Pharmacoepidemiology Basic Principles and MethodologyProfessor Saad Shakir MB ChB LRC&S FRCP FFPM FISPE MRCGPDirector - Drug Safety Research UnitSouthampton

Pharmacoepidemiology is the study of the use and effects of medicines in large numbers of people. or The application of epidemiological methods to study the effects of medicines in large numbers of people.

PharmacovigilanceMonitoring drug safety in clinical practiceIdentification of drug safety hazardsEvaluation of the issuesConducting risk/benefit assessmentTaking actions to optimise drug safety (risk management), when neededMonitoring that actions taken were effectivePharmacovigilance is supported by pharmacoepidemiology

Scope of pharmacoepidemiology Includes all observational (i.e. real world) research studies in man relevant to use of drugsIn observational studies, the investigator does not assign interventionsAlso occasionally includes randomised clinical trials (usually simple clinical trials)

PHARMACOEPIDEMIOLOGY Is mostly based on observational data Links exposure and outcome in terms of adverse events, therapeutic gain, length of life or quality of life, or for any appropriate groups or subgroups in any selected medicinesAlso includes drug utilisation studiesHas developed mainly for exploration and quantification of drug risks Is now being developed for comparative effectivenessBridges medicine, statistics, demography, clinical pharmacology and epidemiology

Pharmacoepidemiology - Why?Limitations of clinical trials in assessing drug safetyToo few patientsToo shortToo healthy (exclusions)Too few other drugsNot too many young or oldToo few women Too specific

Number of patient exposures required to detect ADEs*Statistical power: the probability of detecting an ADR if it really occurs in the population under study (95%)

ADE incidence

1 Event

2 Events

3 Events

1 in 100

300

480

650

1 in 200

600

960

1300

1 in 1000

3000

4800

6500

1 in 2000

6000

9600

13000

1 in 10000

30000

48000

65000

Record LinkageThe use of automated databases to link exposure to medicines with health outcomesExamplesInsurance databasesHealth management databases e.g. MedicaidHealth information databases e.g. GPRD, Mediplus

The advantages of pharmacoepidemiological studiesRepresent real lifeRelatively inexpensiveIncreasing number of databasesIncreasing academic and regulatory interestBUT BEWARE PITFALLS

Some problems with pharmacoepidemiological studiesProne to bias and confoundingMissing dataMisclassificationIn many cases relies on data which have been collected for another purpose (however, follow-up can improve the quality of the data)

The trade off between double blind clinical trials and observational studiesAddress bias and confoundingbut sometimes there arevalid concernsregarding external validityRepresent real world usageUsually large sample sizesbut issues regarding bias and confoundingRCTsObservational studies

Definitions

Populations and SamplesPopulation - a large group of people in a defined settinge.g. because of a characteristic such as presence of a disease, relatively unselectedSample - a subset of a population selected from it.

SamplePopulation

Measures of AssociationsRelative riskAttributable riskOdds ratio

Relative RiskThe ratio of the incidence rate of anoutcome in the exposed group to the incidence rate in the unexposed group.More than 11Less than oneUse with confidence interval

Attributable RiskThe arithmetic difference between the incidence rates in the exposed andunexposed groups.Use confidence intervalsVery important in considering the public health impact of an association.

Oral Contraceptive Pills and Venous Thrombo-embolism

Third Generation COC

Second Generation COC

RR

Attributable Risk

25/100,000 per year

15/100,000 per year

1.66

10/100,000 per year

Pregnancy

Healthy non pregnant women

60/100,000 per year

5/100,000 per year

Odds RatioOdds - If an event has a probability Pr(E), the odds of the event is defined asPr(E)/{1-Pr(E)}Odds ratio - If two events, E1 and E2, have the respective probabilities Pr(E1) and Pr(E2), the odds ratio comparing E1 with E2 is [Pr(E1)/{1-Pr(E1)}]/Pr(E2)/1-Pr(E2)}], namely the ratio of the odds of E1 to the odds of E2

Odds ratioFor rare events the odds ratio is an acceptable estimate of relative risk

The relative risk and the odds ratio are measures of the strength of an association.Neither measure necessarily indicate causation

Number Needed to HarmNNH1/Attributable riske.g. risk of DVT in users 3 rd generationOCP is 10/100,000 women yearsNNH 1/10/100,000NNH 10,000Very useful number for communications

Methods

Types of epidemiological studiescase reportscase seriescross sectional surveysCase-control studiesCohort studiesClinical trials

Cohort Study Cohort is a group of subjects identified at acertain point in time and followed to determine the incidence of a diseaseIn pharmacoepidemiology a cohort includespatients exposed to a medicinal productCompare the frequency with which the disease in question (ADRs) develops with the frequency in an unexposed group

Case-control studyStart with patients who already have thedisease in question (case patients) e.g. ADRCompare frequency of past exposure to the risk factor in question e.g. medicinal product with the frequency of exposure in a group without the disease (controls)

Data collection from Cohort and Case-Control Studiesabcdpresent(cases)absent(controls)present(exposed)StudyDirectionStudyDirectionabsent(not exposed)DrugExposureOdds ratio (OR) = (a/c)/(b/d)Relative risk (RR) = (a/a+b)/(c/c+d)Cohort studiesCase control studiesDisease

Cohort and Case-Control Studies MEASURES OF ASSOCIATIONCohort study

Relative risk (RR) = (a/a+b)/(c/c+d)The risk of the outcome in exposed subjects compared to unexposed subjects.Case-control study

Odds ratio* (OR) = (a/c)/(b/d)The odds of exposure in cases compared to the odds of exposure in controls.It is an estimate of the relative risk.

Case Control StudiesDVT and oral contraceptivesMyocardial infarction and oral contraceptivesClear cell vaginal adenocarcinoma anddiethylstilbesterolOestrogens and endometrial cancer

Cohort StudiesAdvantagesCan calculate rates of outcomesCan study many outcomesCan elucidate temporal relationships between exposure and outcomeBias can be reduced in the acertainment of exposure

Cohort StudiesDisadvantagesInsufficient for rare outcomesLiable to selection biasIn pharmacoepidemiology confounding is commonEven with record linkage requires availability of medical records

Case Control StudiesAdvantagesRelatively quick and inexpensiveGood design for rare outcomesSuitable for conditions with long latency

Case Control StudiesDisadvantagesParticularly prone to bias compared with other methods in particular selection and recall biasCan not directly compute incidence in the comparative groupsSometimes it is difficult to establish the temporal relationship between disease and exposure

Clinical TrialsIn clinical trials each subject has an equal chance of being included in either group

AB

RANDOMISED CLINICAL TRIALSRandomisationInterventionNot the first choice in pharmacoepidemiologyADEs generally infrequentunworkable methodologicallyprohibitively expensive? always valid to extrapolate to real life groups and to individual patients

Types of associations between factors under studyNo AssociationApparent Association

When there is an apparent associationFalseChance (unsystematic variation, random error)Bias (systematic variation)ConfoundingCausal (true)

ChanceBiasConfounding

ChanceStatistical methods measure the role of chance

BIASA process at any stage of inference which produces results that depart systematically from true values. Examples: Selection bias Measurement bias Information bias

SELECTION BIASWhen comparisons are made between groups of patients that differ with respect of determinants of the outcome other than those under study.

Example: patients with hypertension attending a renal clinic

Measurement BiasMethods of measurement are different for some patientsExample - patients who receive ACE inhibitors for hypertension may get more frequent biochemical measurements than those who receive beta blockers.

INFORMATION BIASWhen comparisons are made between groups where there are systematic differences in the information in respect of exposure or outcomeExamples:Mothers of healthy babies forget about use of drugs during pregnancyPatients after MI give better dietary history than controls

Bias- Points to rememberRepresent error in study designStatistical significance is not a protectionProper study design is the best protection.

ONFOUNDCINGA confounder is a variable other than the risk factor which is associated independently with exposure and outcome.

It may create an apparent association or mask a real association e.g. smoking and cervical cancer.

CONFOUNDINGExposurecoffee drinkingOutcomeheart diseaseConfoundersmoking

TYPES OF CONFOUNDINGConfounding by indicationthe indication for the drug is the confounding variable i.e. to prescribe a given drug to patients who have a poorer prognosis than those who not receive the drug

Confounding by associationsmoking is an association between lung cancer and ulcer healing drugs

Approaches for controlling confoundingRandom allocationSubject allocationexclusionmatchingData analysisstratificationmathematical modelling e.g logistic regression

Epidemiological study designsCase reportsCase seriesAnalysis of secular trendsCase-control studyCohort studyRandomised clinical trial

Pharmacoepidemiology in Drug DevelopmentDefine disease burden prevalence and incidencecost and disabilityExamples studies in migraine, asthma and Alzheimers disease

Pharmacoepidemiology in Drug DevelopmentDescriptive epidemiologythe natural historycomplications of the disease and long term sequel (description and frequency)

Background frequency of adverse events of interest

Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs:cohort study using administrative dataHennesy et al. BMJ.2002;325:1070Cohort of patients with schizophrenia treated with antipsychotic drugs, a control group with glaucoma and a control group with psoriasisOutcome measure diagnosis with cardiac arrest or ventricular arrhythmiaPatients with schizophrenia had higher rates of cardiovascular death than controls ranging from 1.7 to 3.2

Epidemiological Data SourcesNational statisticsHealthcare databases (GPRD, MEMO, United Health Care)Clinical databases (diabetes, HIV)RegistriesMonitoring systems (PEM)Teratology centres

Record linkage is linking exposure with outcomes

Drug Utilisation studiesStudy the marketing, distribution, prescription and use of drugs in a society, with special emphasis on the resulting medical, social and economicconsequences. (WHO)

Drug utilisation studiesMeasuring drug use in populationsUnderstanding the reasons for variations in drug usage within and between populationsExploring the determinants of drug useAssessing the appropriateness of prescribing

Some uses of drug utilisation studies in pharmacovigilance and risk managementAny differences between pre- and postmarketing populations and whether these differences impact on safetye.g. differences in age profile or disease severityOff label useMisuseIs the drug being prescribed and taken appropriately, e.g. drug interactions

Prescription Event Monitoring (PEM)

Technique of PEM

Aim to monitor all new products which are expected to be widely used in general practiceStudy starts as soon as possible after drug marketed in UKIdentify all patients prescribed the drug by general practitioners (GPs) in England.

An outline of the PEM Process

DSRU notifies PPA of new drug to be studied

Patient takes prescription to pharmacist

Pharmacist dispenses drug and forwards prescription to PPA for reimbursement purposes

PPA sends prescription data to DSRU in confidence

Patient and GP identified

DSRU send GP questionnaire

GP returns questionnaire to the DSRU

Data from questionnaire entered on DSRU database

Follow-up

Selected eventsPregnanciesDeaths

Write to GPOutcomesCertificate

consultant

records

assess causality

Analysis of Event DataPEM provides:- number of events reported - numerator

number of patients exposed to the drug - denominator

duration of exposure for each patient - days of treatment

Compare event rates in the 1st month of treatment with 2nd - 6th months of treatment Compare event rates during and after drug exposure Identify Reasons for Stopping Identify events considered as ADRs by doctorCompare with incidence without drug exposure (literature, other databases) Compare event rates between drugs- of same class - with similar indications

Hypothesis/Signal Generation

PEM AnalysisCompare event rates in the 1st month of treatment with 2nd - 6th months of treatment Compare event rates during and after drug exposure Identify Reasons for Stopping Identify events considered as ADRs by doctor Compare with incidence without drug exposure (literature, other databases) Compare event rates between drugs- of same class - with similar indications

Hypothesis/Signal Generation

Follow-upevents of medical importancepremarketingpostmarketing in other countriessignals raised during the studyall deaths of uncertain causeall exposure during pregnancychildren

Recently completed/ongoing PEM studiesTadalafil- EDVardenafil - EDCiclesonide - asthmaRosuvastatin -hyperlipaemiaModafanil - sleep disorder Yasmin - COPStrontium - osteoporosisIntrinsa- testosterone patchSitagliptin- type II DMVarenicline- smoking cessation

Tacrolimus- eczemaPimecrolimus- eczemaAtomoxetine - ADSPregabalin neuropathic pain, epilepsyDuloxetine- depression, urinary incontinenceQuetiapine-antipsychoticRimonabant- obesityIbandronate - osteoporosisIvabronate- anginaSolifenacin- bladder dysfunction

Full list www.dsru.org

M-PEMFor certain drugs, the information collected using standard prescription-event monitoring (PEM) methodology is not sufficient to fulfil the aimsof the studyM-PEM methodology is an extension of the standard PEM methodology

M-PEM studies can monitor both safety, detailed drug utilisation andhealth outcomes in patients who were prescribed a particular drug.

M-PEM methodology can be used to compare the events reported before drug use to the events reported after drug use in patients who were prescribed a particular medication

Information on drug utilisation and the characteristics of patients usingparticular medications can also be collected using M-PEM

The DSRU has used M-PEM methodology to monitor the introduction of new drugs onto the market, requesting the patients previous medicalhistory, concomitant medication use and concordance to the prescribed medication under study. M-PEM

The Effects of Risk ManagementCarvedilol in the treatment of heart failureInterim report in 847 patientsAcharya N, Wilton LV, Shakir S. Int J Clin Pharmacol Ther.2005.43;1:1-6.

Treatment initiated by hospital specialists in 735 (87%)Supervision under shared care 595 (70%)>90% started carvedilol in the recommended doseGrades of cardiac failure at start of treatmentGrade II 281 37%Grade III 297 43%On treatment with carvedilol improvement in NYHA was reported for 364 (43%)20

OK! Exclusive: Britney's Little Helpers? Potential for misuse

Pharmacoeconomics and outcomes researchDisciplines related to PE with some common methodologiesPharmacoeconomics Health outcomes research

Post-authorisation safety studies(PASS)Any study relating to an authorised medicinal product conducted with the aim of identifying, charactersing or quantifying a safety hazard,confirming the safety profile of a medicinalproduct or of measurement of risk management measures

PASS General principlesCharacterise the safety profile Provide assurance about absence of a safety concernInvestigate potential or identified risk, e.g. characterise the incidence rate, estimate rate ratio or rate difference in comparison to non-exposed population and investigate risk factors and effect modifiersEvaluate the risks of a medicinal product used in authorised indications by patient groups not studied in the pre-authorisation phase (e.g. pregnant women, elderly patients)To assess patterns of utilisation and use of the medicinal product that may have an impact on its safety (e.g. co-medication, medication errors)To evaluate the effectiveness of risk minimisation activities

Sabine Strauss

PASSAt first authorisationPost-authorisationPASS is a condition of the authorisation and is legally bindingIn the event that the safety concern applies to more than one medicinal product, the EMA/National Competent Authority shall encourage the MAHs to conduct a joint post-authorisation swafety study.

Post authorisation Efficacy StudiesPAESAt authorisation: where concerns related to some aspect of the efficacy of the product are identified or can be revealed only after the product has been marketed.Post authorisation: when the understanding of the disease or the clinical methodology indicate that the previous efficacy evaluations have to be modified significantly.EU Commission may adopt implementing measures regarding situations when PAES may be requiredEMA shall adopt scientific guideline (not expexed before end of 2012) S Strauss

Scenarios for PAES might be:

Effectiveness studies or studies with increased external validityOutcome studies following initial evaluation on biomarkers/surrogate endpointStudies in sub-populationsLong-term/sustained efficacyProducts with narrow benefit/risk

EMA plans a public consultation for Spring 2012

A Spooner

All scientific work is incomplete - whether it is observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer on us the freedom to ignore knowledge we already have, or to postpone the action that it appears to demand at a given time. Sir Austin Bradford Hill

saad.shakir@dsru.org www.dsru.org

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