Second Annual Symposium on PharmacovigilancePharmacovigilance Strategy to Maximse Drug Safety

Thomas Y.K. ChanDivision of Clinical Pharmacology

Department of Medicine and Therapeutics, andCentre for Food and Drug Safety, Faculty of Medicine

The Chinese University of Hong Kong

4 March 2011

Safety Monitoring of Medicines in Children and Pregnant Women

Outline of presentation

• Rationales for pharmacovigilance

• Methods of post-marketing surveillance

• Role of regulatory authorities and stakeholders

• Issues about drug use, needs for and methods of drug safety monitoring in children

• Issues about drug use, needs for and methods of drug safety monitoring in pregnant women

• Plans for Hong Kong

Key references on pharmacovigilance• World Health Organization. Promoting safety of

medicines for children, 2007 • European Medicines Agency. Committee for Medicinal

Products for Human Use. Guideline on conduct of pharmacovigilance for medicines used by the paediatric population, 2007.

• European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on the exposure to medicinal products during pregnancy: needs for post-authorisation data, 2005.

• The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)http://www.ich.org/home.html

Pharmacovigilance"the science and activities relating to the detection,

assessment, understanding and prevention of adverse effects or any other possible drug-related problems"

WHO, 2006

"set of methods that aim at identifying and quantitatively assess the risks related to the use of drugs in the entire

population, or in specific population subgroups"Reggi V, 2001

Signal (>1 report, AE seriousness, data quality)

"reported information on a possible causal relationship between an adverse event and a drug, the relationship

being unknown or incompletely documented previously"

Safety monitoring of medicines – pharmacovigilance

At the time when a medicine is authorised for use, it has only been tested for safety and efficacy in a relatively small number of patients for a limited length of time as part of the clinical trials.Some adverse reactions may not be seen until a very large number of people have received the medicine and begin to use it over longer time periods, i.e. once health care professionals begin prescribing.It is vital that the safety of all medicines is monitored throughout their use ("life cycle") in clinical practice.

European Medicines Agency

To be sure to detect an ADR that occurs once per 2,000 patients treated, we need to treat:

- 6,000 patients for 1 case- 9,600 patients for 2 cases- 13,000 patients for 3 cases

The number of patients in pre-marketing studies is inadequate to provide information on less frequent ADR.

Reggi V, 2001

Rationales for pharmacovigilanceComplete safety data can only be captured through pharmacovigilance

• Tests in animals are insufficiently predictive of human safety

• In clinical trials patients are selected and limited in number

• Conditions of drug use in clinical trials differ from those in clinical practice

• Information about rare and serious adverse drug reactions and chronic toxicity often unavailable

• Some population subgroups are not included

Populations often excluded from clinical trials

• Children

• Pregnant women

• Elderly

• Subjects with concomitant diseases (renal, liver and cardiac diseases)

• Subjects on concomitant medications

• Certain ethnic groups

Objectives of pharmacovigilance

• Improve patient care and safety

• Improve public health and safety

• Encourage safe, rational and appropriate use of drugs

• Promote understanding, education and clinical training in pharmacovigilance

Lalvani P, 2007

Methods of post-marketing surveillance

• Hypothesis-generating methods- Spontaneous reporting of ADRs (national,

international)- Prescription-event monitoring

• Hypothesis-testing methods- Case-controlled studies- Cohort studies (databases, record linkage)- Randomised clinical trials

Dunn N et al, 1999

Aronson JK, 2007

Role of regulatory authorities & stakeholders

• Spontaneous reporting systems to facilitate the detection of new ADRs with active participation by all stakeholders – majority from community, mainly the adult population, proactive?

• Regional monitoring centres?

• Specific studies of ADR reports in children and pregnant women

• Targeted studies

• Clinical trials

Needs for pharmacovigilance in children – 1

Children differ from adults: (a)Infants (preterm, term), toddlers, children, adolescentsContinuing growth, development, maturation → changes in body composition, physiology and pharmacology →affect efficacy, toxicity and dosing of drugsPharmacokinetic changes during development → drug distribution, hepatic and renal elimination of drugsLimited information about the developmental changes in pharmacodynamics

WHO, 2007

Needs for pharmacovigilance in children – 1

Children differ from adults: (b)Childhood diseases may be qualitatively, quantitatively different from adult diseases, thus affecting the benefits and risks (risks-benefits assessment) of treatments

Safety information cannot necessarily be extrapolated from data in adults because:PK and PD of a drug may be different in childrenSome ADRs are only seen in children, e.g. drug-induced growth and developmental disorders

EMEA, 2007

Needs for pharmacovigilance in children – 2

Medicines used in children are not fully tested in relation to efficacy and safety: (a)

Limited data on the safety of medicines used in children are generated during drug development because:Small sample size only identifies common ADRsLikely to miss rare ADRs and ADRs that occur after a latent period, e.g. effects on development or growthThe target population is relatively small, with a number of distinct age ranges

Needs for pharmacovigilance in children – 2

Medicines used in children are not fully tested in relation to efficacy and safety: (b)

Low quality of reporting ADRs in paediatric randomisedcontrolled trials:107 papers on RCTs in English journals, 1/2006-4/2009, 78% mentioned ADRs, 34% used standardised methods to disclose ADRs, 31% tabulated the ADRs, 25% stated numbers of and reasons for withdrawal, 18% reported safety data adequatelyBoth authors and editors share responsibility to improve safety data reporting (de Vries TW et al, 2010)

Needs for pharmacovigilance in children – 3

∼50-75% of drugs used in children are not adequately studied to provide appropriate labelling informationUse of medicines outside the specifications described in the license (formulations, indications, contraindications, route, age ....) is common ⇒ off-label or unlicensed useIf paediatric formulations are unavailable → tablets are crushed or dissolved in solvent, powders in capsule are administered → ? bioavailability, ? efficacy, ? safetyIf formulations of strengths for young children are not available → adult formulations are diluted before use →errors in dosage calculation and infusion rate

Needs for paediatric drug research – 1Why?The use of unlicensed and off-label drugs is thought to be associated with a greater risk of toxicity.Lack of appropriate formulations for children(Mechanisms of) drug toxicity in children are different to those in adults – e.g. chloramphenicol induced grey baby syndrome in neonates (impaired metabolism) and salicylate induced Reye’s syndrome in children

Who?Partnership – paediatric health professionals and the pharmaceutical industry

Choonara I, 2004 (IUPHAR)

Needs for paediatric drug research – 2Where?Child friendly units – clinical trial unitsWhich medicines?ICH Classification of medicinal products for children –the 1st two groups where there is the greatest potential clinical benefits.…. for diseases predominately or exclusively affecting paediatric patients...... intended to treat serious or life threatening diseases occurring in both adults & paediatric patients for which there are currently no or limited therapeutic optionsPharmacovigilance – independent safety monitoring board

Aims of pharmacovigilance in children

• Establish the epidemiology of ADRs in paediatric patients

• Detect new ADRs• Increase awareness of ADRs• Reduce ADRs• Establish the safety of a medicine in a

clinical trial

Choonara I, 2006

Spontaneous reporting of ADRs in childrenPassive surveillance

• Spontaneously reported ADRs – most important source of drug safety information

• No estimates on denominator (number of people exposed), poor numerator estimates since only a small proportion of ADRs reported

• Observer bias, failure to identify/report ADRs• Some children cannot express themselves• Parents/carers as an added step before reporting• Reluctance to report off-label or unlicensed use• ADRs with longer latent period

Safety monitoring of drugs of paediatric exclusivity

FDA allows an extra 6 months of marketing exclusivity for companies that perform paediatric clinical trials ….Limited safety data pre-marketing + drug introduced to a larger, more diverse market post-marketing ⇒ safety?FDA to report to Pediatric Advisory Committee on AEsoccurring in the 1-year period after granting exclusivitySafety reviews ⇒ specific PAC recommendations (e.g. label changes, MedGuides) or routine AE monitoringSafety monitoring during early post-marketing period is crucial to detect rare, serious or paediatric specific AEs

Smith PB et al, 2008

Prescription-event monitoring (PEM)Active surveillance

• Event-based, no need to diagnose the cause, but to record the event

• Drug Safety Research Unit at SouthamptonDispensed prescriptions for reimbursement →details on drug exposureGPs return questionnaire → data on AEsReviewed → follow-up actions

• Not all forms returned, not all forms contain clinically useful data

• Number of reports / number of patient weeks or months of exposure

The developing foetus may be adversely affected by exposure to drugs and environmental chemicals – 1Depending the stage of development and the nature and concentration of the drug or chemical, exposure durationHuman conceptus – 3 major developmental periods: pre-organogenesis (1st 2.5 weeks), active organogenesis (3-8 weeks) and the foetal period (>8 weeks)Very severe damage→spontaneous abortion, foetal deathThe most sensitive period to teratogens = 3-8 weeksTeeth, external genitalia and brain continue to be very active developmentally beyond the 1st trimester and may still be affected by teratogens

The developing foetus may be adversely affected by exposure to drugs and environmental chemicals – 2

Thalidomide – marketed in 10/1957, "wonder drug" for insomnia, anxiety, pain, headache and morning sickness, safe in animals, thought not to cross placenta, withdrawnin 1961 (4 years later) when teratogenicity recognised

Warfarin – foetal risk is the greatest during 6-9 weeks of gestation (heparin used in 1st trimester), approved for human use 1954, foetal warfarin syndrome (hypoplasticnose …) 1st report in 1966, causal relationship proposed in 1968, more reports in 1970s

Valproic acid (VA)Marketed in 1967 as an anticonvulsant1st reports suggesting teratogenicity in early 1980s↑ rate of lumbosacral spina bifida + meningomyeloceleor meningocele in children whose mothers took valproicacid in the first trimester of pregnancy"VA syndrome" described in 1984 (facial dysmorphicfeatures ± developmental delay, IUGR, other congenital anomalies, neurological impairment)If there is no alternative, pregnancy considered high risk → proper follow up, appropriate antenatal diagnosis, usethe lowest possible daily dose

Ornoy A, 2009

Examples of drugs with teratogenic effects

ACE inhibitors – prolonged renal failure in neonates …

Anticholinergic drugs – neonatal meconium ileus

Antihyperglycaemic drugs – neonatal hypoglycaemia

Antithyroid drugs – foetal and neonatal goitre, ↓ T4

Cyclophosphamide – CNS malformations

Androgenic drugs – masculinisation of female foetus

Isotretinoin – microencephaly, mental retardation …

NSAIDs – constriction of PDA, necrotising enterocolitisTetracyclines – staining of teeth, teeth/bone anomalies

Needs for pharmacovigilance in pregnancy – 1Drug exposure in pregnancy is very common

• Cohort & registry based epidemiological studies estimate that 44-99% of women are prescribed medications during their pregnancy

• Unplanned pregnancy, accidental drug exposure• For treatment of pregnancy-related complaints

and minor infections• For treatment of chronic diseases (e.g. asthma)

and medications are continued• Also, non-prescription drugs

Needs for pharmacovigilance in pregnancy – 2Incomplete data about drug safety

• Animal data are not always predictive of human teratogenic risk

• Risk of birth defects → caution in developing drugs for pregnant women, exclusion from drug trials, preventing unplanned pregnancy → only limited number of drugs under development and limited data about drug safety

• The number of pregnancies occurring in studies is too small to reliably predict exposure effect once drug is approved for general population

Aims of pharmacovigilance in pregnancy

• To identify possible adverse pregnancy events associated related to maternal exposure

• To identify signals and establish risks early in the life span of a drug release

• To disseminate this information back to patients and health care professionals → rational choices about disease management in pregnancy

Moretti M, 2007

Assessing the need for drug safety data• Conditions and diseases where drug therapy is

essential for maternal and/of foetal benefit and where discontinuation or omission of treatment would result in ↑ risk for mother and/or foetus

• Conditions and symptoms where drug treatment although not necessarily required, is frequently given, with or without prescription

• Treatment with drugs belonging to a class of substances having a similar chemical structure or mechanism of action to teratogens …

• Drugs with a completely new chemical entity or a new mode of action

Human data from pre-marketing studies

• In clinical trials which include female patients of reproductive age, there may be occasional unplanned pregnancy with inadvertent exposure to study drug → to collect data on drug effects

• For females who must have a medicine during pregnancy for treating an underlying disease →to collect data on drug effects

EMA, 2005

Human data from post-marketing studies – 1

• Spontaneous reports (the most common source)Advantages – investigate drugs in the "real-life" setting, several reports → "signal"Disadvantages – under-reporting, incomplete data, outcome assessment often retrospective

• Record linkage – a registry with drug exposure data linked with subsequent data collected later in life on the exposed individuals (computerisedmedical records), unique identification number

Human data from post-marketing studies – 2

• Clinical studies (randomised controlled trials)May be feasible if this is in the best interest of mother and infant, most reliable methodological approach, rarely suitable for evaluating drugs

• Clinical studies (case-controlled studies)Advantages – cost efficient, fast, allow analysis of rare malformationsDisadvantages – recall bias if retrospective data collection, generally focus on 1 malformation, usually little acceptance of results

Human data from post-marketing studies – 3

• Clinical studies (prospective cohort studies)Patients are identified before the outcomeAdvantages – no recall bias, permit analysis of rare drug exposures, temporal relationship of drug exposure and gestational age determined, results are extrapolated to a defined population, comparatively high acceptance of the resultsDisadvantage – time consuming, loss to follow up, low case numbers, more expensive

Human data from post-marketing studies – 4

• Clinical studies (historical cohort studies)Less time consuming, no recall bias; loss to FU, retrospective, metabolites

• Clinical studies (PK and pharmacogenetic data)Maternal concentrations of active compound & elimination of toxic metabolites → the risk

• Registries – birth defects registries

• Registries – pregnancy exposure registries (vital for systematic evaluation of pregnancies and outcomes exposed to a drug during pregnancies)

What is a patient registry• It collects data from already ongoing medical

care – investigators do not control the exposure• It is based on observational designs (case

series, case-control, cohort, …)• The outcomes defined before data are collected• The population is defined by one or more

common characteristics• Al least one element of registry data collection

is active (some data are collected specifically for the purpose of the registry)

Wyszynski DF, 2009

Cunnington M et al, 2008

Cunnington et al, 2008

Reproductory Toxicology 2005

Teratology Information Services (TIS) provide the public and health professionals with tailor-made information on drug risks in pregnancy.TIS in Europe, Israel and Latin America collaborate in European Network of Teratology Information Services (ENTIS) in order to optimise interpretation of risk data, risk communication, risk management as well as recommendations for drug treatment in pregnant women.In addition, efforts are undertaken to enhance and harmonisedocumentation of exposed pregnancies and their outcomes.These prospectively ascertained data are evaluated like controlled, observational cohort studies, where exposed pregnancies are compared to a non-exposed control group for various outcome variables such as (major) malformations, birth measures and the state of new-born infant, spontaneous abortion. . ………

The Systems for MonitoringAdverse Drug Reactions in Hong Kong

Chan TYK et al, 1993

Take home messagesChildren differ from adults.Medicines used in children are not fully tested in relation to efficacy and safety.Paediatric drug research is needed.Drug exposure in pregnancy is very common.The developing foetus may be adversely affected by exposure to drugs and environmental chemicals.It is vital that the safety of all medicines is monitored throughout their use ("life cycle") in clinical practice.Drug safety concerns all and is the responsibility of all stakeholders.Annual Symposium on Pharmacovigilance in March