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Safety issues of drug use
WHO/EDM Technical briefing seminar
2 October 2002
Geneva
Lembit Rägo, MD, PhD
Coordinator,Quality Assurance and Safety: Medicines
Essential Drugs and Medicines Policy
Health Technology and Pharmaceuticals Cluster
World Health Organization
E-mail: [email protected]
Pharmaceutical gaps
Very different regulatory environments, and likely
very different priorities for regulators
Huge differences exist in regulatory environment - from 191
WHO Member States

One third have advanced regulatory systems
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One third have some regulatory systems

One third have practically no functioning regulatory
systems

How to guarantee safety in circumstances where regulatory
framework is either absent or functioning poorly?
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WHO essential drugs & medicines strategy 4 objectives guide country, regional, global work
(http://www.who.int/medicines)
1. National Drug Policy

guide to coordination of action by all stakeholders
2. Access

selection, financing, pricing, supply systems
3. Quality and safety

standards, effective regulation, information support
4. Rational use

health professionals and consumers,
public and private
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What is WHO doing in order to reduce quality and
safety, and in general regulatory gaps?
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Supporting capacity building and training of regulators

Issuing norms and standards
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Preparing guidance materials
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How to fight counterfeit drugs
How to register generic drugs
How to set up pharmacovigilance centers
Preparing training materials
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Quality Assurance, vol. 1 and 2; TRS publications
Validated GMP training modules on CD-rom
GCP training modules under creation ...
Facilitating information exchange
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WHO Drug Information, WHO Pharmaceutical Newsletter, Rapid
Alerts, increasing information on the web site Biennial International Conferences of Drug Regulatory Authorities
(ICDRAs)
Annual meetings of National Pharmacovigilance Centers
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History of drug safety (1)

2002 - 154 years of pharmacovigilance
 29.01.1848 15 year old Hannah Greener died in course
of routine anaesthesia with chloroform (problem:
ingrown nail of toe; fibrillation of ventricles?). Lancet’i
initiated foundation of a commission and starting
collection of notifications about side effects (1893)

1906 - US Federal Food and Drug Act (required, that the
pharmaceuticals should be “pure” and “free of any
contamination”, nothing was said about the efficacy)

1936 - USA-s 107 lethal cases (diethylenglycol was
used to solubilize sulphanilamides); the law was
amended in 1938
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History of drug safety (2): after thalidomide
era
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
1961 - Dr William McBride (Australia) reported 20% increase in
foetal abnormalities and significant increase of phocomelia in
relation with thalidomide use, later numerous reports from other
countries (more than 4000 cases)

1962 - USA Kefauver-Harrise amendment to the law
(requirement to prove safety and efficacy before issuing MA)

1963 - resolution WHA 16.36 reaffirmed the need for early
action in regard to adverse drug reactions

1964 - UK started “yellow cards” system
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1965 - European Union issued EC Directive 65/65

1968 - start of WHO Programme for International Drug
Monitoring

1990 - ICH - elaboration of intra-regional requirements for
safety starts
WHO - EDM
Drug Safety: some definitions (1)

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Adverse event/adverse experience - Any untoward
medical occurrence that may present during treatment
with a pharmaceutical product but which does not
necessarily have a causal relationship with this treatment
Side effect - Any unintended effect of a pharmaceutical
product occurring at doses normally used in man, which is
related to the pharmacological proprieties of the drug

Essential elements of this definition are the pharmacological
nature of the effect, that the phenomenon is unintended, and
that there is no overt overdose
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Drug Safety: some definitions (2)

Adverse reaction - A response to a drug which is noxious
and unintended, and which occurs at doses normally used
in man for the prophylaxis, diagnosis, or therapy of
disease, or for modification of physiological function
(WHO Technical Report No 498, 1972, ICH definition
regarding marketed products practically the same)

Pharmacovigilance is a science and activities relating to
the detection, assessment, understanding and prevention
of adverse effects or any other possible drug-related
problems.
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Drug Safety: some definitions (3)

Signal - Reported information on a possible causal
relationship between an adverse event and a drug, the
relationship being unknown or incompletely documented
previously.
Usually more than a single report is required to generate a
signal, depending upon the seriousness of the event and
the quality of the information
WHO - EDM
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How do we get information on drug safety?
Main sources of information:
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Pre-clinical studies
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Clinical studies
 pre- and post-marketing
Spontaneous adverse reaction reporting*
 national and international


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Epidemiological studies
 case-control
 cohort
Data collected for other purposes
 routine statistics
 databases of prescription and outcomes
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Limitations of Pre-approval Clinical Trials

Size (maximum 3,000-5,000 subjects)
 Sometimes larger for vaccine

Narrow Population
 Often does not include special groups
(e.g., children, elderly)

Narrow indications not covering actual evolving uses
in practice

Short Duration (1-3 years)
 Latent effects not directly measured
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The Likelihood of Observing an Adverse Drug
Reaction Employing Numbers Usually Studied in
Premarketing Trials
Number of Patients
2,000
Threshold for ADR
Probability
1 / 500
(Lymphoma From Azathioprine)
0.98
1 / 1,000
(Eye Damage From Practolol)
0.86
1 / 10,000
(Anaphylaxis From Penicillin)
0.18
1 / 50,000
(Aplastic Anemia From Chloramphenicol)
0.04
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How many patients one needs to treat to see
with high probability the reaction?

Pre-marketing studies are carried out in limited number
of patients: “The law of three”
 In order to detect for sure SAE that occurs as 1 event per
2000 patients treated we need to treat
 6000 patients
for 1 case
 9600 patients
for 2 cases
 13 000 patients
for 3 cases

The number of patients involved in pre-marketing studies has
been increasing but is still limited in comparison with the exposure
to the drug in post-marketing phase
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Are drugs safer today ? (1)

During 1960-1999 there were 121 safety related
withdrawals Worldwide
 Market life was known for 87 of those
 Market life less than 2 years 31%
 Market life less than 5 years 50%

Fung et al. Drug Information Journal, 2001; 35:293-317

During 1972-1994 in 583 new active substances were
approved
 Of these 59 were withdrawn later

During 1990-2001 in UK 24 drugs were withdrawn due
to safety reasons
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Are drugs safer today? (2)

In England and Wales the number of deaths related to
ADRs has raised during last 10 years
 Study of 3,277 Coroner’s Inquests in one UK district
showed during 1986-1991 10 deaths due to prescribing
errors and 36 due to ADRs
 These 46 deaths made approximately 1 in 2000
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A meta-analysis of 39 prospective studies in USA

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ADRs between fourth and sixth leading cause of death in
USA; fatality rate as a result of ADRs was estimated 0.32%
among hospitalised patients
The annual cost of ADR related hospital costs 1.6-4 billion
US $
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Ferner et al. J R Soc Med, 1994;87:145-148
Lazarou et al. JAMA, 1998;279:1200-1205
WHO - EDM
The cost of adverse drug events: estimated lost
patient activity days per year in hospitalised
patients
Country
Serious ADRs
Lost Activity Days
US
Germany
UK
Australia
Sweden
700,000
206,000
148,000
48,000
22,000
1,218,000
358,440
257,520
83,520
38,280
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WHO Collaborating Centre called Uppsala
Monitoring Centre (UMC): operational arm of
WHO Drug Monitoring Programme
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Established in 1978 as Swedish Foundation
Based on agreement between Swedish Government and
World Health Organization
Originally financial contributions from Sweden, selffinancing today
Formerly Swedish administrative board, international
board today (3 of 6 members nominated by WHO)
WHO headquarters responsible for policy
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From pilot to permanence: Countries
participating in the WHO Programme 2002
Member countries
Associate member countries
18
(68)
(7)
WHO - EDM
Uppsala Monitoring Centre (UMC): major
resource for WHO pharmacovigilance related
activities
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Major areas of work - cooperation and support to
national centres
 Collection and processing of case reports of ADRs
 Data utilization (3 million reports in database)
 Information exchange and feedback
 Education, training and advise
 Harmonization
 Research and evaluation
Main function
 Signal generation (identification of previously
unknown adverse drug reactions) and
communication
WHO - EDM
Uppsala Monitoring Centre (UMC): major
recent achievements

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New innovative tools
 A sophisticated Bayesian confidence propagation
neural network (BCPNN) programme (1998), which
partly automates the signal detection, provides
earlier signals
But effectiveness depends on
 Size of database
 Quality of reports
 Timeliness of reporting
 Active and reliable reporting culture
WHO - EDM
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Recent trends: enlarging the scope of
pharmacovigilance

Pharmacovigilance concerns have been widened to
include:
 herbal medicines
 traditional and complementary medicines
 blood products
 biologicals
 vaccines
 medical devices
WHO - EDM
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World Health Assembly resolution 54.11, 21 May
2001: WHO Medicines Strategy
… bearing in mind the previous report on the subject, that highlight challenges
related to the international trade agreements, access to essential drugs,
drug quality and rational use of medicines, together with the urgent need
to improve access to treating priority health problems such as malaria,
childhood illnesses, HIV/AIDS and tuberculosis, among others;
REQUESTS Director-General: …
(3) to provide support for implementation of drug monitoring systems in
order better to identify developing resistance, adverse reactions and
misuse of drugs within health systems, thus promoting rational use of
drugs;
(6) to provide support to Member States to set up efficient national
regulatory mechanisms for quality assurance that will help ensure
compliance with good manufacturing practices, bioavailability and
bioequivalence
WHO - EDM
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World Health Assembly resolution, May 2002:
Quality of Care: Patient Safety
… Concerned that the incidence of adverse events is a challenge to quality of
care, a significant avoidable cause of human suffering, and high toll in
financial loss and opportunity cost to health services;
Noting that significant enhancement of health systems’ performance can be
achieved … by preventing adverse events in particular, and improving patient
safety and health care quality in general;
REQUESTS Director-General: …
(1) to develop global norms, standards and guidelines for the definition,
measurement and reporting of adverse events..., and to provide support to
countries in developing reporting systems, taking preventive action … ;
(2) to promote framing of evidence-based policies, including global standards
that will improve patient care, with particular emphasis on such aspects as
product safety, safe clinical practice … and safe use of medicinal products
and medical devices, and creation of a culture of safety within health care
organizations.
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What is WHO doing to follow the recommendations by
the World Health Assembly? Publications published and
under preparation.
- Safety Monitoring of Medicinal Products - Guidelines for
Setting Up and Running a Pharmacovigilance Centre (2000)
- The Importance of Pharmacovigilance (2002)
- Safety of Medicines - A Guide to Detecting and Reporting of
Adverse Drug Reactions. Why Health Professionals Need to
Take Action (2002) http://www.who.int/medicines/library/qsm/who-edm-qsm2002-2/esd_safety.pdf
- Safety Monitoring of Medicinal Products in Communities (first
draft)
- Safety Monitoring of Herbal Medicines (process started)
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A Future challenges: safety of drugs for
neglected diseases (1)

Research and developemnt for neglected diseases
intensifying
 Problems with regulatory assessment - who does it?
 Launch in places where no monitoring, no health
systems, no health care professionals
 All drugs immediately OTC
 No incentive for post-marketing studies
 No ...
 More responsibility and care needed that in case of
launching in developed markets!
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Regulatory guidance/requirements missing

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How to ensure drug safety in communities affected by
neglected diseases?
WHO - EDM
A Future challenges: improvement of existing
systems (3)

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Are existing systems exhausted?
 Likely improvement of spontaneous reporting by
medical doctors can enable more early signal detection
Can patients and pharmacists reporting improve
patients safety?
 Initiatives of creating data bases of patient reports
 Pharmacists based reporting
Regulatory guidance in which cases new/alternative
methods have to be imposed
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A Future challenges: improvement of
information, education and communication (4)

Improvement of information
 In many parts of the World information is either not
readily available or of poor quality

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In some countries still only OTC drugs have PIL although both
POM and OTC are delivered without prescription
Education
 Can education of consumers/patients improve drug
safety?
Communication
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Health professionals
Patients
Media
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