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Observational studies

Jesper Hallas

Professor, MD, DrMedSc

Clinical pharmacology and pharmacy

University of Southern Denmark

Paradigm of epidemiology:

Example : does omeprazole cause femoral neck fractures?

Paradigm 1. Basic eksperiment

Measuring cyclic ATPase activity in murine osteoclast cultures in medium with or without omeprazole.

Paradigm 2. Clinical eksperiment

Double blind, randomised trial where a large group of elderly women are allocated to omeprazole or placebo and are followed up with respect to the occurrence of femoral neck fractures..

Paradigm 3. Clinical observational

A large group of elderly women are contacted and asked about their use of omeprazole. The incidence rate of femoral neck fractures in the follow-up period is compared between users and non-users of omeprazole.

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Observational research

� When the investigator does not interfere with study subjects’ exposure (drug use).

� Opposite of experimental / interventional

� Synonyms

� Non-interventional study

� Non-interventional trial

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Definitions of a ”non-interventional trial” (Clinical Trial Directive 2001/20/EC):

� …a study where the medicinal product(s) is(are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practise and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of the collected data”

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Other terms

� Registry studies

� Always observational

� Uses registries as data source

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Aspects of observational approach

� Scientific

� Ethical

� Regulatory

� Validity

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Confounding, definition

Bias generated by the lack of comparability between exposed and non-exposed (drug users and non-users).

Confounder: the factor by which they differ

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Exercise; which confounder explains:

•Users of diet products have fewer femoral neck fractures

than others.

•Persons using a bra have breast cancer more frequently

than others

•Users of low-dose ASA have heart attack more frequently

than others.

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Comparability, large randomized clinical trial

LIPID trial, NEJM

1999

Confounder Control

� IN DESIGN

� Randomisation

� Cross-over

� Restriction

� Matching in cohorte studies

� Matching in case-control studies

� IN ANALYSIS

� Standardisation

� Stratification

� Multivariate modelling

� Propensity scores

� Instrumental variables

� Cross-over

� Symmetry analysis

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Example, PS matching in observational study

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Charlot 2010

Other scientific aspects

� Very large n, narrow confidence intervals

� Possibility of long follow-up

� High-quality retrospective studies in registries

� Exploratory analyses

� Not well suited for study of intended effects

� Well suited for adverse effects

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Ethical

� Risk of harming patient

� Intrusion

� Data confidentiality

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Harm

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Intrusion

� Disturbing privacy

� Affecting natural course

� Dealing with impending risk

� Invasive collection of observations

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Primary vs secondary data

Primary

� Data collected ad hoc

� Nearly always prospective

Secondary

� Data from administrative sources

� Nearly always retrospective

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Data confidentiality

� Data security at ”Forskermaskine”, Statistics Denmark

� Data are pseudomized, .i.e. CPR is replaced

� Log-on for individual researcher

� Secure connection

� Real-time token

� Security checks

� No output allowed with n<5

� Extensive set of rules in ”Datatilsynet”

� Data are there, anyway

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Ethical cost of not conducting observational research

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Legal and regulatory aspects

� In general, observational studies are exempt from GCP

� Exempt from mandatory study registration

� No informed consent

� Pure registry studies are exempt from ethics review in DK

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ENCEPP

� European Network of Centres for Pharmacoepidemiology and Pharmacovigilanc

� EMA based

� Checklists for research standards

� ENCEPP seal

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Hybrid studies

� Streamlined trial, pragmatic trials

� Uses randomisation

� Follow-up in registries

� Analysed like epidemiological studies

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Conditions for performing observationaldrug research in Denmark

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Danish Medicines AgencyPrescription register

� Established by law 1993

� Operational from 1994

� Covers all 288 Danish retail pharmacies and all hospital pharmacies, alltogether 5,7 mio persons

� Individual-level data, using a one-one encryption of CPR-numbers.

� Covers reimbursed and non-reimbursed prescription drugs

� Established for administrative purposes, not research (!!)

� Provide a detailed individual-level drug utilization statistic

Danish Medicines Agency, output

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Danish Medicines Agencyand Danmarks Statistik/Seruminstituttet

� A complete copy of the DKMA prescription register since 1995!

� A complete copy of the Danish Patient Registry since 1977

� Linkage enabled by mutual encrypted CPR-number

� Access through secure connection

� Individual-level data are not given to researchers

� Tables and analyses are transferred by e-mail to the researchers

� ”Forskerserviceenhed”

� Contact: www.dst.dk/forskning

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DST or SSI?

DST pro

� SES data

� Experience

SSI pro

� No backlog of Rx and Dxdata

� Health data

� Different levels of subscriptions

June 200927

June 200928

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Some limitations

� Delay in transfer of data

� Indication in free text

� Dose instruction in free text

� Incomplete capture of magistral preparations

� No capture of hospital dispensed medication

� No capture of over-the-counter dispensings

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Some strengths

� World’s oldest national individual level prescription database

� Covers nursing homes

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Important recent development in DK

� Danish register of reimbursed medication

� Hosted by Clinical Epidemiology Unit at ÅU

� Data can be transferred to researchers with CPR-number

� Only covers reimbursed medication

� From 2004 onwards

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Pharmacoepidemiologic databasesworldwide

Database Population,

million

From

Saskatchewan (Ca) 1 1976

COMPASS (USA) 10 1980

Kaiser Permamente (USA) 2-6 1969

Puget Sound (USA) 0.3 1972

Jämtland, Tierp (S) 0.04 1972

GPRD (UK) 3-4 1987

MEMO (Scotl) 0.4 1989

Odense 1.2 1990

Northern Jutland 1.7 1989

Denmark 5,4 1994

Norway 4,6 2004

Sweden 9 2005

Iceland 0.34 2006

Finland 5 1994

Pharmo, NL 2 1985

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Validity

June 200933

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Describing the process from prescribing to ingestion

Event

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Data on drug exposure

Physician

administrative system,

e.g. GPRD in UK

Pharmacy-based prescription

database, e.g. MEDICAID,

MEMO, OPED

Interview

Event Proxy

Data on drug exposureWhich is best?

Physician administrative

system, e.g. GPRD

Pharmacy-based

prescription database

Interview

Area of major

uncertainty

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Studies of data data validity, findings

� Technical data errors are rarely reported

� Non-compliance is substantial and is difficult to ascertain

� Failure to redeem prescriptions is a minor problem for most drug classes

� Databases may have important limitations, e.g. absence of non-subsidized prescription medication

� Recall errors of omission are much more common than errors of commission.

� Recall is dependent on chronicity

Some measures to ensure technical validity

� Bar code technique

� Modulus 11 check, CTR

� Use of Nordic article number

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Data on drug exposure An example; antibiotics and myocardial infarction

Background: atherosclerosis has been linked to Chlamydia Pneumonia. Antibiotics with effect against CP might protect against AMI

Exposure: any antiobiotic 3 years before the index date.

Cases were 3315 persons with first-time AMI, 13,139 control without AMI. Identified in the GPRD

Meier CR et al. JAMA 1999; 281: 427-31.

Take home messages

� Observational studies do not interfere with subjects’ exposure (drug use)

� Registry studies are observational studies that use registries as data sources

� Main implication

� Scientific: susceptible to confounding (lack of comparability). Possibility of studying rare effects, long-term effects, harms etc.

� Ethical: low risk of harm, confidentiality issue

� Regulatory: important exemptions

� Exceptionally good conditions for conducting observational research in DK

� Validity generally high

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Backup

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Regional vs National prescription databases in Denmark

Regional� Only subsidised drugs

� Covers:

� RSD+RS (OPED)

� RN + RM (PDNJ)

� DK (DRSM)

� 1989(90) onwards

� Data can be transferred to other researchers

National� All prescription drugs

� National coverage

� 1995(4) onwards

� Closed circuit in DST or SSI

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”Study" of anticoagulant effect

Use of oral anticoagulants

and risk of deep-vein thrombosis (DVT)

True risk ratio: <1 (perhaps 0.1?)

Adjusted for age and sex: RR = 27

+ other risk factors for DVT: RR = 4

Miettinen’s conclusions

Confounding by indication can be very strong

It cannot be adjusted completely in a non-

randomised design.

Miettinen OS. The need for randomization in the

study of intended effects. Stat Med 1983; 2: 267-71.