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Introduction To Pharmacovigilance PDF
Introduction To Pharmacovigilance PDF
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Contents
1. INTRODUCTION
2. DRUG HYPERSENSITIVITY
10. CLINICAL TRIALS – WHAT THEY CAN DO AND WHAT THEY CAN’T!!
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.
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:
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
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): ------------
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
Brief description of
Product (chemical class, mode of
action etc)
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.)
<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
Cumulative Up to 1 m
Cumulative Up to 3 m
Cumulative Up to 6 m
Cumulative Up to 12 m
Table 2: BY DOSE
Dose level 1
Dose level 2
etc
M F M F
Age group 1
Age group 2
etc
Ethnic origin 1
Ethnic origin 2
etc
Pregnant women
Lactating women
Renal impairment
(specify or categorise)
Hepatic impairment
(specify or categorise)
Cardiac impairment
(specify or categorise)
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.
Study 2
etc
M F M F
Age group 1
Age group 2
etc
Table 2: BY DOSE
Dose level 1
Dose level 2
etc
Table 3: BY COUNTRY
INDICATION
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.
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
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.
Discussion
1.2.7.1. For each indication, discuss the incidence, prevalence, mortality and
demographic profile of the target population
Indication/target population <>
1.2.7.2. For each indication, discuss the important co-morbidity in the target
population
<> <>
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 <>
Risk 1 Product A
Product B
Product C
Review of adverse
reactions BMJ
2008: 5;
214-217
Risk 2 etc
Action(s) proposed
Objective of proposed action(s) <>
1.2.12.1 For each safety concern from section 1.10, provide a summary
table of planned actions
Safety concern
Names <>
Position <>
Qualifications <>
Signature <>
ANNEXES
List of annexes
Annex No
Large outcome
studies
Further
safety/efficacy
studies of XYZ
Studies in special
subgroups
Paediatric studies
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.
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.
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:
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.
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.
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.
2.6 Desensitisation
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.
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.
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.
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
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.
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.
6.2 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
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.
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
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.
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
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:
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.
9.3.1 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
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).
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.
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.
Coroners
Dentists
Doctors (including pre-registration House Officers)
Nurses
Pharmacists
Patients
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)
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.
9.11 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?
When a drug finally makes it through clinical trials and FDA approval, here's what
we know about it:
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.
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.
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.
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.
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."
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.
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.
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.
"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."
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.
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?
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.
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