INTRODUCTION

 Pharmacovigilance and Good Medicine

 Safety Specification and Risk Management Plan

2. DRUG HYPERSENSITIVITY

3. HOW DO WE FIND USEFUL SIGNALS?

4. VISION FOR PHARMACOVIGILANCE IN EUROPE

5. MONITORING SAFETY OF VACCINES

6. PHARMACOVIGILANCE IN EMERGING COUNTRIES

7. THE SAFETY OF HERBAL MEDICINES

8. BAYESIAN STATISTICS AND PHARMACOVIGILANCE

9. WRITING A PROPER ADVERSE EVENT REPORT

10. CLINICAL TRIALS – WHAT THEY CAN DO AND WHAT THEY CAN’T!!

11. GUIDELINES ON PHARMACOVIGILANCE

 CHAPTER1
1.1 Pharmacovigilance and Good Medicine

1.2 Safety Specification and Risk Management Plan

1.1 Pharmacovigilance and Good Medicine

Over the past decade, two important public health trends have become entwined
like the twin serpents in the caduceus: (1) increasing clinical attention across all
medical specialties to the undertreatment of pain, and (2) shifting patterns of drug
abuse from illicit to prescription drugs—most notably a dramatic rise in diversion
and non-medical use of opioid pain medications within the United States. The
collision between the War on Pain and the War on Drugs has created a “perfect
storm” of controversy. And, for better or worse, physicians are being enlisted to
fight on both fronts: combating pain while simultaneously reducing the risk of
diversion and abuse of, as well as addiction to, pain medications. Many of us
bristle at adding “pharmacovigilance” and “risk management” to our already
lengthy task list. But the combination of potential therapeutic benefit and high risk
associated with opioid* analgesics leave us no alternative but to become more
sophisticated risk managers. Millions of legitimate patients rely on these
medications for pain relief and functional improvement, so we must include them
in our repertoire of potential medication therapies. However, we cannot ignore
the potential risks associated with the use of controlled substances, including
addiction. Managing risk is what we physicians do every day with every patient,
whether we’re considering procedures, medications, or non-medication
interventions. Every treatment plan carries potential risks, as does the decision
not to treat. Managing risks associated with opioids is fundamentally the same as
pharmacovigilance concerning adverse reactions to any class of drugs:
essentially following sound principles of medical practice and prescribing and
achieving transparency in treatment decisions. The difference with opioids is that
these drugs are increasingly diverted or otherwise abused.

* The term opioid refers to natural and semi-synthetic derivatives of the opium poppy, as well as
similar synthetic compounds that have analgesic or pain relieving properties because of their
effects in the central nervous system. These include codeine, morphine, hydromorphone,
hydrocodone, oxycodone, methadone, and fentanyl among others. Opioids are often
inappropriately referred to as narcotics, a legal term that is no longer used in medicine because it
suggests that opioids relieve pain by inducing sedation; while sedation can be a side effect of
opioids, it is not the mechanism that produces pain relief.

1.1.1 Scope of the Problem

A statistical snapshot of prescription drug abuse and diversion in the United
States reveals the scope of this alarming public health crisis: ¦In 2005 (the latest
year for which data are available), more than 10 million Americans were abusing
prescription drugs—which is more than the combined number of people abusing
cocaine, heroin, hallucinogens, and inhalants. ¦The Centers for Disease Control
and Prevention report that prescription opioids are now associated with more
drug overdose deaths than cocaine and heroin combined: between 1999 and
2002, there was a 91.2 percent increase in the reporting of opioid analgesics on
death certificates.

 Continuing a decade’s long trend, in 2005 more new drug users began
abusing pain relievers (2.2 million) than marijuana (2.1 million) or cocaine
(872,000). By
Comparison, in 1990 only an estimated 628,000 people initiated illicit use of pain
killers.
 Data from a set of selected states show that almost 13,000 incidents of
prescription controlled substances were diverted by theft from 2000 to
2003. In 2003 alone, 2 million dosages of six opioid analgesics were
reported stolen from the supply chain, mainly from retail pharmacies.
Behind these figures lie millions of individual stories of personal tragedy: untimely
death, fractured families, shattered dreams, and wasted lives. Certainly the same
spectrum of ills can be found in the wake of any abused drug, but the magnitude
of the current problem makes it imperative that physicians become vigilant risk
managers who demonstrate transparency in the decisions behind the care they
deliver. Much remains to be learned about the nature of prescription drug abuse
in the United States. For example, the exact contribution of prescribers to
prescription drug diversion and abuse is not presently known. Because the rise of
prescription drug abuse has occurred alongside increased use of opioids in
legitimate pain relief, it is tempting to assume cause and effect. However,
preliminary evidence does not support this conclusion and more information
about how prescription drugs are diverted is crucially needed. If we are to have
responsible and effective responses to prescription drug abuse, the problem
must be considered in its full context. To avoid penalizing those with legitimate
needs, solutions must factor in the full complexity of drug abuse, addiction and all
of the related social and medical disorders. In particular, we must be careful with
implications that prescription drug abuse is mostly related to prescribers and their
patients, and be careful with implying that limiting medically appropriate use may
have significant effects on reversing this disturbing trend.
1.1.1.1 Countervailing Need
Concurrent with the epidemic of prescription drug abuse, patients and patient
advocates have been pushing to address the equally legitimate cause of
undertreated pain. Although these efforts began in the relatively circum-scribed
spheres of end-of-life care and cancer-related pain, medicine has appropriately
widened its perspective to include all debilitating pain that has lost its purpose as
an adaptive alarm signal, regardless of the source. Significant effort has been
made to reduce the incidence of untreated or undertreated pain in children, older
patients, and in all other vulnerable patient populations. And at least at the level
of clinical guidelines, policy statements, and organizational goals, the following
general principles are widely accepted: Pain management is integral to good
medical practice for all patients;
 Opioid therapy to relieve pain and improve function is a legitimate medical
practice for acute and chronic pain of both cancer and non-cancer origins;
 Patients should not be denied opioid medications except in light of clear
evidence that such medications are harmful to the patient;
 The use of opioids for other than legitimate medical purposes poses a
threat to the individual and society; and Physicians have a responsibility to
minimize the potential for the abuse and diversion of controlled
substances.

If opioids had no medically redeeming value, the issue of their abuse would be
tragic but physicians would have no role to play in minimizing abuse by changing
their behaviors or monitoring their actions. The current need for guidance on
opioid prescribing arises from the fact that, as addictive and life-destroying as
opioids can be for some, they are life-enhancing and non-addictive for others.
Four key factors contribute to the ongoing problem of under-treated pain:

1. Lack of knowledge of medical standards, current research, and clinical

guidelines for appropriate pain treatment;
2. The perception that prescribing adequate amounts of opioids will result in
unnecessary scrutiny by regulatory authorities;
3. Misunderstanding of addiction and dependence; and
4. Lack of understanding of regulatory policies and processes.
To these factors might be added a fifth: the lack of clearly written government
regulations and professional guide-lines for prescribing, or assistance with how to
easily and efficiently incorporate these approaches into the hectic daily practice
of physicians.

1.1.2 Filling an Unmet Need

This book is intended to help the responsible clinician understand and implement
practices that support rational and transparent opioid prescribing. The following
chapters examine each of the seven steps in the FSMB’s Model Policy:
1. Patient Evaluation
2. Treatment Plan
3. Informed Consent and Agreement for Treatment
4. Periodic Review
5. Referral and Patient Management
6. Documentation
7. Compliance with Controlled Substance Laws and Regulations
Each of these steps, which are only briefly described in the Model Policy, are
here given an expanded discussion from the perspective of real-world clinical
practice. Most physicians already perform many of the key steps recommended
in the Model Policy. This book focuses on explanations and techniques that
specifically address the issues that arise when prescribing opioids. Sometimes
this simply means adhering to existing standards of care. At other times—such
as in the creation of function-based treatment plans—a significant paradigm shift
in perspective will be presented that translates into novel models for creating,
monitoring, and modifying treatment goals for your patients in pain. Prescription
drug abuse and undertreated pain are both serious public health crises, but the
solution to one need not undermine the other. The least we clinicians can do is
make sure that the casualties of this clash are not suffering patients who
legitimately deserve relief. Informed clinicians can take simple steps to ensure
that opioids are pre-scribed safely and transparently—and in the process, those
prescribers can justify their decisions should they encounter the scrutiny of
regulators. Regulators and law enforcement agencies, such as the Drug
Enforcement Administration, have urged prescribers to be vigilant when
prescribing abusable drugs, particularly for patients with known or suspected risk
of abuse. Clearly, effective solutions must address the current state of
inadequate education that most clinicians receive on safe and effective
prescribing of controlled substances. This book is intended as a much-needed
step in that direction. Unfortunately, simply knowing the tenets of the FSMB
Model Policy will not be of value without a basic knowledge of pain, substance
abuse, and their treatment. Although this book will not serve this role, other
resources are avail-able, many of which are recommended in Appendix A.
Moreover, this book will not substitute for maintaining the desire to relieve
suffering or the recognition that an important part of mitigating pain is simply
being present with your patients and showing them that you care. Although the
elements of care described here are critically important for maintaining
appropriate delivery of controlled sub-stances, unless you also incorporate the
personal part of care, your patients will continue to feel alone and uncared for—
and may even resist treatment. As a physician who specializes in Pain Medicine,
I’m optimistic about the future of pain treatment. The confusions and frustrations
that currently characterize pain management may simply be the growing pains of
a wiser, saner, and more uniformly effective patient care approach. Appropriate
concerns about the potentially harmful or addictive aspects of opioid medications
can be balanced with the equally valid needs of optimal pain relief with adequate
risk management. Medicine is all about managing risk while improving health and
easing suffering; the safe and effective use of opioids is no different. Opioids are
ancient drugs that have been both glorified and demonized in past centuries. It is
time we found ways to harness their very real gifts while curbing their very real
dangers.

The Pharmacovigilance Process

Traditional Detect Signals Data

Methods Mining

Generate Hypotheses
Insight
from Public Health
Refute/Verify Impact,
Type A Benefit/Risk
(Mechanism-based) Estimate
Act
Incidence
Type B Inform
(Idiosyncratic) Restrict use/
Change Label withdraw

1.2 Safety Specification and Risk Management

Plan
 1.2.1 SAFETY SPECIFICATION
 1.2.2 Limitations of the human safety database
  1.2.3 Populations not studied in the pre-authorisation phase
 1.2.4 Post authorisation experience
 1.2.5 Adverse events/Adverse reactions
 1.2.6 Identified and potential interactions with other medicinal
products, food and other substances
 1.2.7 Epidemiology of the indication(s) and important adverse events
 1.2.8 Pharmacological class effects
 1.2.9 Additional EU Requirements
 1.2.10 Summary – Ongoing safety concerns
 1.2.11 PHARMACOVIGILANCE PLAN
 1.2.12. EVALUATION OF THE NEED FOR RISK MINIMISATION
ACTIVITIES
 1.2.13. RISK MINIMISATION PLAN
 1.2.14. SUMMARY OF THE EU RISK MANAGEMENT PLAN
 1.2.15. CONTACT PERSON FOR THIS EU-RMP

Annex C: TEMPLATE FOR EU RISK MANAGEMENT PLAN

(EU – RMP)
This template provides advice on how the data requested in the Guideline, if
available, should be presented. It is anticipated that, particularly in section 1, all
the information will not be available for all drugs and that the type of product and
where it is in its lifecycle will affect how much information can be provided.

Overview of EU Risk Management Plan Template

Section
Product information
1 Safety Specification
2 Pharmacovigilance Plan
3 Evaluation of the need for risk minimisation activities
4 Risk Minimisation Plan
5 Summary of the EU-RMP
6 Contact person details
Annex 1 Interface between EU-RMP and Eudravigilance .To be provided in
electronic Form only
Annex 2 Current (or proposed if initial EU-RMP) SPC, Package Leaflet
Annex 3 Synopsis of ongoing and completed clinical trial programme
Annex 4 Synopsis of ongoing and completed pharmacoepidemiological study
programme
Annex 5 Protocols for proposed and ongoing studies in pharmacovigilance plan
Annex 6 Newly available study reports
Annex 7 Other supporting data
Annex 8 Details of proposed educational programme (if applicable)

To be valid an EU-RMP MUST contain sections 1,2 & 3. With the exception of
section 4 (which must be completed if additional risk minimisation activities are
proposed) all sections should be provided. Annex 1 should be provided in
electronic form only.

Please ensure that the data provided in this document are coded in MedDRA
terms where appropriate and are consistent with those submitted electronically in
the template attached in Annex 1.

PRODUCT DETAILS
Invented name of the medicinal product (product short name): ------------

Active substance(s) (INN or common name): --------------- - --------------

Pharmaco-therapeutic group (ATC Code): ------------------------------------

Medicinal Product Code (From EudraVigilance) ----------------------------

Authorisation procedure(s) (central, mutual

recognition, decentralised, national) ------------------- -------------

Name of Marketing Authorisation Holder or Applicant: --------------------

Date and country of first authorisation worldwide --------------------------

Date and country of first launch worldwide --------------------------------

Date and country of first authorisation in the EEA If different from above

Date and country of first launch in the EEA If different from above

Data lock point for EU – RMP---------- Version --------------

(dd/mm/yyyy)

Brief description of
Product (chemical class, mode of
action etc)

Indication(s) Current if applicable

Proposed if applicable
Dosage Current or proposed for each indication
and duration of therapy

Pharmaceutical form(s)
and strength(s)

PART I
1.2.1 SAFETY SPECIFICATION
Non-clinical
1.2.1.1. <Outline of safety concerns that have not been adequately addressed by
clinical data or which are of unknown significance>; for example Toxicity
(including repeat-dose toxicity, reproductive/developmental toxicity,
nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity etc.)

General safety pharmacology (cardiovascular [including QT interval

prolongation,] nervous system, etc.)

Mechanisms for drug interactions

Other toxicity-related information or data

SAFETY CONCERN (from non clinical RELEVANCE TO HUMAN

studies) USAGE

<repeat dose toxicity>

<Reproductive toxicity> a summary of

important findings (including negatives)
should always be included if the drug is
intended for use in women of
childbearing age.

<developmental toxicity>

Etc

1.2.1.2. <Specify need for additional non-clinical data if the product is to be used
in special populations>

Clinical
1.2 .2 Limitations of the human safety database
1.2.2.1. Exposure
Clinical trial exposure
The following tables should be provided, separately for each indication with a
summary table showing total exposure. Provide each table, where available,
based on exposed (to medicinal product of interest) persons in:
a) randomised, blinded trial population only
b) All clinical trial populations (including open extension).

Table 1: BY DURATION

INDICATION (or TOTAL)

Duration of exposure Persons Person time

Cumulative Up to 1 m

Cumulative Up to 3 m

Cumulative Up to 6 m

Cumulative Up to 12 m

Table 2: BY DOSE

INDICATION (or TOTAL)

Dose of exposure Persons Person time

Dose level 1

Dose level 2

etc

Table 3: BY AGE GROUP AND GENDER

INDICATION (or TOTAL)

Age group Persons Person time

M F M F
Age group 1

Age group 2

etc

Table 4: BY ETHNIC ORIGIN

INDICATION (or TOTAL)

Persons Person time

Ethnic origin 1
Ethnic origin 2
etc

Table 5: SPECIAL POPULATIONS

INDICATION (or TOTAL)

Persons Person time

Pregnant women

Lactating women

Renal impairment
(specify or categorise)

Hepatic impairment
(specify or categorise)

Cardiac impairment
(specify or categorise)

Sub populations with

genetic polymorphism
(specify)

Note the categories provided, are suggestions only and the tables should be
tailored to the product, clearly identified and justified. For example, for parenteral
administration, consider number of administrations e.g. 1, 2, 3 or more repeated
exposures. For age and gender make explicit reference to paediatric and elderly
populations.

Epidemiological study exposure

Study Study type Population Duration Number Person time

(eg cohort studied (study of (if
or period) persons appropriate)
case/control (in each
group or
of cases
and
controls)
Study1

Study 2

etc

Post marketing (non study) exposure

Data on patients exposed post marketing should be provided based on market
research where possible. When the number of persons is calculated on the basis
of sales data, details and justification should be provided of the measure used to
calculate exposure. Tables should be provided for each indication where
possible.

Table 1: BY AGE GROUP AND GENDER

INDICATION (or TOTAL)

Age group Persons Person time

M F M F
Age group 1

Age group 2

etc

Table 2: BY DOSE

INDICATION (or TOTAL)

Dose of exposure Persons Person time

Dose level 1

Dose level 2

etc

Table 3: BY COUNTRY

INDICATION

Persons Exposure(eg packs or

person years)

EU
NON EU

If possible, EU use should be broken down into country or sales area. Note the
categories provided, are suggestions only and other relevant variables can be
used eg oral versus iv, duration of treatment etc.

1.2.3 Populations not studied in the pre-authorisation phase

For each pivotal and supporting study, list exclusion criteria for studies.
Study No of patients Age range Exclusion
number exposed to this criteria for study
product in the
study

The limitations of the human safety database should be discussed in terms of the
relevance of inclusion and exclusion criteria and the populations actually studied
in relation to the target population(s). Where exclusion criteria are not proposed
as contraindications to treatment this should be discussed and justified.
Populations to be considered for discussion should include (but is not limited to):
 Children Elderly
 Pregnant of lactating women
 Patients with relevant co-morbidity such as clinically significant renal,
hepatic or cardiac impairment
 Patients with disease severity different from that studied in clinical trials
 Sub-populations with genetic polymorphisms
 Patients of different ethnic origins

1.2.4 Post authorisation experience

1.2.4.1. <Projected post-authorisation usage data>

For the initial EU-RMP, or when seeking a significant change to the indication,
provide details on Projected pattern, estimated population drug usage over time,
place in treatment and market position.

1.2.4.2. <Actual post-authorisation usage data>

For updates to the EU-RMP, specific reference should be made to how the
realised pattern of exposures has differed from that predicted, including off label
use.

1.2.4.3. <Regulatory action taken>

For updates to the EU-RMP only, please list regulatory action taken (worldwide
cumulative table)
Issue Country Action taken Date

Issue 1 Country 1 Action 1 Date 1

Country 2 etc Action 2 etc Date 2 etc

Issue 2 etc Country 1 etc

1.2.5 Adverse events/Adverse reactions

1.2.5.1. Newly identified safety concerns (since EU-RMP last submitted

Safety concern 1
Details Source
Implications for product literature
New studies proposed in pharmacovigilance plan? Yes/No
New risk minimisation actions proposed? Yes/No
Safety concern 2 etc

1.2.5.2. Details of important identified and potential risks (including newly

identified) for each important identified and potential risk provide the following if
available:

Identified Risk <> MedDRA PT terms

Seriousness/outcomes <tabulate the distribution of outcomes

e.g. % fatal, % recovered/with/without
treatment/sequelae, % not recovered,
% hospitalised etc>

Severity and nature of risk <e.g. tabulate grades of severity where

available>

Frequency with 95 % CI <as per the guideline section 4.5.2.3:

Background incidence/prevalence
give relative and excess (over placebo
or comparator) as incidence rates and
incidence risk for populations:
1) randomised, blinded trial population
only
2) all clinical trial populations (including
open extension)
3) epidemiological studies stratified by
indication Where there are clear
differences in rates between
populations, this should be
discussed>
Background incidence/prevalence in
the target population(s)

Risk groups or risk factors <describe use, dose, time and

susceptibility data or other factors
where available. Cumulative hazard
function may be provided>
Potential mechanisms <describe>

Preventability <provide data on predictability or

preventability of ADR>

Potential public health impact of safety <describe or enumerate if possible,

concern using e.g. Numbers Needed to Harm
and/or expected number of patients
affected, hospitalizations, fatalities
given in the predicted population use>

Evidence source <identify and cross refer to supporting

data in CTD or annex data> or PM
clinical trials, safety studies,
pharmacoepidemiological studies,
PSUR, other safety reports etc.

Regulatory action taken <country, type of action>

1.2.6 Identified and potential interactions with other medicinal products,

food and other substances

For each important interaction, provide the following:

Interacting substance <>

Effect of interaction (including MedDRA

terms if appropriate)
Evidence source <>

Possible mechanisms <>

Potential health risk <>

Discussion

1.2.7 Epidemiology of the indication(s) and important adverse events

1.2.7.1. For each indication, discuss the incidence, prevalence, mortality and
demographic profile of the target population
Indication/target population <>

Incidence of target indication < > (note if specific inter-country

 variation is known)

Prevalence of target indication <>

Mortality in target indication <>

Potential health risk < > (note if specific inter-country
variation is known)

Demographic profile of target <Provide age sex distribution>

population

1.2.7.2. For each indication, discuss the important co-morbidity in the target
population

Indication/target population List important co-morbidity in the target

population.
For each important co-morbidity,
provide incidence,
prevalence and mortality in the target
population and main
co-prescribed medicinal products

<> <>

1.2.7.3. For each identified or potential risk e.g. hepatic failure, provide the
epidemiology of the condition in the target population when unexposed to the
product
Identified or potential risk <>

Incidence of condition <>

Prevalence of condition <>

Mortality of condition <>

1.2.8 Pharmacological class effects

Identify risks which are believed to be common to the pharmacological class. If a
risk which is common to the pharmacological class is not thought to be a safety
concern with the medicinal product this should be justified and supporting
evidence provided.
Risk Frequency in Frequency seen Comment
clinical trials of with
 medicinal product other products in
same
pharmacological
class
(source of
data/journal
reference)

Risk 1 Product A
Product B
Product C
Review of adverse
reactions BMJ
2008: 5;
214-217

Risk 2 etc

1.2.9 Additional EU Requirements

1.2.9.1. Potential for overdose

1.2.9.2. Potential for transmission of infectious agents

1.2.9.3. Potential for misuse for illegal purposes

1.2.9.4. Potential for off-label use

1.2.9.5. Potential for off-label-paediatric use

1.2.10 Summary – Ongoing safety concerns

Important identified risks <.> List

Important potential risks <.> List

Important missing information <.> List

1.2.11. PHARMACOVIGILANCE PLAN

The pharmacovigilance plan covers the actions intended to identify and

characterise safety Concerns. It should not include actions intended to reduce
or prevent risks.
1.2.11.1 Routine pharmacovigilance practices
Briefly summarise the routine pharmacovigilance system. If the application is via
the centralized Procedures please cross refer to the section in Module 1.

1.2.11.2 Summary of safety concern and planned pharmacovigilance

actions
For each safety concern, provide a summary table of planned pharmacovigilance
actions. Include newly available results for updates to the pharmacovigilance
plan. Where no action beyond routine pharmacovigilance is planned, please
justify.

Safety concern Planned action(s)

Important identified risks <.> List

Important potential risks <.> List

Important missing information <.> List

1.2.11.3 Detailed action plan for specific safety concerns

For each important identified or potential risk or missing information, provide the
following:

Safety concern <>

Action(s) proposed
Objective of proposed action(s) <>

Rationale for proposed action(s) <>

Detail further measures which may be < >

adopted on the basis of the results of
this action and the decision criteria for
initiating such measures
Milestones for evaluation and reporting < >
including justification for choice of
milestones
Titles of protocols (Annex full study
protocols and provide cross reference < >
to position in annex 5)

1.2.11.4 Overview of study protocols for the pharmacovigilance plan

Study Protocol Protocol Planned date Planned date

version status for for
submission of submission of
interim data final data

1.2.11.5 For updates to the EU-RMP

Safety concern Summary of newly Implications of all

available available
results data for safety concern
(attach study report as
an
annex and provide
cross
reference)

Important identified < > List < > List

risks
Important potential < > List < > List
risks
Important missing < > List < > List
information

1.2.11.6 Summary of outstanding actions, including milestones

Present list of actions to be completed (ongoing and planned) with milestones

and timelines.

Actions Milestones/exposure Milestones/calendar Study status

time
PART I I
1.2.12. EVALUATION OF THE NEED FOR RISK MINIMISATION ACTIVITIES
The evaluation of the need for risk minimisation activities should list all safety
concerns presented in section 1.10. Evaluate and justify whether routine (ie
product information, labelling and packaging) risk minimisation activities will be
sufficient or whether additional risk minimisation activities (e.g. educational
material or training programmes for prescribers, pharmacists and patients,
restricted access programmes) will be required. If additional risk minimisation
activities are necessary a risk minimisation plan should be provided (see section
4). If, for any safety concern, no risk minimization activities at all are proposed
this should be fully justified.

1.2.12.1 For each safety concern from section 1.10, provide a summary
table of planned actions

Safety concern Routine risk If yes, provide

minimisation activities description of
sufficient? routine activity and
justification

Important identified Yes/No

risks (List)
Important potential Yes/No
risks (List)
Important missing Yes/No
information
(List)

1.2.12.2 Potential for medication errors

MAAs/MAHs are encouraged routinely to consider the likelihood of medication
errors. In particular, they should assess prior to marketing, common sources of
medication errors. During the development phase and during the design of the
medicinal product for marketing, the applicant needs to take into account
potential reasons for medication error. The naming (taking into account the
“Guideline on the acceptability of invented names for human medicinal products
processed through the centralised procedure. CPMP/328/98”), presentation (e.g.
size, shape and colouring of the pharmaceutical form and packaging),
instructions for use (e.g. regarding reconstitution, parenteral routes of
administration, dose calculation) and labelling are among the items to be
considered. If a product has life-threatening potential when administered by an
incorrect route, consideration should be given as to how such administration can
be avoided. This is particularly important when it is common practice to
administer the product at the same time as other medicinal products given by the
hazardous route. The need for visual (or physical) differentiation between
strengths of the same medicinal product and between other medicinal products
commonly administered or taken at the same time should be discussed. When a
medicinal product is likely to be used by a visually impaired population, special
consideration should be given to the potential for medication error. Consideration
should be given to the prevention of accidental ingestion or other unintended use
by children. Medication errors identified during product development should be
discussed and information on the errors, their potential cause(s) and possible
remedies given. Where applicable an indication should be given of how these
have been taken into account in the final product design. If post marketing, it
becomes apparent that adverse reactions are occurring as a result of medication
errors, this topic should be discussed in the updated EU-RMP and ways of
limiting the errors proposed.

1.2.13. RISK MINIMISATION PLAN

For each important identified or potential risk for which additional risk
minimisation measures are planned, provide the following:

Safety concern

Routine risk minimisation activities <Short description of what will be put in

(i.e. product information, labelling and the SPC, labelling etc to minimise risk
packaging) e.g. warning in 4.4 that caution should
be used in patients with cardiac failure
etc>

Additional risk minimisation Objective and rationale

activity 1
(e.g. educational material or training
programmes for prescribers,
pharmacists and patients, restricted
access programmes)
Proposed actions
Criteria to be used to verify the success
of proposed risk minimisation activity

Proposed review period

Additional risk minimisation Objective and rationale

activity 2 etc
Proposed actions

Criteria to be used to verify the success

of proposed risk minimisation activity
 Proposed review period

1.2.14. SUMMARY OF THE EU RISK MANAGEMENT PLAN

Safety concern Proposed Proposed risk

pharmacovigilance minimisation
activities activities
(routine and additional) (routine and additional)

Safety concern 1 E.g. E.g.

routine
contraindication in
pharmacovigilance section 4.3 of the SPC

drug utilisation study
warning in section 4.4
to investigate ……. of the SPC that…….

Educational material

Controlled distribution

Safety concern 2 etc

1.2.15. CONTACT PERSON FOR THIS EU-RMP

Names <>

Position <>

Qualifications <>

Signature <>

ANNEXES
List of annexes
Annex No

1. Interface between EU-RMP and

EudraVigilance ( to be provided in
electronic format)

2. Current (or proposed if initial EU-RMP)

SPC, Package leaflet

3. Synopsis of ongoing and completed

 clinical trial programme

4. Synopsis of ongoing and completed

pharmacoepidemiological study
Programme
5. Protocols for proposed and ongoing
studies from Pharmacovigilance
Plan
6. Newly available study reports

7. Other supporting data

8. Details of proposed educational
programme (if applicable)

Examples of annexes include the following:

Annex I: Interface between EU-RMP and EudraVigilance
EU Risk Management Template: Data Elements to be provided in Electronic
Format for Centrally Authorised Medicinal Products
As part of the EU Risk Management Plan it is important to monitor the identified
or potential risks in the context of the suspected adverse reactions reported to
EudraVigilance. This applies to centrally authorised medicinal products. To allow
the identified and potential risks to be monitored in EudraVigilance, these
elements should be provided electronically. A template for capturing the relevant
data elements will be provided at the EudraVigilance website
(http://eudravigilance.emea.europa.eu) to coincide with the release of Volume 9A
in one of the following formats:
- Access Database
- Microsoft Word Macros Enabled
For centrally authorised medicinal products the completed template should be
provided at the initial submission of the EU Risk Management Plan and each
time the plan is updated, with regard to the data elements captured in the
template.

Annex 3: Ongoing & completed clinical trial programme

Study Description , Design, No of Estimated/Actual

Phase, patients completion date
Countries Follow-up

Large outcome
studies

Study ABC Short description Double-blind 4000 Jan 2005

 of 1 year
study (1 – 2
sentences
including
comparator
name(s)/placebo)
Phase III
Germany, USA,
Chile

Study DEF Etc Double-blind 2000 Feb 2008

1 year

Further
safety/efficacy
studies of XYZ

Study GHI Etc Etc Double-blind March 2005

1000
26 weeks

Study JKL Etc Etc Open-label Nov 2005

2000
48 weeks

Studies in special
subgroups

Study MNO Etc Open-label 1000 Feb 2005

12 weeks

Paediatric studies

Study PQR Etc Open-label 500 Feb 2005

48 weeks

Annex 4: Pharmacoepidemiological programme

Study Description Study designs Estimated/actual
No of patients completion date
Duration of (dates when
follow-up interim
and final study
reports are
expected)
 CHAPTER 2

DRUG HYPERSENSITIVITY
 2.1 Adverse drug reactions
 2.2 Making the diagnosis
 2.3 Blood specific IgE testing
 2.4 Evaluation: to challenge or not?
 2.5 Management of ADRs
 2.6 Desensitisation
 2.7 Some specific drugs
 2.8 Non-steroidal anti-inflammatory drugs (NSAIDs)
 2.9 Angiotensin-converting enzyme (ACE) inhibitors
 2.10 Sulfonamide antibiotics
 2.11 When to refer

Doctors are frequently faced with patients who report that they are “allergic” to a
drug or a range of drugs. In some cases, further questioning reveals only scant
information about a possible reaction in early childhood, with no recollection of
the circumstances or reaction, and no documentation available; in other cases,
detailed history taking reveals that the reaction was a side effect, intolerance or
some other adverse drug reaction (ADR) rather than a true drug allergy. A
common problem faced by doctors is trying to determine the specific cause of a
possibly drug-related skin rash in patients taking multiple medications. Often
there is also uncertainty as to whether the rash may be due to the underlying
disease (eg, an infection) or to the antibiotic prescribed to treat it.

Trying to determine whether a causal relationship exists (and, if so, with which
medication), the true nature of the reaction, and implications for future drug
prescription can be a frustrating experience for both doctors and patients. Lack of
knowledge and experience in this important area can lead to fear of multiple
“drug allergies” and unnecessary avoidance of appropriate medications, with
reliance on more expensive, or less effective, alternatives without a rational
basis.

The pragmatic approach taken in my article is to consider carefully all patients

presenting with a supposed “drug allergy”, give a clinical framework to determine
causality, and clarify which reactions are likely to be the result of true drug allergy
in the context of all adverse drug reactions. Specialist procedures such as drug
challenge or desensitisation are beyond the scope of my article, but the
principles behind them will be explained. This will also help guide doctors as to
which patients would benefit from referral for such investigation and
management.

2.1 Adverse drug reactions

The World Health Organization defines an ADR as a response to a drug that is

noxious, unintended or undesired occurring at doses normally used for the
prevention, diagnosis or treatment of disease. A pharmacological classification
divides most ADRs into one of two major subtypes: type A and type B reactions.

Type A reactions are pharmacological effects that are predictable and dose-
dependent. Most ADRs (about 80%) are type A reactions, which include toxic
effects (such as digoxin toxicity, and serotonin syndrome caused by selective
serotonin reuptake inhibitors); side effects; secondary effects (eg, antibiotic-
associated diarrhoea); and drug interactions.

Type B reactions are hypersensitivity reactions that are unpredictable and not
dose-dependent. They lead to objectively reproducible symptoms or signs at a
dose tolerated by normal people.Type B reactions comprise about 10%–15% of
all ADRs. Drug allergies, which comprise 5%–10% of ADRs, are hypersensitivity
reactions that involve an immune mechanism (IgE- or T cell-mediated, or, rarely,
involving an immune complex or cytotoxic reaction). All other hypersensitivity
drug reactions without an immune mechanism (5%–10%) — or in which an
immunological process is not proven — are classified as non-immune (or non-
allergic) hypersensitivity reactions.

2.2 Making the diagnosis

Clinical history: is it an adverse drug reaction?

The most important step in assessing a possible ADR is to take a detailed clinical
history — to assess causality, determine the underlying mechanism
(pharmacological effect or hypersensitivity reaction) and assess whether the
reaction may be allergic in nature (ie, immune-mediated hypersensitivity
reaction). Careful documentation by the attending doctor of the circumstances
and type of reaction of the suspected ADR is critical. Important initial questions
on clinical assessment include the following:

 What was the temporal relationship between ingestion/administration of

the drug and onset of the reaction?
 Was the nature of the reaction in keeping with known adverse reactions to
the drug?
 Did the reaction resolve with cessation of the drug, and did it recur if the
drug was recommenced?
  Were other drugs administered concurrently that could have caused the
reaction?
 Was/Were there any underlying condition(s) of the patient that could
explain the reaction?

If a clear clinical history and supportive documentation are available, a probability

(or index of suspicion) can often be assigned to the likely cause. For example, a
high probability can be assigned if there was a clear temporal relationship, a
reaction consistent with known adverse reactions to the drug, an improvement
after cessation of the drug or recurrence of a reaction after re-challenge, and no
reasonable alternative explanation for the reaction (such as reaction to another
drug or underlying condition).

The pharmacological features of type A adverse reactions (toxicity, side effects,

secondary effects and drug interactions) can often be determined by searches of
pharmacological references and databases such as the Australian medicines
handbookor MIMS annual. However, doctors are sometimes faced with an
unclear history or lack of supportive documentation, making this important part of
the evaluation indeterminate.

Clinical history: is it a true drug allergy?

If there is high probability of a causal relationship and the reaction is not

pharmacologically mediated, the following three questions can help to distinguish
immune-mediated (allergic) from non-immune-mediated hypersensitivity:

 Did the observed reaction occur on first exposure to the drug?

 What was the nature of the reaction?
 What was the time course of the reaction?

Did the observed reaction occur on first exposure?

Immunologically mediated reactions require previous exposure and time for an

immune response (sensitisation) to develop. Hence, they do not usually occur
the first time a drug is taken. It is not uncommon for a patient to be tolerant to the
first course of a drug (during which they are sensitised) and then to experience a
reaction on taking the first dose of the next course some weeks or months later.
An exception to this is when there is previous sensitisation to another drug that
has common antigenic determinants (eg, penicillin and cephalosporin have
shared β-lactam determinants).

What was the nature of the reaction?

Urticaria, angioedema, bronchospasm and anaphylaxis signify mast cell

activation, and usually indicate an immune mechanism mediated by drug-specific
IgE antibodies). However, some drugs (eg, radiocontrast media, aspirin or
vancomycin) may activate mast cells directly, or through non-immune
mechanisms, without previous exposure.

Maculopapular exanthems such as morbilliform, fixed drug eruptions and other

non-specific rashes are mediated by T cells. Hence, detailed history and
documentation — such as getting the patient to take a photo of the rash, if it is
transient — can often help to elucidate the nature of the reaction, distinguish
between urticarial and morbilliform rashes, and guide appropriate testing and
management.

Life-threatening conditions such as erythema multiforme major (Stevens–

Johnson syndrome) and toxic epidermal necrolysis, which cause widespread
desquamation, mucosal ulceration and high fevers, are also mediated by T cells.
The effector cells in these reactions are drug-specific memory T cells, but the
exact mechanism is unclear.

What was the time course of the reaction?

Immediate reactions (occurring from several minutes to 1 hour after drug

administration) suggest an IgE-mediated event caused by pre-formed IgE
antibodies.

Non-immediate reactions (occurring more than 1 hour after drug administration)

suggest a drug-specific T cell-mediated mechanism. These late reactions may
present in a variety of ways, including fixed drug eruptions, maculopapular
morbilliform rashes, and bullous or pustular exanthems. Other non-cutaneous
manifestations may include unexplained pyrexias, arthralgia, myalgia,
eosinophilia or other haematological abnormalities, and derangement of liver
function. These non-immediate reactions are not IgE-mediated, which has
implications for diagnostic testing and management.

Detecting allergen-specific IgE

Skin testing

Skin testing (by skin prick or intradermally) is of predictive value for only a limited
group of IgE-mediated drug allergic reactions. The best characterised drug is
penicillin, for which the immunogenic isotopes (the parts of the molecule
recognised by the immune system) have been identified. They consist of a major
determinant (accounting for 95% of penicillin degradation metabolites) and minor
determinants (accounting for 5% of metabolites). Testing with major and minor
determinants is done with a skin prick test, followed by an intradermal test if the
skin prick test is negative. (The commercial product Pre-Pen [Hollister-Stier],
which contains the major determinant of penicillin, is currently unavailable
anywhere, but alternatives may be available in the near future.) A weal diameter
of at least 3 mm greater than that of the negative control, together with erythema,
constitutes a positive test. US studies have shown that a negative test in patients
with an indeterminate clinical history indicates that penicillin can be administered
with less than 4% risk of an immediate reaction (similar to the risk in the general
population). However, more recent European research indicates that the
predictive value is much lower in patients with a documented high probability
clinical history of immediate reaction. Amoxycillin and ampicillin should be
included in the skin test array to improve the diagnostic value. This is because,
with changes in drug prescription patterns, some patients are developing
immunological reactivity to β-lactam sidechains specific to amoxycillin and
ampicillin molecules, rather than the classical major and minor determinants
common to all synthetic penicillin β-lactams.

Other drugs for which skin prick and intradermal tests are of predictive value
include muscle relaxants, insulin, and biological agents such as Gelofusine (B.
Braun) (a plasma volume expander) and streptokinase. Patch tests are done by
making a 5% concentration of the relevant drug in a vehicle such as petrolatum,
applying it to the skin and measuring the reaction after 48–72 hours. They are
used to study non-immediate reactions, although their clinical diagnostic value is
limited. However, for the vast majority of allergic drug reactions, there are no
validated skin tests that have been shown to be of predictive value. This is
because the reactions are either not IgE-mediated, or the relevant immunogenic
epitopes (which may be derived from unidentified drug metabolites or breakdown
products) have not been identified for most drugs.

2.3 Blood specific IgE testing

The radioallergosorbent test (RAST) and the non-radioactive enzyme-linked

immunosorbent assay (ELISA) are commercially available in-vitro tests for
detecting serum specific IgE antibodies. The tests are only available for some β-
lactam antibiotics, as the immunogenic epitopes for most drugs are unknown.
Like other in-vitro tests, they are generally more specific but less sensitive than
skin tests. Hence, they have poor negative predictive values but better positive
predictive values, and are used in conjunction with clinical evaluation and skin
tests.

The lymphocyte transformation test detects drug-specific T cells, which may be

involved in some delayed allergic hypersensitivity reactions, but this is used for
research purposes and has limited clinical application.

2.4 Evaluation: to challenge or not?

A drug provocation challenge is the controlled, graded administration of a drug in

order to diagnose a drug hypersensitivity reaction. There are three situations in
which a drug provocation challenge may be considered when evaluating allergic
drug hypersensitivity:
  When the clinical evaluation suggests low or indeterminate clinical
probability of a causal relationship between the drug and the ADR, the
reaction is not severe, and skin or in-vitro tests are not available or helpful,
a drug provocation challenge may be considered, to eliminate suspicion
and allow the drug to be used in future;
 When clinical evaluation suggests a moderate to high probability that a
particular drug was the cause of an ADR and a safe alternative is
required, another chemically or structurally different or unrelated drug may
be given under monitored challenge to exclude the possibility of cross-
reactivity between the two drugs;
 When a drug is implicated with high probability (with or without supportive
skin and in-vitro tests, if available) and is the drug of choice, a drug
provocation challenge may be given to confirm the diagnosis, followed (if
positive) by desensitisation (see below) and therapeutic administration of
maintenance doses.

The general principle of a drug challenge is to start at a very low dose (well
below the normal therapeutic dose) and give repeated administration at
increasing (usually doubling) doses of the drug until a threshold of reaction is
reached, when first objective symptoms occur. (If no symptoms appear, the
challenge stops when the therapeutic dose is reached.) Intervals between dosing
may range from 15 minutes to several hours, depending on the drug, and it may
be given orally or intravenously.

Provocation tests should be done in specialised clinics or hospitals with

established protocols and resuscitation facilities, and should never be conducted
in patients with a history of severe, life-threatening vasculitic syndromes,
exfoliative dermatitis, erythema multiforme major, drug-induced hypersensitivity
reactions with eosinophilia, or toxic epidermal necrolysis.

2.5 Management of ADRs

The approach to the patient with a suspected ADR must be very methodical
(Firstly, as outlined above, a causal relationship must be established between the
drug and the reaction. Then the reaction type must be determined, if possible.

For type A (pharmacological) drug reactions, dosage modification may be all that
is necessary before drug re-administration. Toxicity, as well as drug-induced side
effects and secondary effects (eg, nausea and vomiting caused by opiates, or
antibiotic-associated diarrhoea) may resolve at lower drug doses.

For type B (hypersensitivity) drug reactions, several options may be considered.

After severe or life-threatening reactions, the drug should not be re-administered.
For less severe reactions, a drug provocation challenge may be considered. For
type B immunologically-mediated (allergic) reactions, the management option
depends on the mechanism responsible for the reaction. If validated confirmatory
tests are available, they should be used to determine the allergic status of the
patient (eg, tests for penicillin-specific IgE antibodies). If such tests are not
available — and in most cases they are not — several approaches can be taken.
The simplest approach is to avoid the drug if an alternative agent is available. If
an alternative drug does not exist, a graded challenge with the implicated agent
can be done if the previous reaction was not life-threatening and not consistent
with an IgE-mediated reaction. However, if the medication is needed as the drug
of choice, then desensitisation should be considered.

2.6 Desensitisation

Desensitisation is possible for many drugs by continuing repeated administration

of doubling doses after a positive drug challenge until a therapeutic dose is
reached. (The desensitisation process is identical to a drug challenge, except
that a drug challenge is stopped when a positive reaction occurs, whereas, in
desensitisation, drug administration is continued in spite of an initial mild
reaction.) The mechanism of drug desensitisation is not well understood, but
may, in some cases, involve controlled degranulation of mast cells. However, the
desensitised state is not permanent — in contrast to some allergen
immunotherapy (eg, bee venom immunotherapy) — and is sustained only with a
daily maintenance dose of the drug. Cessation of the maintenance dose will
allow the drug hypersensitivity to return, usually within a few days, and
subsequent administration will require a repeated desensitisation process if the
maintenance drug has been stopped. Drugs for which desensitisation may be
successful include allopurinol, cotrimoxazole, β-lactam antibiotics and aspirin.

2.7 Some specific drugs

β-lactam antibiotics

Allergic reactions to β-lactam drugs are the most common group of type B
hypersensitivity ADRs. The clinical, diagnostic and management approach to
IgE-mediated immediate penicillin allergy has already been discussed (see
“Detecting allergen-specific IgE: skin testing”, above). For the majority of
reactions that produce non-immediate exanthems (and are probably mediated by
T cells rather than IgE), the approach depends on the severity of the reaction and
the potential need for penicillin-based therapy in the future.

Lifelong avoidance of a drug is necessary for the rare but severe reactions such
as erythema multiforme major or toxic epidermal necrolysis. With more common
morbilliform maculopapular exanthems, as seen when amoxycillin is
administered concurrently with a viral infection (eg, infectious mononucleosis),
the exact mechanism is not clear, but may be due to viral infection altering the
immune status of the host. In this situation, the drug can be administered safely
again once the viral infection has resolved, highlighting the critical role of taking a
detailed clinical history and making a careful assessment.
When a patient with immediate penicillin allergy requires an alternative β-lactam
drug, consideration can be given to prescribing a cephalosporin. A review of
11 studies of cephalosporin administration to patients with a history of penicillin
allergy found cephalosporin reactions in 4.4% of patients with positive skin tests
for penicillin. A practical approach is to ascertain whether the previous penicillin
reaction was an immediate IgE-mediated allergy, and, if not, a graded challenge
can be performed to determine whether the cephalosporin is a safe alternative. If
the previous penicillin reaction was immediate, evaluation with penicillin skin
testing should be done first.

2.8 Non-steroidal anti-inflammatory drugs (NSAIDs)

Hypersensitivity reactions to aspirin and other NSAIDs may have a number of

clinical manifestations. One clinical syndrome is late-onset asthma (onset age in
the 30s or 40s) with nasal polyposis, and later development of aspirin
hypersensitivity, with NSAID ingestion provoking asthma and rhinitis. This may
affect 5%–10% of people with asthma. It involves a non-immune hypersensitivity
mechanism of increased leukotriene production caused by inhibition of the cyclo-
oxygenase-1 (COX-1) enzyme. Such people are sensitive to aspirin and all older
non-specific NSAIDs, but tolerate specific COX-2 inhibitors (such as celecoxib).
However, there are other clinical syndromes in which there is no history of
asthma or rhinitis and the patient has an isolated sensitivity to a specific NSAID.
This may have an immunological basis with a putative IgE mechanism. Clarifying
the history and recognising the clinical patterns can allow specific provocation
challenges to ascertain safe alternatives and prevent unnecessary avoidance of
aspirin or other NSAIDs

2.9 Angiotensin-converting enzyme (ACE) inhibitors

Angioedema is a well recognised adverse reaction that affects 0.1%–0.5% of

patients taking ACE inhibitors. Angioedema can first appear anywhere from a few
hours to 8 years after an ACE inhibitor is taken, with up to 20% of cases being
life-threatening. The reaction involves a non-immune hypersensitivity mechanism
caused by the accumulation of plasma kinins (such as bradykinin) as the result of
inhibition (by ACE inhibitors) of the kininases that normally metabolise and
inactivate bradykinin. If a patient taking an ACE inhibitor develops angioedema,
the cause must be assumed to be the ACE inhibitor, and the drug should be
ceased immediately (until such time as the drug is proven not to be the cause)
Rare instances of angioedema have also been reported after taking angiotensin-
receptor antagonists, but these reactions may not be mediated by bradykinin.

2.10 Sulfonamide antibiotics

Delayed reactions, such as maculopapular exanthems, associated with

cotrimoxazole are probably mediated by T-cell responses to reactive sulfonamide
metabolites. There is increased frequency of these reactions in certain clinical
situations (eg, they affect 20%–80% of patients infected with HIV, compared with
1%–3% of non-HIV-infected patients, possibly due to altered drug metabolism).
Management is by avoidance, but desensitisation is possible in some cases.

Another common clinical problem is the putative cross-reactivity between

sulfonamide antibiotics and other sulfonamide-derived drugs (eg, diuretics,
sulfonylureas, celecoxib and sumatriptan). Patients may report that they are
“allergic” to “sulfur antibiotics”. Although the true nature of their reaction may
often be obscure, they are excluded from taking drugs in these groups because
of concern about supposed cross-reactivity with their sulfonamide component.
However, this is only a theoretical concern that has not been borne out in clinical
practice, and need not necessarily exclude their use if clinically indicated.
Furthermore, there is no relationship between sulfonamide allergy and
intolerance to sulfite preservatives in food.

2.11 When to refer

In assessing ADRs, it is important for physicians to distinguish between those

that represent hypersensitivity from those that are pharmacological. If possible,
hypersensitivity reactions need to be differentiated further into those that are truly
allergic in nature and those that are not immunologically mediated. Clinical
evaluation is the most important means of assessment, with supportive skin tests
and laboratory tests helpful if validated and available. Referral for specialist
assessment is warranted:

 for early assessment of possible drug reactions when the mechanism of

reaction is unclear;
 for advice on distinguishing sulfur antibiotic reactions from risk of reaction
to sulfur-containing non-antibiotics or dietary sulfites;
 for assessment of severe reactions, such as toxic epidermal necrolysis;
 when avoidance of a particular drug is not an option;
 to help choose a suitable NSAID when a patient has reacted to a drug in
this class; or
 When considering desensitisation if an implicated medication is the drug
of choice.

However, until we have a better understanding of the mechanisms

responsible for hypersensitivity drug reactions, our management tools will
remain limited.

1. Classification of adverse drug reactions, including hypersensitivity and

immune-mediated drug allergy
2. Florid lip and face angioedema due to β-lactam immediate

3. Immediate hypersensitivity urticarial rash secondary to vancomycin

administration

Courtesy of Department of Dermatology, Alfred Hospital,

Melbourne.
4. Toxic epidermal necrolysis secondary to sulfasalazine administration

Courtesy of Department of Dermatology, Alfred Hospital,

Melbourne.

5. Management of drug allergy

6 Case scenario*
A 45-year-old man who was previously well (apart from mild seasonal hayfever,
treated occasionally with antihistamine) presented for review of a recent
documented anaphylactic reaction. He had woken one morning with a sore knee,
for which he took a tablet of naproxen 500 mg after his usual breakfast. Within
10 minutes (while sitting on the toilet), he felt itching on his scalp, which became
generalised. When he got up to wash his hands, he felt dizzy and fainted. On
regaining consciousness (within a minute, according to his wife), he felt
shortness of breath and the need to open his bowels again. When he fainted
again, this time on the toilet seat, his wife rang for an ambulance.

At the hospital emergency department, he was noted to be faecally incontinent,

with an unrecordable blood pressure and slow respiration. Treated with
adrenaline, intravenous fluids and steroids, he recovered within an hour and was
discharged the following day.

On further questioning, it was found he had injured his knee while playing football
and had taken a 1-week course of naproxen within the previous 3 months, with
no side effects. He had taken no other medications at that time.

In this case, naproxen was the “smoking gun”, with no other reasonable or
rational alternative explanation for the witnessed events. No supportive skin or in-
vitro tests are available for naproxen or other non-steroidal anti-inflammatory
drugs (NSAIDs). As there were no alternative explanations, a confirmatory drug
challenge was not needed; in any case, the severity of the reaction ethically
precluded it. However, the issue of whether the patient could take other NSAIDs
or aspirin for future cardiovascular prophylaxis was an important one to resolve.

The patient had no history of asthma or nasal polyposis (for which the clinical
syndrome includes sensitivity to all cyclo-oxygenase-1 [COX-1] inhibitors),
suggesting that this was a single-drug immune hypersensitivity reaction. The
reaction was possibly mediated by an as yet unidentified IgE mechanism —
perhaps involving sensitisation after the previous course of naproxen.

A negative reaction on challenge with aspirin confirmed that the mechanism of

the patient’s anaphylactic reaction was not COX-1 inhibition, and that he could
take aspirin safely for cardiovascular prophylaxis in future. He was also
challenged with diclofenac, which is structurally unrelated to naproxen, to which
he had no reaction. Thus, he was advised to use diclofenac in the future if an
NSAID was required. He was instructed to avoid naproxen lifelong, as well as its
structurally related NSAIDs (including ibuprofen, ketoprofen and flurbiprofen), in
order to avoid possible, but as yet unproven, immune cross-reactivity to
structurally related drugs.

* This is a fictional case scenario based on similar real-life cases.

7 Evidence-based practice tips*

 Drug desensitisation can allow safe administration of the drug in

immediate hypersensitivity reactions, even in cases of anaphylaxis (Level
III-3).
 If a patient taking an angiotensin-converting enzyme (ACE) inhibitor
develops angioedema, the cause must be assumed to be the ACE nhibitor
until proven otherwise (Level IV).

* Based on National Health and Medical Research Council levels of evidence

 CHAPTER 3
HOW DO WE FIND USEFUL SIGNALS?- volume 1
 CHAPTER 4
VISION FOR PHARMACOVIGILANCE IN EUROPE
 4.1 INTRODUCTION
 4.2 SCOPE AND WORKING METHODOLOGY
 4.3 KEY INITIATIVES ENVISAGED DURING THE PERIOD MID 2007-
MID 2009
 4.4 REPORTING

Implementation of the Action Plan to Further Progress the European Risk

Management Strategy:
4.1 Introduction
The 2005 document “Action Plan to Further Progress the European Risk
Management Strategy”, hereafter called “Action Plan”, describes at a high-level
how to achieve high standards of public health protection for all medicines
available on the European Union (EU) market, which is the primary objective of
the European Risk Management Strategy (ERMS).In a report (“Public Status
Report on the Implementation of the European Risk Management Strategy
(Reporting Period Mid 2005 – Mid 2007”), published in July 2007, information is
provided on all initiatives undertaken since mid 2005 up to the end of May
2007. The aim of the current document is to describe how the further
implementation of the ERMS will be undertaken, by providing information on the
initiatives envisaged for the period 2008-2009.

4.2Scope and Working Methodology

During the previous reporting period activities focused, as per the “Action Plan”,
on three priority areas, i.e. the implementation of new Community legislation,
complementary initiatives to arrive at the envisaged intensive drug monitoring
system, and a further strengthening of the EU Pharmacovigilance System as part
of the EU Regulatory System network. Although overall progress has been very
good (cfr. “Public Status Report on the Implementation of the European Risk
Management Strategy (Reporting Period Mid 2005 – Mid 2007)”), it needs to be
acknowledged that progress in some areas has been more important than in
other areas. In addition, there is a need to take due account of environmental
changes which will impact on the further implementation of the ERMS.
Such environmental changes are:
 European Commission’s Strategy to Better Protect Public Health by
Strengthening and Rationalising EU Pharmacovigilance:
Reference is made to the European Commission’s announcement in
February 2007 to strengthen medicines safety monitoring. Whilst one important
pillar in the European Commission’s Strategy refers to the need for changes to
existing Community legislation, the European Commission has also emphasised
that efforts should be undertaken to improve the implementation of the current
legal framework
  Implementation of new Community legislation:
The EU Regulatory System is being confronted with the implementation of two
new important pieces of Community legislation, i.e. in the fields of paediatric
medicines and advanced therapies. Especially in the field of advanced therapies
a lot of preparatory work needs to be undertaken when implementing the new
legal provisions in order to create an environment which provides for a safe use
of these novel technologies.
 Transatlantic Administrative Simplification exercise:
In the context of the “Framework for Advancing Transatlantic Economic
Integration between the European Union and the United States of America”,
agreed at the EU/US Summit on 30 April 2007, administrative simplification in the
application of regulation of medicinal products will be promoted. Since the area of
Pharmacovigilance/safety of medicines is important in the framework of
medicines regulation, it has been agreed to explore if administrative simplification
can be achieved between the two regions in this field.
 Regulatory cooperation between the EU and non-EU Regulatory
Authorities:
Regulatory cooperation between the EU (European Commission and the
EMEA) recently has been strengthened with both the US and the Japanese
Health Authorities. As announced on 18 June 2007, current regulatory
cooperation between the Food and Drug Administration (FDA) and the EU will be
further expanded in several important areas. This will also relate to the field of
safety of medicines, and an important topic in this respect will be the still novel
concept of risk managements plans/Risk Maps for the medicinal products
covered by the EU/FDA Confidentiality Arrangements. On 2 February 2007 the
EU and Japan (Ministry of Health, Labour and Welfare (MHLW) and the
Pharmaceuticals and Medical Devices Agency (PMDA)) concluded confidentiality
arrangements in the area of human medicines regulation. Safety of medicines
wills also here become an important area for regulatory cooperation.
 EU Regulatory System Strategic Papers:
Reference is made to both the EMEA Road Map and the Heads of Medicines
Agencies (HMA) Strategy Paper. HMA adopted in February 2007 a revised Work
Plan to implement their Strategy Paper. Whilst a number of recommendations
focus on further improving patient safety, others relate to a further strengthening
of the EU Regulatory System networking model, e.g. by reinforcing the
involvement of HMA in regulatory activities undertaken at EU level. The EMEA is
in the process of complementing its Road Map Implementation Plan with
initiatives to be undertaken up to 2010.
The working methodology applied during the previous reporting period has
proven to be appropriate. A targeted approach was applied in advancing the
envisaged initiatives and best use was made of the available resources and
established discussion fora, hence avoiding duplication of work. It needs to be
acknowledged that the third pillar of the applied working methodology, i.e.
involving all relevant stakeholders of the EU Pharmacovigilance System in the
overall process, was not addressed to its full potential. Therefore, the working
methodology during this reporting period should be adapted to allow for more
stakeholder involvement, whilst continuing giving priority to those initiatives which
should most contribute to further improving patient safety. Stakeholders (e.g.
patients, healthcare professionals, pharmaceutical industry, academia/learned
Societies) will be involved, where relevant, in the further development and
implementation of the initiatives.
4.3 Key Initiatives Envisaged During the Period Mid 2007 – Mid 2009
Taking into account the scope and working methodology, as described in Section
II, various initiatives will be undertaken during the next two years. Some are
initiatives which were planned during the previous reporting period but have not
yet started or are still ongoing as a result of the aforementioned combination of a
targeted approach and limited available resources. Other initiatives either had to
be adapted because of recent developments, or have to be considered as new
and additional to what was already planned in 2005. All envisaged activities
should provide for a robust although challenging work programme for the next
two years, but are considered necessary in order to provide an important
contribution to the fulfilment of the requirements necessary to enhance drug
safety in the 21 st century (as already elaborated upon in the previous Work
Programme), i.e.
 moving–up the evidence (best evidence concept);
 applying a more proactive conduct of pharmacovigilance;
 finding the right balance between timely access for patients to medicines
and the knowledge needed on the safety profile of medicines at the
moment of licensing, along with the most robust post-licensing
programme.
The key initiatives that are envisaged for the reporting period 2008-2009 are
described below. They have been classified into two categories, i.e. further
improving the operation of the EU Pharmacovigilance System, and strengthening
the science that underpins the safety monitoring of medicines for human use.

4.3.1 Further Improving the Operation of the EU Pharmacovigilance System

An efficient operation of the EU Regulatory System networking model, and in
particular its pharmacovigilance component, is vital in order to adequately handle
safety concerns for medicinal products for human use, both in the pre- and the
post- authorisation phase. The European Commission’s “Strategy to Better
Protect Public Health by Strengthening and Rationalising EU Pharmacovigilance”
has indicated the need to improve the implementation of the current legislative
framework in which the EU Pharmacovigilance System operates. Four aspects
will need ongoing particular attention during the next phase of the ERMS
implementation, i.e. the implementation of current Community legislation and its
continuous monitoring, the organisation of the EU Pharmacovigilance System,
quality assurance within the EU Pharmacovigilance System, and transparency
and communication aspects within the networking model.

4.3.1.1 Fully implementing and continuously monitoring current legislative

Provisions
Although important progress has been made during the previous reporting period
(mid 2005 – mid 2007) in relation to the implementation of the 2005 Community
legislation, there is still ongoing work, primarily as regards a fully operational
EudraVigilance system and a strengthening of transparency in the field of safety
of medicines. Furthermore, an efficient implementation can only be achieved if
adequate monitoring is in place and correctives measures are being applied,
when considered necessary. Particular emphasis will be put on the risk
management plan concept as it is an important tool for proactive
pharmacovigilance. The Review and Learning project will be broadened to also
investigate the impact of risk management plans (with particular focus on the
harmonised implementation of risk minimisation measures across the EU and the
appropriateness of the agreed post-authorisation safety studies). Regular
feedback from stakeholders is paramount for achieving an efficient
implementation of the 2005 legislative provisions
Key initiatives
 Establishing a fully operational EudraVigilance system in the field of
medicines for human use by addressing
 identified areas of disharmony in the implementation of Community
legislation, in terms of national adverse reaction reporting requirements
and procedures, and
 non-adherence to the expedited reporting requirements and the
agreed
reporting principles
(cfr. also the attached “Action Plan Addressing the Areas of Disharmony in
the Implementation of Community Legislation and the Impact on the
Establishment of a Fully Operational EudraVigilance System in the Field of
Medicines for Human Use”, as agreed upon by both Heads of Medicines
Agencies and the EMEA Management Board during the first half of 2007).
 Providing appropriate levels of access to EudraVigilance data to the
various stakeholders.
 Contributing to the ongoing international standardisation work in
relation to ICH E2B (R3) and M5.
 Updating Annex 6 (Distribution Requirements and Address Lists for
Data
Submission) of Volume 9A of “The Rules Governing Medicinal Products in
the European Union – Guidelines on Pharmacovigilance for Medicinal
Products for Human Use” in line with the European Commission’s Strategy
to Better Protect Public Health by Strengthening and Rationalising EU
Pharmacovigilance, as announced in February 2007.
 Monitoring the implementation of the various legal tools introduced in
2005,
e.g. in relation to the concept of risk management plans, and taking remedial
actions, whenever needed, after consultation with the relevant stakeholders

4.3.1.2 Addressing organisational aspects within the EU Pharmacovigilance

System
An adequate organisation of an increasingly complex EU Regulatory System
(consisting of 27 Members States and 3 European Economic Area (EEA)
Countries) is an important prerequisite in order to achieve a smooth functioning
and an efficient operation of the networking model. Various aspects need to be
considered in this respect, ranging from an increasing workload to be handled in
sometimes very tight timeframes by limited resources, the need to continuously
provide training for regulators to keep abreast of new scientific and technical
developments, adequate crisis management, etc. Furthermore, initiatives
undertaken by the European Commission to provide for better regulation and to
reduce administrative burden will need to be taken into account.
Key initiatives
 Optimising the availability of limited resources within the EU Regulatory
System, and in particular its pharmacovigilance component, by
 performing adequate workload and resource planning (within the frame
of the activities undertaken at the level of the HMA Resources Planning
Group), fully implementing established work-sharing concepts (i.e. in the field of
Periodic Safety Update Reports (PSURs)) and exploring additional
opportunities for work-sharing (e.g. in the context of the “Action Plan
Addressing the Areas of Disharmony in the Implementation of
Community Legislation and the Impact on the Establishment of a Fully
Operational EudraVigilance System in the Field of Medicines for Human
Use”, or in other fields such as signal detection through the
EudraVigilance Datawarehouse and Analysis System (EVDAS)).
 Progressing work within the frame of the Transatlantic Administrative
Simplification exercise (pharmacovigilance related aspects) in accordance
with the agreed Action Plan.
 Establishing a Competence Development Programme for regulators
within the EU Pharmacovigilance System in the context of the activities
undertaken by the HMA Training Project Team.
 Finalising the development of an EU Regulatory System Incident
Management Plan for medicines for human use, implementing and testing it
at regular intervals, and subsequently introducing any necessary
amendments taking into account lessons learnt.
 Strengthening the pandemic influenza preparedness by testing at regular
intervals the available crisis management plan for the evaluation and
maintenance of pandemic influenza vaccines and antivirals.
 Strengthening the interaction with the World Health Organisation (WHO)
in various aspects of pharmacovigilance and reflecting such
strengthening through a revision of the document “Principles of
Collaboration with the World Health Organisation in Matters of
International Pharmacovigilance”, included in Volume 9A of “The Rules
Governing Medicinal Products in the European Union - Guidelines of
Pharmacovigilance for Medicinal Products for Human Use”.
 Monitoring compliance by Marketing Authorisation Holders with
Community legislation and the guidelines included in the aforementioned
Volume 9A.
4.3.1.3 Strengthening quality assurance within the EU Pharmacovigilance
System
It is paramount to build a culture of continuous improvement into the quality of
the work performed by regulators. In order to achieve this objective the
Benchmarking of European Medicines Agencies (BEMA) initiative was launched
by the EU Regulatory System. Activities during the next reference period will
focus on making available top quality scientific expertise to the EU Regulatory
System, in particular the Committee for Medicinal Products for Human Use
(CHMP) and the Pharmacovigilance Working Party (PhVWP), reinforcing and
expanding the existing peer review concept, etc.
Key initiatives
 Enhancing the overall quality of the EU Pharmacovigilance System by
ensuring the availability at EU level of top quality scientific expertise through
the development of an EU-wide up-to-date inventory of the available
scientific expertise (including expertise from academia/learned societies and
non-EU Regulatory Authorities
 Reviewing the composition of both the CHMP and the PhVWP as a
consequence of the new three years’ mandate of their members, with the
aim of reinforcing the scientific expertise, taking into account the outcome of
a gap-analysis of the available expertise, and providing for any additional
specialist input, whenever needed, in order to better support the CHMP and
the PhVWP in the execution of their scientific assessment work.
 Reinforcing the quality assurance of the scientific review processes by
- further improving the existing peer review system for the scientific work
undertaken at CHMP level in the pre-authorisation phase, and
- exploring an extension of the peer review concept to the post-authorisation
Phase, both in relation to the CHMP and the PhVWP activities, taking due
account of experience gained with the current peer review arrangements in the
pre-authorisation phase.

4.3.1.4 Improving transparency and communication on safety related

aspects within the EU Pharmacovigilance System
It needs to be acknowledged that there is an increasing call for more
transparency as regards the work undertaken by Regulatory Authorities. This
certainly is the case in the field of safety of medicines. Two aspects need to be
considered in this respect, the overall transparency on the handling of safety
issues and the routine provision of information, as well as effective and timely
risk communication. Initiatives, which will complement current legislative
provisions, will address both aspects.
Key initiatives
 Increasing the transparency in the field of safety of medicines for human
use by
- developing a dedicated Q&A document explaining the operation of the
EU Pharmacovigilance System, including the roles and responsibilities of
all involved parties,
- providing better targeted and more timely pharmacovigilance related
information, and
- developing a policy on the publication of the scientific rationale for
opinion-making (to allow for better targeted and more timely information
on the opinion-making, including the rationale) and subsequently
implementing such policy.
 Improving the communication on safety related issues by finalising the
development of an EU Regulatory System Communication Strategy on
emerging safety related issues for medicines for human use (including
external consultation with the various stakeholders) and subsequently
implementing such Strategy within the networking model, including
evaluation of its efficiency.

4.3.2 Strengthening the Science and Methodology that Underpins the

Safety
Monitoring of Medicines for Human Use
A robust scientific assessment, in particular as regards the risks associated with
the use of a medicinal product, is paramount in order to obtain a clear picture on
the medicine’s safety profile. Strengthening the science that underpins the safety
monitoring of medicines, needs, however, always to be put into the context of the
benefit/risk concept, whereby the overall aim is to continuously evaluate the
benefit/risk balance of a medicine throughout its entire lifecycle. In addition, there
is also a need to progress work on methodological aspects. Efforts to strengthen
both areas will focus over the next two years on several topics, such as the data
resources, the scientific tools, research aspects, etc. The spontaneous reporting
scheme will remain one of the corner stones of the pharmacovigilance system
and, therefore, initiatives in this field will relate to further improving it. The further
development and the full implementation of EudraVigilance, which should lead to
a better use of the database and its functionalities, should provide an important
contribution to an improved conduct of pharmacovigilance at EU level.
Acknowledging the importance of the spontaneous reporting concept, there is,
however, a need to further increase the knowledge and to move-up the evidence.
The European Network of Centres for Pharmacoepidemiology and
Pharmacovigilance (ENCePP) is being established in order to provide an
important contribution to the best evidence concept by generating more reliable
Pharmacoepidemiological data for pharmacovigilance purposes. Alongside
ENCePP, investing in research (through the Innovative Medicines Initiative (IMI)
and the Health Theme of the 7 th Framework Programme) will be equally
important to allow for a more proactive conduct of pharmacovigilance.
Finally, there is also a need to adequately prepare for the implementation of the
new Advanced Therapies legislation. New challenges stemming from such
legislation will require new scientific approaches into the understanding of risks
associated with emerging therapies.
Key initiatives
 Providing for a full roll-out EVDAS and making available detailed
guidance
on the use of statistical signal detection methods in EVDAS.
 Further developing EudraVigilance by introducing additional
functionalities, especially in the field of signal detection and data mining.
Further developing ENCePP, building on the important progress already
achieved during the previous reporting period, hereby maintaining and even
further strengthening the active interface with academia/learned societies
and implementing such network in order to broaden the access to and
optimising the use of pharmacoepidemiology resources.
 Contributing to IMI in the field of pharmacovigilance, especially in relation
to studies to be performed as regards the methodologies to conduct
pharmacovigilance and the development of new data resources as well as
the strengthening of existing ones.
 Contributing to the Health Theme of the 7 th Framework Programme, in
particular by identifying important public health issues in drug safety affecting
groups/classes of medicines including off-patent products, and providing
such information to the responsible European Commission Services in the
context of future calls for proposals.
 Exploring other methods of risk detection by taking due account of similar
initiatives undertaken by EU and non-EU Regulatory Authorities..
 Further improving opinion-making within the EU Regulatory System,
building on the activities already undertaken at CHMP level by
- integrating the most useful features of benefit/risk assessment models
and methods into CHMP guidelines and assessment report templates,
and
- further investigating the methodology of benefit/risk assessment.
 Undertaking outcome evaluation by
- developing and subsequently implementing methods to monitor the
outcome of regulatory action, and
- assessing the impact of regulatory action and taking corrective
measures, whenever needed.
 Preparing for an adequate implementation of the Advanced Therapies
legislation by drafting guidance in the fields of post-authorisation follow-up of
efficacy, adverse reactions and risk management.
 Expanding activities in the frame of the pandemic influenza preparedness
by
- looking into signal detection aspects with a view to strengthening the
review of adverse reaction data related to the use of influenza vaccines,
and
- providing recommendations (working in close collaboration with WHO) to
the pharmaceutical industry in relation to risk management planning for
influenza vaccines used in a pre-pandemic situation.
 Exploring if additional activities need to be undertaken in order to achieve
a more proactive approach in some specific areas, such as paediatric
pharmacovigilance and pharmacovigilance for vaccines (as regards the
latter, in close cooperation with the European Centre for Disease Prevention
and Control (ECDC)).

4.4 Reporting
Information on the follow-up to all initiatives will be provided in a yearly Status
Report which will be made publicly available. In addition, in order to strengthen
the interaction with stakeholders, a yearly workshop will be jointly organised by
the EMEA and HMA with representatives of patients, healthcare professionals
and pharmaceutical industry, to discuss progress made and look into work still to
be undertaken. This should allow for better active involvement of such
stakeholders in the further development and implementation of the ERMS.
 CHAPTER 5
SAFETY OF VACCINES
5.1 To ensure safety during mass immunization campaigns with injectable
vaccines
5.2 Checklist- 5.2.1 Detailed campaign plans must
- 5.2.2 Safe vaccine administration
- 5.2.3 Sharps waste management
- 5.2.4 AEFI management and monitoring
5.3 Words of advice
5.4 Key elements Planning for mass campaigns, including Safety
components
5.5 Vaccine administration
5.6 Sharps waste management
5.7 AEFI monitoring

5.1 To ensure safety during mass immunization campaigns with injectable

vaccines
Mass immunization campaigns pose specific safety challenges, due to their
objective of immunizing large populations over a short period of time and often
being conducted outside the normal healthcare setting. Two of the most notable
challenges are injection safety and adverse events following immunization
(AEFI). Firstly, with respect to injection safety, the large number of injections to
be administered and the large volume of waste generated pose added strains on
the system. This increases the probability that breaches in safety may occur.
Secondly, with respect to AEFI, there might be the perception of increased rates
of AEFI. Reasons for this include the large number of doses being given over a
short period of time and the administration of vaccine to a wider, usually older,
age group. If not prevented or managed properly, these safety issues can result
in transmission of infections, impaired public and donor confidence in the
campaign, and ultimately, reduced coverage and public health impact. However,
one can avoid such problems by considering safety issues from the start of the
campaign. Components to ensure safety include:
1. Assessing the existing injection safety situation
2. Preparing a detailed campaign plan which addresses key issues identified by
the assessment.
3. Implementing the plan.
4. Monitoring the results.
Managers also need to ensure that they have a simple and timely monitoring
system for adverse events for campaigns. Such a system not only supports the
ongoing campaign, but also provides opportunities to identify key immunization
and injection safety issues. These issues should then be addressed in routine
immunization activities and included in a longer term immunization safety plan.
The main elements in ensuring immunization safety during a mass campaign are:
 An assured source of safe vaccines, safe injection supplies and other
materials.
 Measures to ensure safety of vaccine administration.
 Measures to ensure safe sharps waste management.
 A system for AEFI monitoring and management.
 An advocacy and safety awareness strategy for the public and health staff.
 A budget to ensure funding of all planned components..
5.2 Checklist
5.2.1 Detailed campaign plans must
 Identify all key players and partners
 Plan, budget for and order adequate supplies of all necessary items
 Assess the current injection safety situation
 Include a detailed budget with costs of all safety components
 Plan for staff training and media messages
 Include safety in the campaign from the start
 Monitor, document and disseminate results
 Evaluate and identify lessons learned
5.2.2 Safe vaccine administration
 Use WHO/UNICEF pre-qualified or nationally approved vaccine and
injection material
 Bundled distribution of vaccine and diluent with reconstitution syringes,
auto-disable (AD) syringes and sharps boxes to the immunization sites
 Emphasize need for sterile technique, correct reconstitution and safe
administration
 Train healthcare workers in proper techniques
 Ensure traceability of vaccine by manufacturer and lot number
5.2.3 Sharps waste management
 Assess local regulations and possibilities for sharps treatment and
disposal
 Identify practical, simple solutions for waste collection and disposal
 Ensure availability of sharps waste disposal facilities, adequate safety
boxes.
 Plan transportation, storage and disposal procedures before the
campaign begins
 Provide clear instructions and guidelines for health staff on disposal
 Monitor disposal on a daily basis
5.2.4 AEFI management and monitoring
 Assess or set up AEFI monitoring system
 Develop rapid reporting channels
 Decide which AEFI are to be reported and which contraindications to
observe
 Train health care workers to investigate and manage AEFI and respond
to rumours
 Explain to key people involved in the campaign why the campaign may
result in the perception of increased rates of AEFI.
  Plan and transmit media messages on the campaign which address
locally perceived safety concerns.
 Form an AEFI review committee
 Keep alert for “issues” and rumours Safety of mass immunization
campaigns
5.3 Words of advice
 ·Campaign policies and strategies should be identified well in advance of
the campaign.
 Practical, country-specific solutions for sharps waste management should
be identified and planned well in advance.
 All supplies and materials should be ordered at least six months before
the campaign.
 Roles and responsibilities for the campaign should be clearly stated from
the start and should include deadlines for completing all tasks.
 All players and partners (including nongovernmental organizations,
medical and nursing associations, religious groups, etc.) should be
contacted to help disseminate safety awareness messages.
 Regular monitoring throughout the campaign, followed by a final
evaluation should be conducted so as to identify successes, problems and
lessons learned. The findings should then be disseminated to all partners.
5.4 Key elements planning for mass campaigns, including Safety
components:
 Identify the different key players and clearly assign activities, roles and
responsibilities to each player.
 Ensure that campaign advocacy messages include safety issues.
 Conduct an assessment of current injection safety practices to assess the
situation and identify the needs and challenges for the forthcoming
campaign. The standard WHO tool for the assessment of injection safety
practices might be considered for this.
 Include the following safety components in immunization mass
campaigns:
1. A detailed budget with identified funding sources;
2. A micro-plan for distributing vaccines, diluents, injection and reconstitution
materials, and safety boxes;
3. A plan for training on safe injections and AEFI monitoring;
4. A comprehensive waste disposal plan;
5. The information flow on AEFI;
6. A crisis management plan with communication strategies to prevent rumours
from endangering the campaign.
 Prepare “Questions and Answers” for the media on the background for the
campaign and the potential for AEFI.
 Decide on a protocol for treatment of anaphylaxis, and provide the
necessary training, drugs and equipment.
 Review contraindications to vaccination (e.g. AIDS) and implications for
the campaign; train staff accordingly.
  Plan to monitor activities, successes and problems through routine
reporting by all vaccination sites.
 Plan from the start to undertake a final evaluation and use this to develop
a long-term plan of action to address the problems and issues that have
been identified. Disseminate lessons learned so that others can learn from
the experience.
5.5 Vaccine administration
 Procure vaccines, AD syringes and safety boxes (and reconstitution
syringes if necessary), from pre-qualified WHO/UNICEF or national
regulatory authority-approved sources.
 Ensure that quantities of all supplies match and that all distribution is
bundled. Plan logistics carefully to ensure availability of all supplies at all
vaccination posts.
 Place orders well in advance (at least six months) before the start of the
campaign.
 Raise health care worker awareness on the need for safety throughout the
campaign
 Needles should never be recapped but must be placed into an approved
safety box or puncture-resistant container immediately and disposed of
safely as soon as possible after use.
 The training of staff at each level must include reconstitution of freeze-
dried vaccine (use only the diluent supplied with the vaccine, use whole
amount of diluent), the use of AD syringes and of the need for proper
disposal in a safety box.
5.6 Sharps waste management
 The safe disposal of used injection equipment is one of the most important
issues in assuring injection safety. There is no single, universally accepted
method, but a locally acceptable solution needs to be identified and
agreed upon with all partners before the campaign.
 Assess local possibilities of sharps treatment and disposal (e.g. identify
functioning incinerators, sites for burning, re-cycling, safe burial, etc.).
 Construct incinerators where needed, or find temporary treatment sites.
 Plan for transportation, storage and treatment of sharps waste. Safety
boxes should be numbered so as to verify their return to the destruction
point.
 Identify practical, simple solutions that can be implemented during the
campaign. Use the waste disposal plan and system developed for routine
sharps waste management in the future. (Possibilities include incineration,
burning, recycling, and safe burial.)
 Prepare clear instructions and guidelines for health staff on sharps
disposal and waste management.
 Instruct personnel on practices recommended for the campaign and
monitor the compliance on a daily basis.
5.7 AEFI monitoring
 Institute a simple surveillance system for adverse events, if one does not
exist already, with case definitions, a reporting form and instructions on
 how and where to report. Monitor the distribution and use of all vaccine
lots.
 Ensure routine reporting and managing of AEFI at vaccination sites/clinics
through training staff at all points where AEFI might occur, points for acute
AEFI and points for delayed AEFI.
 Maintain monitoring for at least four weeks after the campaign and
introduce as a permanent system wherever possible.
 Estimate the expected rates of AEFI for the vaccine(s) to be used, and the
differences in background rates of diseases in target age groups involved
in the campaign. Use these baseline figures to compare with actual rates
occurring in the campaign.
 Identify a focal point and form a committee to receive and review reports
of AEFI during the campaign.
 Ensure rapid response to AEFI with the necessary investigation and
correction of potential programmatic errors.
 Be sensitive to rumours that might arise about AEFI and follow them up
actively.
 CHAPTER 6
PHARMACOVIGILANCE IN EMERGING
COUNTRIES
6.1 INTRODUCTION
6.2 PHARMACOVIGILANCE- 6.2.1 The scope of pharmacovigilance
- 6.2.2 The WHO Programme
- 6.2.3 Increased global engagement
- 6.2.4 Special challenges
-6.2.5 Setting up a centre
6.3 PHARMACOVIGILANCE AND PUBLIC HEALTH PROGRAMMES

6.1 INTRODUCTION
Requires collaboration between stakeholders to develop novel models of funding

Efforts are increasing to ensure that resource poor countries, which bear almost
90% of the global disease burden, have access to effective medicines. As a
result, drug companies are facing increased pressure from governments, the
World Health Organization, and patient lobby groups to remove legal and
financial barriers to access. However, although these campaigns are necessary
and clearly laudable, they are not accompanied by the development or upscaling
of processes for monitoring drug safety. Although many drugs have been
extensively used and studied in developed countries (thus informing global
practice), their safety profile cannot necessarily be generalized to developing
countries, where the incidence, pattern, and severity of adverse reactions may
differ markedly because of local environmental and genetic influences.

After the thalidomide disaster in the 1960s, most Western countries developed
national pharmacovigilance systems. These systems use spontaneous reporting
or other pharmacoepidemiological methods to systematically collect and analyse
adverse events associated with the use of drugs, identify signals or emerging
problems, and communicate how to minimise or prevent harm. Although these
processes are not perfect, as exemplified by recent problems, they do provide
evidence that can be used to institute regulatory action to protect public health.

At the global level, the WHO programme for international drug monitoring at the
Uppsala Monitoring Centre collates adverse drug reaction reports via the national
pharmacovigilance centres of the 81 member countries (www.who-umc.org).
However, currently only six sub-Saharan African countries (South Africa,
Zimbabwe, Tanzania, Mozambique, Nigeria, and Ghana) are full members of the
programme. In fact, less than 27% of lower middle income and low income
economies have national pharmacovigilance systems registered with the WHO
programme, compared with 96% of the high income countries in the Organisation
for Economic Co-operation and Development. The main reasons for this are lack
of resources, infrastructure, and expertise. Thus, although access to medicines is
increasing in developing countries, there is a danger that their risk benefit profiles
in indigenous populations will not be fully monitored and acted upon.

So what can be done to improve drug safety monitoring in developing countries?

In the short term, we need to make better use of ongoing or planned studies. The
ability to detect an adverse drug reaction depends on its frequency and the total
number of people exposed to the drug. A logical approach would be to encourage
collaboration between academic investigators, drug companies, and
governments undertaking clinical studies to develop common adverse reaction
reporting forms and to deposit the data into a single database.

Similar partnerships could also be established with organizers of public health

and drug access campaigns and with regional surveillance systems, such as the
East African network for monitoring antimalarial treatment and the network for
assessing health and demography in developing countries. The operational
advantages of this approach are that data can be obtained from a range of
studies and that pre-existing manual and technical infrastructures can be used to
acquire the data. This would provide demographically relevant data from large
(and less homogeneous) populations in a structured and systematic fashion, and
these data could then be used to identify warning signals.

Individual investigators would still own their data and publish results of their trials,
but the pooling of data on adverse drug reactions would add value to ongoing
studies. This has already happened on a small scale. For example, an increased
risk of serious neurological reactions was identified in people taking ivermectin
who were infected with Loa loa before treatment started. Such pooling of data
needs to be increased and considered for all drug classes within a formulary.

What role should the drug industry have in promoting pharmacovigilance? The
current model for drug development in resource poor settings depends on public-
private partnerships, such as the Medicines for Malaria Venture. These
partnerships should be encouraged to continue beyond the point of obtaining a
drug license to developing a proactive phase IV programme. Such a programme
could be designed to show the effectiveness of the drug in a real world situation,
and through this obtain safety data in much larger cohorts of patients. A few
examples of this approach already exist in Africa, but these need to become the
norm rather than the exception.

In the long term, every country should develop its own national
pharmacovigilance system, which contributes to a global database such as that
held by the Uppsala Monitoring Centre. This will need an extensive infrastructure,
however, which would be costly. In a climate where health resources are limited,
funding a pharmacovigilance system will come second to other competing
priorities such as implementing a new vaccine programme. The funding model for
pharmacovigilance activities in the United States recently advocated by the
Institute of Medicine is unlikely to work in developing countries if it increases drug
costs, as this defeats the aim of increasing access to medicines. No easy
answers are available, but WHO needs to lead a dialogue between the major
stakeholders with the aim of developing a novel funding model that supports
pharmacovigilance activities in developing countries. The lack of local expertise
in pharmacovigilance could be tackled through developing exchange
programmes with the major drug regulatory agencies and sharing of best
practices.

Commitment to pharmacovigilance has increased enormously since the first

systems were set up in the 1960s. Then, following the thalidomide disaster, 10
developed countries, under the leadership of WHO, saw the need for
international collaboration in drug monitoring to prevent a similar disaster
recurring. Now there is world-wide recognition of the importance of the early
detection of potential drug hazards and the sharing of information.

6.2 Pharmacovigilance

The science and activities relating to the detection, assessment, understanding

and prevention of adverse effects or any other possible drug-related problems.

6.2.1 The scope of pharmacovigilance

From an exclusive concern for physicians to report only serious and unexpected
pharmacological or immunological adverse reactions (ADRs) to modern
medicines, pharmacovigilance has grown. It now encompasses a broader range,
such as blood products, vaccines and traditional medicines, and additional safety
issues, including:
 quality defects
 unexpected therapeutic failure (may be due to resistance, interaction,
inferior product quality) .substandard or counterfeit products
 drug dependence
 overdose and poisoning
 medical error.
It is now well known that many drug-related problems result from health system
failures (procurement and logistics, for example) or irrational prescribing and use
and are, therefore, preventable. The cost of such failures to health systems
around the world, and the burden on patients, are enormous.. Pharmacovigilance
systems are designed to detect early signs of a wide range of failures, to prevent
harm to patients, waste of resources and the repetition of avoidable harm.
6.2.2 The WHO Programme

Over seventy countries, all full members of the WHO International Programme
for Drug Monitoring, have pharmacovigilance systems for the collection of ADR
data. A further 14 associate member countries are in the process of setting up
their systems. The Programme is coordinated by PSM’s Quality and Safety of
Medicines unit at WHO Headquarters, while the operational aspects are
managed by the Uppsala Monitoring Centre (the UMC) whose formal title is the
WHO Collaborating Centre for International Drug Monitoring. Countries send
their ADR data to the WHO ADR database, known as Vigibase. This unique
resource, managed by the UMC, holds more than three million case reports.
Around 250,000 new reports are added each year. The primary purpose of the
Programme is to detect information about potential new drug hazards, especially
those that are unexpected, serious or rare and which have not come to notice
previously or are little documented. Signals of such suspected new hazards are
then communicated throughout the network of member countries. The UMC was
the first organization to use data mining and pattern recognition for
pharmacovigilance, a leading-edge technology whose results are routinely
available for all countries. The UMC also produces a number of world-standard
tools and resources, such as the WHO Drug Dictionary and the WHO Adverse
Reaction Terminology, for use in international drug safety activities. Another
important role is to maintain a communications network between
pharmacovigilance centres throughout the world. Member countries each have a
designated national pharmacovigilance centre, responsible for communicating
with health care professionals, collecting adverse reaction reports, submitting
case reports to the WHO database, and often, a range of other activities

6.2.3 Increased global engagement

Many factors have contributed to a greater interest in pharmacovigilance in

emerging countries over the last decade, including the direct influence of the
WHO Programme. Some of these are:
 Following the success of essential medicines programmes, medicines are
now more widely available and it is recognised that the desired results in
terms of improved public health are obtained only if medicines are of good
quality and are used rationally
 Epidemiological and other studies have revealed the enormous scale of
medicines-related problems in health care
 It is now recognized that, although the majority of medicines-related safety
problems are universal, many are unique to the local setting. Each country
therefore needs to have in place its own system for detecting and
following-up medicine treatment outcomes.
 Training courses and guidelines in pharmacovigilance practice have been
more readily available and strongly supported. The first international
course was organized by the UMC in 1993. The ninth UMC course was
held in Canberra, Australia, in November, 2004. So far 205 health
professionals from 86 countries have participated in these two-week
 courses. WHO Regional Offices and national authorities have arranged
regional and national courses. The four courses arranged in Bolivia,
Colombia and Guatemala by the Spanish Medicines Agency 2000 – 2003
are particularly significant for that region.
 Drug safety issues have been increasingly recognised by public health
programmes.

6.2.4 Special challenges

Countries with less well developed health care systems, where record keeping
and documentation are often poor, require methodological innovation. ADR
reporting must be extended beyond trained physicians to all health professionals.
Widespread self-medication and the use of traditional medicines mean that
traditional healers and patients also need to report adverse drug experiences.
The mass media need to be involved in creating awareness of drug safety
issues. In countries with less well-regulated drug markets, pharmacovigilance
has an important part to play in identifying drug-related risk areas that should
have priority from a public health perspective. The overall aim is to enter into an
active dialogue with all health care providers and the public about their
experiences with medicines and about how to use them safely and rationally.

6.2.5 Setting up a centre

Resources needed to set up and run a national pharmacovigilance centre are

relatively limited. Political support, professional commitment, basic reference
sources, office facilities and means
of communication are indispensable however. All come at a cost far below that of
the problems they aim to prevent. Particularly in developing countries, is
beneficial for pharmacovigilance activities
to be associated with other vital functions like drug information and/or poison
centres, or located in hospitals or medical schools. The long-term challenge is to
educate health professionals, patients, the media and the general public that
 no medicine, including herbal and traditional medicines, is 100% safe for
all people in all circumstances
 it is everybody’s business to be critical prescribers or users
 the reporting of suspected drug-related problems will help improve public
health and reduce harm to patients and wastage of resources.
We can avoid drug-related problems only when we know that they exist, and
their detection is the fundamental purpose of the WHO Programme and of
worldwide pharmacovigilance. .

6.3 Pharmacovigilance and public health programmes

In recent years new drug therapies have been introduced in the treatment of the
major tropical diseases. Since large populations, often with complicating co-
morbidity, are exposed to these new medicines, there need to be systems for
follow-up of possible adverse consequences. The antimalaria programmes in
sub-Saharan African countries are recent examples of public health initiatives
where safety has been seen as a priority. Because of severe resistance to older
medicines, many countries have introduced artimisinin-based products as first–
or second-line treatment of malaria. These preparations have not been used on a
large scale in Africa before. The WHO Roll Back Malaria Programme is now
collaborating with the WHO Drug Monitoring Programme in establishing
pharmacovigilance systems, particularly for anti-malarials, in several African
countries. The starting point was a training course in Zambia in 2003. A similar
approach is now followed by providing training for representatives of
pharmacovigilance centres and HIV/AIDS programme managers in Africa. A first
course was held in South Africa, 1–10 September, 2004. A further example is the
ambitious approach of the Expanded Programme on Immunization to record
Adverse Events Following Immunization (AEFI). The WHO Global Training
Network on vaccine quality has so far carried out twelve training courses on
AEFI. The global programme on eliminating lymphatic filariasis has also
increased its efforts in collecting information on adverse effects to the medicines
used.
 CHAPTER 7
THE SAFETY OF HERBAL MEDICINES

 7.1 Challenges in monitoring the safety of herbal medicines

 7.2 Safety monitoring of herbal medicines
 7.3 Communication

7.1Challenges in monitoring the safety of herbal medicines

o 7.1.1 Regulation, quality assurance and control Regulation
National regulation and registration of herbal medicines vary from country to
country. Where herbal medicines are regulated, they may be categorized as
either prescription or non-prescription medicines. Herbal products may also be
categorized other than as medicines. Moreover, the regulatory status of a
particular herbal product may differ in different countries. The national regulatory
framework usually also includes involved qualified providers and distributors of
respective substances. Regulatory status consequently determines the access to
or distribution route of these products. If trade in a particular herbal product is
made between countries where different regulatory status is given,
reclassification of the regulatory status in the importing country depends not on
the nature or characteristics (medical or therapeutic value) of the product itself,
but on the regulatory framework of the importing country. Further, herbal
products categorized other than as medicines and foods are becoming
increasingly popular, and there is potential for adverse reactions due to lack of
regulation, weaker quality control systems and loose distribution channels
(including mail order and Internet sales). National regulatory information on
herbal medicines is not fully shared among national regulatory authorities, and is
often not shared between national regulatory authorities and national safety
monitoring/pharmacovigilance centres. Almost all new medicines are introduced
to the market as prescription medicines, and a significant volume of post-
marketing safety data from spontaneous reporting will have been realized over
time. At some stage, some of these medicines will subsequently be reclassified
as non-prescription medicines and will become major sources of self-medication.
However, in many countries, a significant proportion of herbal products enters
directly into the non-prescription medicines category rather than by
reclassification from the prescription medicines category.

7.1.1.1 Quality assurance and control

Quality assurance and control measures, such as national quality specification
and standards for herbal materials, good manufacturing practices (GMP) for
herbal medicines, labelling, and licensing schemes for manufacturing, imports
and marketing, should be in place in every country where herbal medicines are
regulated. These measures are vital for ensuring the safety and efficacy of herbal

WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance

systems medicines. Weak regulation and quality control may result in a high
incidence of adverse reactions attributable to poor quality of herbal medicines, in
particular resulting from adulteration with undeclared potent substances and/or
contamination with potentially hazardous substances and residues.
Requirements and methods for quality control of finished herbal products,
particularly for mixture herbal products, are far more complex than for other
pharmaceuticals. The quality of such products is influenced by the quality of the
raw material used. Good agricultural and good collection practices (GACP) for
medicinal plants, including plant selection and cultivation, are therefore important
measures.
7.1.1.2 National/regional pharmacopoeias
National and regional pharmacopoeias define quality specifications and
standards for herbal materials and some herbal preparations, such as essential
oils and powdered herbal materials. Use and inclusion of herbal materials in such
pharmacopoeias are based on local availability of these products. Availability is
dependent on the original medicinal plants, which have ecologically and
environmentally specific habitats. Therefore, even if the same pharmacopoeial
monograph name is given to a herbal material, its listing in one pharmacopoeia
may refer to a different original medicinal plant and/or processing method from
that defined in another (see also section Reporting of suspected adverse
reactions, under Recording and coding the identity of herbal medicines).
Action required
As with other medicines for human use, herbal medicines should be covered by a
drug regulatory framework to ensure that they conform to required standards of
safety, quality and efficacy.
o 7.1.2 Appropriate use
7.1.2.1 Providers of herbal medicines
A variety of health-care professionals serve as qualified providers of herbal
medicines, according to each country’s national health-care delivery system and
legislative framework. In those countries where herbal medicines are classified
as prescription medicines, prescribers and dispensers other than physicians,
dentists and pharmacists are sometimes excluded from current reporting
systems. In many countries, prescriptions are not required to obtain herbal
medicines since these are categorized as non-prescription medicines or products
suitable for self-care. Providers of herbal medicines in this category are not
normally physicians. They include providers of traditional and complementary or
alternative medicine as well as community pharmacists and nurses.
Action required
All providers of herbal medicines should play a role in monitoring the safety of
non-prescription herbal medicines. Nurses are becoming increasingly involved in
this area and are making a valuable contribution to safety monitoring. For
Challenges in monitoring the safety of herbal medicines providers of herbal
medicines to be effectively involved, it is essential to create an atmosphere of
trust to enable the sharing of knowledge about the use and safety of herbal
medicines.
7.1.2.2 Lack of proper knowledge of herbal medicines
Providers of medicines, such as physicians, nurses and pharmacists, may have
little training in and understanding of how herbal medicines affect the health of
their patients, who are often also taking other medicines, prescription or non-
prescription. An appropriate knowledge base is also relevant to diagnostic and
treatment decision-making. Other health-care professionals who are not
providers of herbal medicines are also likely to be poorly informed about these
products and how they are being used. If they see patients who are taking herbal
medicines, they should ask about their use. Health professionals who work in
poisons centres and health information services also need to be informed about
herbal medicines. The use of medicinal plants is the most common form of
traditional medication, worldwide. Herbal medicines are used within many
different healing traditions with different knowledge bases and so there is still a
question as to the suitability of the categories defined in section Herbal products
targeted for safety monitoring. Traditional medicines are increasingly being used
outside the confines of traditional cultures and far beyond traditional geographical
areas without proper knowledge of their use and the underlying principles. They
are also being used in different doses, extracted in different ways and used for
non-traditional indications. The concomitant use of traditional medicines with
other medicines, which is now quite frequent, is quite outside the traditional
context and has become a particular safety concern.

7.1.2.3 Patient/consumer attitudes to herbal medicines

As mentioned in section 1, there is often a misconception that “natural” means
“safe” and many consumers believe that remedies of natural origin carry no risk.
Patients who use herbal medicines and other medicines together, as is often the
case, will often not mention the use of herbal medicines to their physician.
Likewise, patients commonly fail to mention the use of other medicines to their
providers of herbal medicines. Health-care professionals and providers of herbal
medicines should ask patients directly, respectfully and persistently what other
medicines they are taking, including prescription medicines, herbal medicines
and other health products for self-care.
Action required
The education of health-care professionals, providers of herbal medicines and
Patients/consumers is vital for the prevention of potentially serious risks from
misuse of herbal medicines.

7.2 Safety monitoring of herbal medicines

o 7.2.1 Sources of reports
The Council for International Organizations of Medical Sciences (CIOMS)
Working Group V has recommended that, as a general guiding principle,
emphasis should be placed on the quality of a report and not on its source. Thus,
the value of a report lies not in who made it, but in the care and thoroughness
with which it is prepared, documented, received, recorded, followed-up, clarified
and analysed . However, the source of a report can be an important factor in
evaluating the report as it may affect the quality and value of the information.
The nature, degree and even feasibility of any follow-up will also be highly
dependent on the source. The most common sources of information on adverse
events and reactions to medicines are clinical trials and spontaneous reports
(voluntary, unsolicited communications on marketed medicinal products). The
latter ordinarily far exceed the former in numbers and type, especially serious
reports, over the lifetime of a product. In some countries, adverse reaction
reporting by physicians is mandatory; such reports are regarded as spontaneous.
In many countries, providers of herbal medicines other than physicians, dentists,
pharmacists and nurses are excluded from reporting systems. If adequate
coverage of herbal medicines is to be achieved, national reporting schemes
should be developed to include all providers of herbal medicines (both
prescribers and dispensers), and providers of traditional, complementary and
alternative medicine, according to national circumstances.
I. Reports from health-care professionals
Internationally, adverse drug reaction reporting systems in the post-marketing
safety surveillance setting depend primarily on voluntary reporting by health-care
professionals, preferably those directly associated with the care of the
patient/consumer (i.e. the patient’s primary health-care provider or
specialist).This is appropriate, since the understanding of adverse drug reactions
depends on medical knowledge and such professionals should be aware of the
patient’s medical history and attuned to the subtleties of clinical differential
diagnosis. A substantial proportion of herbal medicines are non-prescription
medicines, and many come directly into this category without prior post-
marketing safety monitoring as prescription medicines. It is therefore most
important to take measures to strengthen pharmacovigilance activity in the non-
prescription medicines setting. Community pharmacists and nurses can play a
particularly useful role in monitoring the safety of non-prescription medicines,
although many such products are sold outside pharmacies.

ii. Reports from consumers

The involvement of consumers in the use of herbal medicines and herbal
products in health care, and their concern regarding possible adverse effects
should be valued positively. Consumer reports on adverse reactions should be
accepted as a serious source of information, which can contribute to the
identification of signals for unknown effects of herbal medicines. For non-
prescription medicines, often taken without health professional involvement,
reports received directly from consumers may provide the only source of signals.
With herbal medicines in the non-prescription medicines setting, there is clearly
an essential role for consumer reporting. Consumer reporting, in one form or
another, is therefore an essential development if adequate information on risk is
to be obtained. However, only a few national regulatory authorities currently
explicitly require collection of direct reports from consumers. The CIOMS
Working Group proposes several policy approaches and practices aimed at
ensuring that consumer reports are treated with appropriate respect and that
there is a rational approach for handling them (Annex 4).
iii. Manufacturers 1
Manufacturers of herbal medicines could be a source of information on adverse
events associated with their products. Some countries include reporting of
adverse events by manufacturers as part of their regulatory framework.
Consumers may report directly to companies or their representatives. However,
there are reasons other than concern about an adverse effect that might prompt
consumer to contact a company. These include legal concerns and, most
frequently, requests for further information about the product. Another source of
consumer reports derives from a variety of industry programmes in which
adverse reaction information may be solicited; such cases are not regarded as
spontaneous reports.
iv. Reports from other sources
Problems associated with herbal medicines may be reported as toxicity to the
Following. .
 National poisons centres. Where resources are very limited in the national
situation and where no pharmacovigilance centre has been established, a
poisons centre could play a core role in pharmacovigilance for and safety
monitoring of herbal medicines.
 Drug information centres may also be a first point of contact and may
provide a wealth of clinical information. National pharmacovigilance
centres should have a good level of communication with such centres.
 Consumer organizations receive complaints about any type of product in
the marketplace and may obtain relevant information about herbal
medicines
 Clinical trials and studies can also be a source of information (see section
Herbal products targeted for safety monitoring).
For the purpose of these guidelines, the term "manufacturer" refers to the
producer, importer, distributor or marketer of a finished herbal product and,
where applicable, to the holder of the marketing authorization or registration for
that product in the country in question.

o 7.2.2 Herbal products targeted for safety monitoring

In order to obtain comprehensive coverage, it is useful to think of herbal products
in the following categories:
 according to their regulatory status
– herbal medicines in the prescription medicines category
– herbal medicines in the non-prescription medicines category
– other herbal products intended for use in health care
 according to their registration/marketing status
– herbal medicines undergoing the new drug development process: in clinical
trials prior to national drug regulatory approval
– herbal medicines undergoing the new drug development process: under post-
marketing safety surveillance
– herbal medicines undergoing re-evaluation under the current protocol: in
clinical trials
– herbal medicines undergoing re-evaluation under the current protocol: under
post-marketing safety surveillance
– herbal medicines on the market: under post-marketing safety surveillance
– other herbal products marketed for health care, such as dietary supplements.
Recommendations on how to record and report adverse events occurring during
clinical trials should be covered by national guidelines on good clinical practice
for trials on pharmaceutical products (GCP) (9).
o 7.2.3 Reporting of suspected adverse reactions
I. Who should report and to whom?
The setting (see section 4.2) in which an adverse reaction is noted and the status
of the person noting the reaction will determine the most appropriate means of
reporting. Although the term “national pharmacovigilance centre” has been used
in these guidelines, it is recognized that in some countries the national
pharmacovigilance system consists of a network of national and regional centres.
Reports should be sent to the appropriate centre in accordance with the
particular national reporting scheme. The following should provide reports.
 Health professionals who are providers of herbal medicines, including
physicians, pharmacists and nurses, should report to the national
pharmacovigilance centre.

 Patients/consumers should normally report to their physicians or providers

of herbal medicines. They may also report directly to the national
pharmacovigilance centre, consumer organizations or manufacturers.
 Manufacturers should report directly to the national pharmacovigilance
centre or national regulatory authority.

II. What information should be requested?

Any suspected adverse reaction associated with the use of a herbal medicines
should be reported. A case report should contain information on the following
Elements:
 where it is permitted by the country health information privacy code, and
with appropriate confidentiality, some form of identification of the
patient/consumer in order to avoid duplications and facilitate follow-up
 age, sex and a brief medical history of the consumer/patient (when
relevant); in some countries, ethnicity may need to be specified
 details of suspected herbal product(s) if known: species name (Latin
binomial name and common vernacular name of medicinal plant) and/or brand or
ingredient name(s), including the part of medicinal plant used, preparation
methods; manufacturer, country of origin, batch number, expiry date and provider
 administration details: dose and quantity supplied, dosage form, route,
Start/stop dates
 indication or reason for use
 .adverse reaction data: date of onset (or duration from first administration
to onset of event), description with symptoms and signs, severity and
seriousness, results of clinical investigations and tests, course and outcome, and
dechallenge/rechallenge with the same product, where appropriate
 all other medicines used (including self-medication), with administration
details
 risk factors, e.g. age, impaired renal function, previous exposure to the
herbal medicine(s) concerned, previous allergies, drug misuse or abuse, the
social use of drugs
 name and address of reporter (to be considered confidential and to be
used only for data verification, completion and case follow-up). Details of the
factors to consider when developing a report are provided in
Annex 5, together with an example of a reporting form.
III. How to report
A single reporting form covering all medicines, including herbal medicines,
should be used. For health-care providers already included in a national
pharmacovigilance system, a familiar form will facilitate reporting; the introduction
of a second type of reporting form may cause confusion. It is desirable to use a
standard printed or electronic reporting form and to ensure that forms are widely
available. It should also be acceptable to receive reports by telephone, letter or
e-mail. If possible, a sample of the herbal product and its packaging should be
submitted with the report. Consideration should be given to the distribution of
reporting forms to those involved in the provision of herbal medicines, such as
providers of traditional medicine and of complementary/alternative medicine, who
may not previously have been part of the national pharmacovigilance system. It
may be necessary to design a special reporting form for those not familiar with
the reporting of suspect reactions to medicines. Educational materials, including
a list of simple terminology that can be understood by all parties, should be
developed to inform and assist those not familiar with reporting.

IV. Recording and coding the identity of herbal medicines

Use of a standardized classification and identification for transmitting reports to
UMC is desirable. Coding of adverse events/adverse reactions to herbal
medicines should be compatible with that for other medicines. UMC therefore
proposes the use of the WHO Drug Dictionary (WHO-DD) (10), as it has been
developed to store structured, classified information on the names of herbal
products and their ingredients in the same way as similar information on other
medicines. For the therapeutic classification of herbal products, UMC proposes
the herbal anatomical-therapeutic-chemical (HATC) classification, which is
structurally equivalent to the anatomical-therapeutic-chemical (ATC)
classification used for chemical substances in other medicines. HATC is being
implemented within the WHO-DD structure as part of the global WHO database.
A combination of the use of the HATC classification and the expanded global
WHO database structure can manage all levels of data input, however imprecise
(Annex 6). In addition, UMC also proposes a system checklist for cross-
referencing of botanical and vernacular names used as names of ingredients.
UMC suggests that the WHO-DD, the HATC classification and the checklist
should prove useful tools for national pharmacovigilance centres when asking
questions of the reporter to increase the clarity and accuracy of reports.
Herbal medicines usually contain multiple ingredients and it is not always
possible to identify them all. In such cases, the product name should be recorded
and referred to UMC, which will assist with identification. If the product is not
already in the global WHO database, it will be added, together with the available
information. A particular herbal product may have a number of indications and
therefore appear in several places in the HATC classification. Local input by the
reporter as to the precision or otherwise of the information on the product is most
useful. This can be provided in free text, as a commentary on the report, or by
the submission of manufacturer’s information or the original packaging. A
national inventory or catalogue of medicinal plants may also serve as a reference
on medicinal plants and their use in the community. In many countries, however,
knowledge of medicinal plants and their medicinal use has not been
documented. The establishment of a national inventory or catalogue should
therefore be encouraged. If the finished herbal product concerned or its raw
materials were imported from other countries, the drug regulatory authority of the
exporting country may be able to provide helpful information. The precise Latin
binomial botanical name (genus, species, author; as well as name of family) of
the medicinal plants concerned should be used whenever possible, together with
information about the plant parts used and the extraction and preparation
methods employed. This information allows accurate comparison with other
reports. A common vernacular name may be used in order not to delay or cancel
submission of a report. National pharmacovigilance centres should collaborate
with the pharmacognosy departments of universities and with botanists,
zoologists and botanical garden staff regarding taxonomic (botanical and
chemical) identification and botanical and vernacular nomenclature.

Further classification systems may need to be specially developed in order to

cover additional products used in traditional medicine.
V. Other reporting issues
Under no circumstances should information obtained during pharmacovigilance
activities be divulged for commercial purposes. The identity of both the patient
and the reporter should remain confidential unless their written permission to
reveal this information is obtained (Annex 3). Reporting on herbal medicines
should be as accurate and complete as possible. On the other hand, that fact
that information is less than optimal should not deter reporting.
o 7.2.4 Assessment of case reports
Individual case reports
Assessment of reports on adverse reactions to herbal medicines should be
undertaken by national pharmacovigilance centres in the same way as for other
medicines. Each data element in the report should be considered and a causality
assessment made using a standard approach. The assessment is usually based
on:
 .the association in time between administration of the herbal product and
the event
 the outcome of dechallenge and rechallenge
 .known pharmacology (including current knowledge of the nature and
frequency of adverse reactions)
 medical or pharmacological plausibility (the sequence of symptoms, signs
and laboratory tests and also pathological findings and knowledge of
mechanisms)
 likelihood of other causes or their exclusion
 .testing for adulterants or contaminants that could be the source of
adverse events.
 inappropriate use.
The WHO causality categories benefit from long and extensive use and have the
advantage of being internationally agreed and easy to use. The causality
categories are listed in Table 1 (1).
It is most important to determine whether a reaction is caused by the way a
herbal medicine has been used or prepared. Particular attention to these factors
should be given when an adverse reaction is suspected in connection with the
use of herbal medicines usually employed in a traditional medicine. Misdiagnosis
and use outside an established tradition by poorly trained providers and
practitioners can be unsafe and may lead to overdose and adverse reactions. A
change in the procurement sources of herbal materials, misidentification of the
medicinal plant(s) and/or herbal material(s) used, or a change in the mode of
preparation may lead to entirely preventable and sometimes serious adverse
reactions. This should be taken into account when assessing individual cases.
The best evidence should be sought to determine the established standards of
practices.

Table 1. Causality categories

The causality categories described by the Uppsala Monitoring Centre

1 Certain: a clinical event, including laboratory test

2 Probably/Likely:
abnormality, occurring in a plausible time
relationship to drug administration, and
which cannot be explained by concurrent
disease or other drugs or chemicals. The
response to withdrawal of the drugs
(dechallenge) should be clinically
plausible. The event must be definitive
pharmacologically or phenomenologically,
using a satisfactory rechallenge procedure
if necessary.
a clinical event, including laboratory test
abnormality, with a reasonable time
sequence to administration of the drug,
unlikely to be attributed to concurrent
disease or other drugs or chemicals,
and which follows a clinically reasonable
response on withdrawal (dechallenge).
 Rechallenge information is not required to
fulfil this definition.
3 Possible: a clinical event, including laboratory test
abnormality, with a reasonable time
sequence to administrations of the drug,
but which could also be explained by
concurrent disease or other drugs or
chemicals. Information on drug withdrawal
may be lacking or unclear.
4 Unlikely: a clinical event, including laboratory test
abnormality, with a temporal relationship to
drug administration which makes a
causal relationship improbable, and in
which other drugs, chemicals or underlying
disease provide plausible explanations.
5 Conditional/Unclassified: a clinical event, including laboratory test
abnormality, reported as an adverse
reaction, about which more data is
essential for a proper assessment, or the
additional data is under examination.
6 Unassessable/Unclassifiable: a report suggesting an adverse reaction
which cannot be judged because
information is insufficient or contradictory,
and which cannot be supplemented or
verified.
As a step towards harmonization in drug regulation in the countries of the
European Union (EU), three
causality categories were proposed by the EU pharmacovigilance working
parties

Category A: "Reports including good reasons and sufficient

documentation to assume a causal relationship, in the
sense of plausible, conceivable, likely, but not necessarily
highly probable".
"Reports containing sufficient information to accept the
Category B: possibility of a causal relationship, in the sense of not
impossible and not unlikely, although the connection is
uncertain and may be even doubtful, e.g. because of
missing data, insufficient evidence or the possibility of
another explanation".
"Reports where causality is, for one or another reason,
Category C: not assessable, e.g. because of missing or conflicting
data".

I. Feedback to reporters
The receipt of each report should be acknowledged and a new reporting form
supplied to the reporter. The reporter will also appreciate receiving further
information about the reaction concerned, for example, on experience held at the
national pharmacolovigilance centre or that may be helpful in further use of the
medicines, unless the provision of such information is in conflict with regulatory
policy. Such feedback will motivate the reporter to send in further reports.
II. Detection of signals at national level
The national pharmacovigilance centre should, at regular intervals, analyse the
case reports in its database by class of organ system and in smaller groups of
clinically related events. This may reveal case series of similar events that could
constitute a signal and/or indicate the need for further study or regulatory
action. Such signals should be communicated to UMC. Weak signals may be
strengthened by examination of reports from other countries held in the global
WHO database.
III. Detection of signals at international level
The major aim of pharmacovigilance is the early detection of signals of previously
unrecognized adverse reactions. Early signals may be strengthened by
combining the experiences reported in various countries. Regional studies may
be of particular value in the monitoring of herbal medicines. Data-mining
techniques can be helpful in individual countries, but are most effective in the
global WHO database managed by UMC.
IV. Use of an advisory committee
Each national pharmacovigilance centre should have an advisory committee
composed of experts to give advice on:
 maintaining quality standards in data collection and assessment
procedures
 data interpretation
 publication of information
 follow-up action required.
The committee should be selected according to the expertise available but it
should not be too large, so that it may not be possible to have all of the relevant
disciplines represented. A committee might be selected from the following
disciplines: general medicine, pharmacy, pharmaceutics, clinical pharmacology,
clinical toxicology, pharmacogenetics, epidemiology, pharmacoepidemiology,
pathology, drug regulation and quality assurance, drug information, information
science, medical anthropology, communications, ethnopharmacology,
pharmacognosy, phytochemistry, traditional medicine and/or
complementary/alternative medicine.
V. Investigation and analysis of the cause of suspected adverse reactions
Some adverse reactions, particularly serious ones should be further investigated
scientifically. The investigations may include the following:
 medical investigation of the adverse reactions: pathology, clinical
pharmacology, clinical toxicology, pharmacogenetic studies
 pharmaceutical investigation of the adverse reactions: pharmacokinetics,
pharmacodynamics and pharmaceutical, pharmacological and toxicological
analysis
 pharmacognosical/phytochemical investigation (including authentification)
of the herbal medicines
 physicochemical analysis to identify the constituents of the herbal
medicines
 pharmacoepidemiology.
VI. Technical expertise and basic equipment
Where possible, national pharmacovigilance centres should have the necessary
technical expertise to handle herbal medicines. This might include:
 access to reliable information support on herbal medicines
 trained personnel in relevant technical areas (e.g. pharmacognosy,
phytochemistry, ethnobotany, ethnopharmacology) and in the use and
provision of herbal medicines
 access to facilities for analysis of potentially causative products about
which there is often insufficient information.
Not all countries have access to suitable analytical laboratories. The
establishment of regional laboratories specializing in the analysis of herbal
products should be considered.
o 7.2.5 Data management
 Data quality. Strenuous efforts should be made to ensure that there are
quality controls on data processing and that the data elements of reports are as
complete and accurate as possible. Mechanisms to check for duplications
should be instituted.
 Data storage. Computer databases should be managed to as high a
standard as possible to facilitate access to and use of the data. Software should
be selected with expert advice so that analytical needs can be met.
 Data analysis. Programmes should be developed to provide for regular
analyses and data output appropriate for local needs.
 Analysis of the global WHO database. The global WHO database
managed by UMC is being improved on the basis of the proposed “Database
management and classification for coding of herbal medicines”, of which the
previously mentioned HATC is one part (Annex 6). Data-mining techniques that
have proved effective on the very large numbers of reports for other medicines
will be used for signal detection on reports for herbal medicines. The success of
these techniques depends on the volume and quality of data submitted by
national pharmacovigilance centres.
 Support on technical and data management is available from the WHO
Collaborating Centre for International Drug Monitoring, UMC (http://www.who-
umc.org/).

7.3 Communication
o 7.3.1 General
The successful safety monitoring of herbal medicines depends on good
communication (Annex 2). There are many barriers to be broken down if all the
players in this field are to be involved. There is distrust between some and
ignorance of the work and function of different groups. Transparent
communication is essential to overcome these problems and ensure that all
players collaborate to meet the goal of the safe and effective use of herbal
medicines. National pharmacovigilance centres should ensure that
manufacturers receive timely information so that they can take appropriate action
regarding their products. Effective communication of the results of monitoring is
also essential so that pharmacovigilance activities can have a positive impact on
the health of the people.
If there is no national pharmacovigilance centre, consideration should be given to
designating other relevant organizations, such as the national regulatory
authority, poisons centres, drug information centres and consumer complaints
authorities as the focal point.

Communication should be established at many different levels, for example,

between:.
 the national pharmacovigilance centre and health professionals
 the national pharmacovigilance centre and providers of herbal medicines
 health professionals and providers of herbal medicines, and consumers
and patients
 providers of herbal medicines and those for other medicines
 the national pharmacovigilance centre and consumers
 the national pharmacovigilance centre and the regulatory authority
 the national pharmacovigilance centre and such centres in other countries,
within the region or in other regions
 the national pharmacovigilance centre and UMC
 the national pharmacovigilance centre and the mass media.
The development of effective communication needs to be adequately resourced.
It is likely that this most important part of the safety monitoring programme for
herbal medicines will require proportionately greater resources than is the case
for other medicines.

o 7.3.2 Risk communication

Communication strategies should be established to effectively reach all relevant
target audiences, such as providers of herbal medicines, other health
professionals, manufacturers and patients/consumers. Communication of safety
information is a shared responsibility between national pharmacovigilance
centres, national regulatory agencies, manufacturers and health professionals.
Different risk communication vehicles can be considered, including: .
 adverse reaction bulletins or articles distributed in reputable journals
 public advisories or warnings
 “Dear Health Professional” letters.

Various methods of information dissemination can be considered, such as:

 Internet posting
 direct mass mailing to providers of herbal medicines and health
professionals
 briefings to the mass media
 briefings to patient/consumer associations
 education sessions at health professional society meetings.

In order to reach consumers and the wide range of providers of herbal medicines
successfully, messages should be tailored to suit the recipients, including
translation into local languages where appropriate.
 CHAPTER 8

8. BAYESIAN STATISTICS AND PHARMACOVIGILANCE- volume 2

 CHAPTER 9
WRITING A PROPER ADVERSE EVENT REPORT

 9.1 INTRODUCTION
 9.2 DEFINITION OF ADVERSE DRUG REACTION
 9.3 PREDISPOSING FACTORS FOR ADVERSE DRUG REACTION
(ADR)
 9.4 WHAT NEEDS TO BE REPORTED
 9.5 WHO CAN REPORT AN ADVERSE DRUG REACTION (ADR)?
 9.6 TO WHOM SHOULD AN ADVERSE DRUG REACTION (ADR) BE
REPORTED?
 9.7 LOCAL FEEDBACK ABOUT ADVERSE DRUG REACTIONS (ADR)
 9.8 INFORMATION REQUIRED REGARDING A SUSPECTED
ADVERSE DRUG REACTION
 9.9 ADVERSE DRUG REACTION (ADR) TEAM
 9.10 MAIN POLICY POINTS
 9.11 SUMMARY

9.1 INTRODUCTION

Adverse Drug Reactions (ADRs) are common, often unrecognised and typically
under-reported [1-3]. The major aim of this policy is to prevent avoidable ADRs
in Coventry and Warwickshire. Specific aims are to:

I. ensure that doctors, pharmacists, nurses and other health care professionals
have a good understanding of:

 the nature of adverse drug reactions;

 major risk factors for adverse reactions;
 which adverse drug reactions to report;
 how to report these reactions.
II. improve the reporting of ADRs
III. establish feedback systems to Hospital and Community based Clinicians and
other Health Care Professionals about ADRs
The success of this policy depends on the involvement of Clinicians, Pharmacists
and other Health Care Professionals and patients.
9.2 DEFINITION OF AN ADVERSE DRUG REACTION (ADR)

An Adverse Drug Reaction (ADR) is a harmful and unintended response to a

drug which occurs at dosage used for prophylaxis, diagnosis, or treatment. The
simplest classification is type A and B ADRs.

a) A type A ADR is a reaction involving a usual but increased and undesirable

response to a drug. Examples include low blood glucose with sulphonylurea
drug treatment or dizziness due to a fall in blood pressure with an anti-
hypertensive drug. Other type A reactions result from interactions between
medicines given at the appropriate dose but in combination leading to an adverse
effect e.g. a combination of drugs used to treat disorders of heart rhythm.

b) Type B ADRs are not predictable from the pharmacological actions of drugs
and are usually caused by immunological or pharmacogenetic mechanisms
(under- or over-active genetic pathways important for drug absorption, response,
metabolism or excretion). Examples include aplastic anaemia from
chloramphenicol, anaphylaxis (acute severe allergy) with penicillin or lupus like
syndrome with hydralazine.

9.3 PREDISPOSING FACTORS FOR ADVERSE DRUG

REACTIONS (ADRs)

Multiple drug therapy

Incidence of ADRs from drug interactions increase sharply with the number of
drugs taken.

9.3.1 Age

The very young and very old are more susceptible to having adverse reactions.
This reflects age related differences in body composition and in activity of
metabolic pathways.

9.3.2 Gender

Women appear to be at greater at risk of ADRs than men.

9.3.3 Current disease

Drug handling may be altered in patients with impaired metabolism such as renal
or liver impairment. Diseases in which multiple drug treatment occurs are also
associated with greater likelihood of ADRs.

Pharmacokinetic Differences
There may be increased toxicity from a drug because of genetic factors (e.g.
difference in enzyme activity) or environmental influences (e.g. high alcohol
intake).

9.3.4 Ethnic Differences

Ethnic genetic or dietary differences may increase the risk of ADRs. Examples
include interaction of diet with glucose 6-phosphate dehydrogenase deficiency;
and iron overload resulting from giving iron supplements to sickle cell patients
when they do not need it.

9.3.5 Pharmaceutical Factors

Examples include differences in pharmacokinetics (processes by which a drug is

absorbed, distributed, metabolized, and eliminated by the body) resulting from
different delivery systems; and reactions to drug excipients (e.g. binding agents,
solvents, anti-bacterial agents).

Incomplete Medicines Reconciliation

Medicines reconciliation refers to the checking of medicines patients are taking,
either prescribed, over the counter, folk medicines, or from other sources. High
risk settings where medicines reconciliation is a problem include acute
presentation to the Accident and Emergency Department and new interactions
within parts of the NHS which may currently hold separate clinic records e.g. HIV
services.

9.4 WHAT NEEDS TO BE REPORTED?

The Committee and Safety of Medicine (CSM) monitors Adverse Drug Reactions
using a yellow card system and a black triangle warning sign for drugs which
should be more carefully monitored. The Regional Medicines Health products
Regulatory Agency (MHRA) Yellow Card Centre is based at the West Midlands
Centre for Adverse Drug Reaction Reporting in Birmingham (www.csmwm.org).
CSM Guidelines are:
 Newer drugs or new indications or combinations of older drugs are indicated
by a black triangle symbol for the first two years. For black triangle drugs, any
minor or major ADR should be reported to the CSM.
 Any suspected minor or major ADR should be reported for paediatric use of
drugs, no matter how long since the drug has been licensed by the CSM.
 Established drugs: Report any serious suspected reactions even if well
recognized. These include ADRs suspected to have led to admission to
Hospital or to have prolonged hospital stay and other serious reactions with
life-threatening results or leading to incapacity.
 All the above ADRs should be reported: you do not have to prove causality.
 Do not be discouraged from reporting ADRs because you feel the reaction is
too trivial (in the case of a black triangle or any paediatric use of a drug), too
well known or because the patient may be on more than one drug.

9.5 WHO CAN REPORT AN ADVERSE DRUG REACTION (ADR)?

 Coroners
 Dentists
 Doctors (including pre-registration House Officers)
 Nurses
 Pharmacists
 Patients

9.6 TO WHOM SHOULD AN ADVERSE DRUG REACTION (ADR)

BE REPORTED?

 Black triangle or ADRs as summarized above should be reported on a yellow

card and sent to the CSM Yellow Cards are available in the back of the British
National Formulary (BNF) and Data Sheet Compendium.

 A copy of the ADR report should also be sent to the local ADR Steering
Group c/o Medicines Information Dept. Medicines Information can forward the
yellow card to the CSM.

 The ADR group will also forward a copy to the Clinical Risk Co-ordinator for
inclusion of the ADR within the local Clinical Adverse Event incident reporting
system and will simplify future audit reports.
9.7 LOCAL FEEDBACK ABOUT ADVERSE DRUG REACTIONS
(ADRs)

 Regular information on ADRs will be fed back to Doctors, Pharmacists, and

Nurses in hospital and in Primary Care Trusts.
 Feedback to GPs about a given patient remains the duty of the responsible
Clinician.
 In addition a regular newsletter will be prepared by the ADR Group and
distributed to all hospital and community doctors, pharmacists and nurses.
 ADRs will also be reported within the Hospital and in General Practice within
audit and clinical governance meetings.

9.8 INFORMATION REQUIRED REGARDING A SUSPECTED

ADVERSE DRUG REACTION (ADR)

Information required is as for Yellow Card reporting i.e. initials, hospital number,
d.o.b., medical and drug history, description of the suspected ADR and the
outcome of the ADR, including any remedial treatment required and any
complications.

9.9 ADVERSE DRUG REACTION (ADR) TEAM

An ADR team will be established consisting of Clinical Pharmacologist, GP, ADR

Pharmacist, Nurse and Clinical Risk Manager and ADR Administrator. The team
will be led by the Steering Group and charged with:

 establishing mechanisms for implementing this ADR policy within hospital

and the local community;
 reviewing ADR patterns and trends;
 developing preventative and corrective interventions;
 co-ordinating feedback to appropriate healthcare staff in the form of
written reports and presentations at hospital and community meetings;
 regular audit to inform the effectiveness of the ADR policy.
9.10 MAIN POLICY POINTS

Main policy points for improving ADR reporting and prevention:

 Developing written hospital policy on ADR reporting and prevention.

 Securing time/resources and staff to improve ADR reporting and prevention.
This will include designated physician, GP, pharmacist and ADR
Administrator support.
 Education about risk factors for ADRs, how to report them, and improving
communication between patient and prescriber regarding ADRs, to promote
ADR awareness, reporting and prevention within the hospital and
community setting. An important component of this is the use of approved
non-proprietary names of drugs when prescribing, to reduce the potential
for confusion in prescribing as a source of ADRs.

9.11 SUMMARY

 ADRs are a serious burden for individual patients and have a major impact
on NHS costs and bed availability.
 This policy is an important practical aspect of Clinical Governance and will
contribute to achieving the aims of the Spoonful of Sugar Audit Commission
Report (1) on ways to limit medication related problems.
 It is already official Trust policy that all serious ADRs and any ADR for
‘black triangle’ drugs or drugs in paediatric use should be reported on a
Yellow Card to the Committee on the Safety of Medicines.
 This new local policy will raise awareness within the Trust and Community
about the importance of ADRs and their prevention thus improving patient
health and safety in relation to preventable medication problems.
 Resulting improvements in prescribing practice will improve quality of life for
patients on drug treatment, decrease the need for admissions to hospital
and shorten bed stay in patients at risk.
 CHAPTER-10
CLINICAL TRIALS – WHAT THEY CAN DO AND
WHAT THEY CAN’T!!
10.1 What do clinical trials test?

10.2 How are clinical trials supposed to work?

10.3 What roles do drug companies play in clinical trials?

10.4 What roles do independent scientists play in clinical trials?

10.5What's wrong with the clinical trial process?

10.6 Some examples:

10.1 What do clinical trials test?

When a drug finally makes it through clinical trials and FDA approval, here's what
we know about it:

 The new drug, in combination with standard treatment, is more helpful

than standard treatment alone.
 If the trial tested one drug against another, the new drug is at least as
good as the other.
 Benefits of the new drug — for narrowly defined groups of patients —
outweigh the drug's risks.

But there are a lot of important things clinical trials usually don't tell us:

 Clinical trials don't tell whether a new drug works better than existing
drugs — unless the trial compared one drug to another.
 Clinical trials don't show that a drug is risk-free.
 Clinical trials usually don't show whether a drug is safe to take in
combination with other drugs, vitamins, or supplements.
 Clinical trials don't show whether a drug might have unexpected long-term
side effects.
 Clinical trials don't show how well a drug might work in people, such as
pregnant or breastfeeding women, who weren't included in the study.

10.2 How are clinical trials supposed to work?

The clinical trial system is designed first to look at whether a drug is safe enough
for further testing (phase I clinical trials), then to look at whether a drug seems
both safe and effective (phase II clinical trials), and then to compare the drug to
an inactive placebo or standard treatment to see whether the drug is both safe
and at least minimally effective (phase III clinical trials).

After a drug is shown to be safe and effective in phase III clinical trials, the drug
maker may ask the FDA for approval. The new drug does not have to be more
effective than existing drugs, just more effective than placebo in defined patient
groups. FDA approval, if granted, sets the conditions under which the drug can
be sold.

In 2007, Congress passed a law (the Food and Drug Administration

Amendments Act) allowing the FDA to make drug approval contingent on
agreement to perform a post-approval clinical trial (sometimes called a phase IV
clinical trial). This is done to evaluate possible long-term side effects. And, as
before, all drug makers must collect and send to the FDA patient and doctor
reports of adverse events possibly related to taking the drug.

Phase III trials are the crux of the system. These trials can make or break a new
drug. Virtually all of these extremely expensive trials are paid for by the
companies that make the drug.

"The vast, vast, vast majority of clinical trials in this country are performed by
pharmaceutical companies that must do these studies to get FDA approval,"
DeAngelis tells WebMD. "The government doesn't pay for them. That is not what
NIH [National Institutes of Health] money is used for. Until we decide that it is
worth it in this country to put many billions of dollars into clinical trials, then the
drug companies will have to do it. And there is nothing wrong with that."

Drug companies don't just pay for clinical trials. User fees paid by drug and
device manufacturers — largely dedicated to speeding the approval process —
account for about 25% of the FDA's annual budget.

10.3 What roles do drug companies play in clinical trials?

Advocates of this system say it's only fair that companies that stand to benefit
from sales of new drugs should underwrite the cost of testing them — and of
approving them in a timely manner.

Many of the most helpful medicines now in routine use emerged from drug-
company-sponsored clinical trials. Drug companies "are committed" to making
information from these trials available to patients and their doctors, says Ken
Johnson, senior vice president of the Pharmaceutical Research and
Manufacturers of America (PhRMA), the lobbying group that represents the drug
industry.
"It is patently unfair to suggest that a manufacturer-sponsored clinical trial is
inherently biased," Johnson says in a news release sent in response to the
articles in The Journal of the American Medical Association. "PhRMA and its
member companies believe that protecting the integrity of clinical research is
paramount to patient safety."

Critics of the system say the drug industry's money has a corrupting influence on
the clinical trial process. DeAngelis agrees with Johnson that there's nothing
inherently wrong with drug companies paying for clinical trials. But she notes that
companies focus more on maximizing profits than on maximizing public health.

"Fifteen years ago or so, pharmaceutical companies transferred most of their

resources and emphasis into their marketing divisions rather than their science
divisions," DeAngelis says. "There are relatively few new drugs or devices in the
pipeline. Most of what they are doing now is testing drugs that are already out
there to get approval for people who don't really need them."

Far worse, DeAngelis says, is companies sometimes put marketing ahead of

science when reporting clinical trial results. Merck's apparent misrepresentation
of data about deaths among Vioxx patients is just one example, she says.

Pharmaceutical companies "are doing their darndest to hide the side effects of
the drugs they are developing," DeAngelis says. Everybody who uses a drug has
to judge its cost — not just the financial cost but cost in terms of side effects — to
understand its benefits. But you can't do that unless you have the data. Some of
them are trying to suppress the data on side effects."

10.4 What roles do independent scientists play in clinical trials?

Drug companies employ many eminent scientists. But the companies usually ask
outside scientists to serve as "principal investigators" for clinical trials. These
scientists are responsible for conducting the trial in a scientific manner and for
guaranteeing that the sponsor has not exerted undue influence either in
conducting the trial or in reporting its results.

These outside scientists usually are prominent experts in their fields. For
performing this work, sponsoring drug companies pay the university or institution
with which the scientist is affiliated, says Margaret Dale, JD, dean for faculty and
research integrity at Harvard Medical School.

"We do not accept contract language that restricts publication of study findings,"
Dale tells WebMD. "We have policies that relate to whether that investigator can
have any financial interest in the sponsoring company, and their obligation to
disclose it."
In addition, these experts often are paid to discuss the study findings at scientific
meetings, symposia, advisory-board meetings, and drug-company-sponsored
events. Dale says Harvard restricts investigators to $20,000 in such consulting
fees — and requires them to disclose this support in publications and scientific
presentations.

Most journals require study authors to declare that they have received such
payments. Dale says that journals are becoming more and more insistent that
scientists disclose all consulting fees.

Troubled by the appearance of conflict of interest, a few prominent researchers

have recently announced they will no longer accept payment for these services.

When clinical trials are over, the results appear as official reports in peer-
reviewed medical journals. These journals have their own rules to ensure that the
studies are scientific. The Journal of the American Medical Association even
requires the statistical analysis of the study findings to be done by someone who
does not work for the sponsor and who has an academic appointment.

When clinical trial studies are submitted to a journal, they undergo a process
called peer review. During this process, draft versions of the manuscripts are
sent — anonymously — to experts who were not involved in the study. These
experts tell the journal whether, in their opinion, the study meets acceptable
scientific standards. They often suggest changes or ask for more information and
do not deem the manuscript acceptable until their questions are answered.

The peer review process seems to have failed to detect the statistical sleight of
hand chronicled by The Journal of the American Medical Association. And, as the
journal's studies suggest, journal editors permitted publication of study reports
and review articles written by drug company employees and contractors that
were signed by independent scientists who actually had little to do with the
study's research or writing. Moreover, some of the company hires who worked on
the study were not listed as investigators or authors.

"Drug companies shouldn't be paying people to ghostwrite a paper and then find
an author who would prostitute him or herself — that is the proper word, I believe
— to put their name and reputation on a paper for which they had very little to
do," DeAngelis says.

Dale notes that Harvard forbids its scientists from being listed as study
investigators unless they made substantial contributions to the work. And she
says the school also insists that everyone who made substantial contributions to
a study must be listed as authors.
Richard Bookman, PhD, executive dean for research at the University of Miami,
says many medical schools and academic research institutions are tightening
their policies so that potential conflicts of interest always are declared.

10.5 What's wrong with the clinical trial process?

Today's studies in The Journal of the American Medical Association suggest —

not for the first time — that not all clinical trials are designed, conducted,
analyzed, or reported ethically.

DeAngelis says it's wrong to blame the drug companies. The misdeeds
suggested by the report "could not occur without the cooperation (active and
tacit) of clinical researchers, other authors, journal editors, peer reviewers, and
the FDA," DeAngelis and Fontanarosa write.

Directly asked about this allegation by WebMD, the FDA chose not to respond.

How can the process be fixed? DeAngelis and Fontanarosa detail an 11-point
program they say is a starting point. Their recommendations include:

 There should be a registry for all clinical trials that clearly shows — before
patients enter the study — the names of the principal investigators.
 The statistician who analyzes study results should not be employed by a
for-profit company.
 All study investigators should fully disclose all pertinent relationships with
for-profit companies.
 All of the investigators listed as study authors should make substantial
contributions to the work — and all investigators who make substantial
contributions should be acknowledged.

The medical research community already is taking action, Bookman says.

"It is absolutely clear that in academic medicine, awareness of these issues has
mushroomed over the last five years," Bookman tells WebMD. "The pendulum
has swung too far one way, but it is already returning. It is clear that the
academic medical community has waked to the fact they have to look at this
more carefully. Academic medicine in five years will be transformed with much
more complete conflict-of-interest disclosure policies and much more
management capability to avoid conflict of interest."

10.6 Some examples:

Six men on life support after being given experimental drug in clinical trials

March 2006

Taxi driver: How come they are allowed to give this untested stuff to human
beings? Because if something goes wrong, people get seriously ill. I'd vote for
anyone that bans that - its not what a civilised society should do.

Stephen: No matter what the substance - aspirin, antibiotics, lettuce - someone

has to be the first person to put it in their mouths and swallow, and until they do,
nobody actually knows for certain what will happen.

Taxi driver: But what about the scientists? They are supposted to be able to
work these things out. They have obviously made a mistake if they didn't see this
side-effect coming.

Stephen: Scientists can attempt to make exact predictions about anything, but
the more complicated the context of the prediction, the less accurate the result is
likely to be. The phenomena which affect us (such as gravity, electricity, and so
on) and the elements which make us, all existed before life did. But when
evolution got started, the organisms using all these forces and elements became
more and more complicated: now there may be millions of steps in a process,
and millions of processes, and we will never know what all of them are exactly.
The way all these things interact in our bodies is extremely subtle, and slightly
different in each one of us, because we are all different after all. So if you
measure the speed of light in 100 different places on the planet, the results are
always exactly the same. On the other hand, when you apply the same stimulus
to 100 people, the results are usually similar, but not identical.

So instead of making an exact calculation where we can say "This will definitely
happen", drug developers can only ever say "This will probably happen" - to a
greater or lesser extent. Before any new drug is given to people to try, huge
numbers of experiments are carried out to check everything that can be checked,
and this builds confidence in the predicted effect on patients.

Taxi driver: I don't understand why they can't just do all of this in the lab. Then
you could test it, and test it, and test it, millions of times on cells from all sorts of
people.

Stephen: Well, are you exactly like all other taxi drivers? Do you all react in
exactly the same way to everything, so that a scientist can predict what would
happen? Would you be the first person to take a drug that had never been taken
by a living person before? You'd be happy to do that, knowing that men in white
coats can predict what happens in millions of glass jars?
Taxi driver: Oh, I see what you mean... no, probably not. It just doesn't seem
right, though, does it? I mean, that a clinical trial can go wrong like this.

Stephen: But the trial hasn't gone wrong. Of course it feels like that to the
subjects - the ones who took the experimental drug - but the trial is an
experiment designed to find out if it does any harm before the rest of us take it.
And now we know. In fact there are two stages: first healthy people take it to see
if it does any harm; then, if it is safe for healthy people, it is given to sick people
(the ones you hope it will help) knowing that there is little risk of it doing any
damage. Then you can see if it has any benefits.

Taxi driver: So why not just give it to the sick people to start with? They might be
grateful to take the risk.

Stephen: If you give it to sick people they are weak already, and if there were
any side effects it might make them worse or kill them - that would be unethical.

Taxi driver: Ethical? Don't talk to me about ethics! I mean, there are stories in
the paper all the time about drugs with side effects that have to be withdrawn...
People won't stand for it and quite right too. We have to make a stand or nobody
in those big drugs companies would do anything ethical. They're just out to make
money from our suffering.

We don't have any really big diseases left here, anyway. Why aren't they making
cures for all the awful things that people get in Africa? It just seems a bit much
that they are giving things to healthy people in rich western countries when they
could be putting a lot more effort - maybe the UN could pay for this - curing all
those diseases in Africa. That would be ethical.

Stephen: But what if I told you that drugs already exist that would cure a lot of
those people in Africa at a stroke?

Taxi driver: I wouldn't believe you.

Stephen: It could be true. Maybe they have come up with cures, but they are
cures that have bad side-effects for some people. Maybe for every thousand it
cures, it causes all kinds of extra trouble for one person. Drug authorities
wouldn't approve something like that: they'd get in all sorts of trouble. Imagine
the headlines: "Regulator Approves Drug With Known Side Effect Horror"!
Once some people suffer serious side-effects, it's likely to get withdrawn,
however effective it is for the vast majority.

Taxi driver: Are you saying the authorities are only interested if a drug company
comes up with a cure that cures everybody? They'd rather many people die of
the disease than one person dies of the cure? If one person has bad side effects,
they'd allow millions to die?
Stephen: I'm sure it's not what they want, but you can understand how they'd
make that decision. You said it yourself two minutes ago - once the public finds
out about the side-effects, they wouldn't stand for it and rightly so.

So what do I owe you?

Taxi driver: Well now, Brick Lane to Oxford street, that'll be
1273.00... No, gov,
only joking. Thought you might be one of those one-in-a-million guys...

Discussion points

Drug trials are there to help us balance the needs of a sick population for
effective medicine against the human rights of an individual not so suffer harm.
Where do you draw the line? If you had a treatment that killed one and cured
two, you wouldn't let it go ahead - but if you had a treatment that killed one and
cured 100 million, what then?

Surgery always carries a greater risk than public opinion would be prepared to
put up with from a drug treatment. Despite this, increasing numbers of people
choose to undergo non-essential surgery, for example, to improve their
appearance. Why do you think so many people find this risk acceptable and the
risk of side-effects from drugs not acceptable?

What do you think the pharmaceutical companies should do to minimise the risks
to people who help them in drugs trials, and to patients?
 CHAPTER 11
TOTAL GUIDELINES IN PHARMACOVIGILANCE
- volume 3