Pharmacoepidemiology

Dr Lateef M Khan

Introduction

Application of epidemiological methods to the clinical use and

effects of drugs in a large population is called as

Pharmacoepidemiology.

Pharmacoepidemiology was primarily concerned with post-

marketing studies of drug safety.

Pharmacoepidemiology research is often based on large health care

utilization databases using non experimental study of intended and

unintended drug effects outside of randomized controlled trials.

In addition to identifying adverse events, one of the key objectives of

Pharmacoepidemiology is to identify reasons that may explain the

adverse events. These questions can include:

Pharmacoepidemiology.

Are the events dose related?

Does the pharmaceutical interact with other

medications or substances to promote adverse events?

Are there high-risk subpopulations or pertinent

lifestyle factors that can be identified as being related to

the event?

Are drugs being used differently than originally

intended

Furthermore, it also define patterns of physicians’ prescription and

patients’ use and compliance of medications.

Analyze the influence of health system factors (policies, coverage

and reimbursement differences) on the quality of medication use.

Design, implement, and test innovative programs to improve the

appropriateness of medications prescribed by physicians and used

by patients.

Short duration Premarketing studies are limited in time. Effects that develop

following chronic use or those that have a long latency period

cannot be detected

Small sample size Few drugs are studied in more than 4,000 subjects before FDA

approval. Effects that occur with a frequency of less than

1/1,000 are difficult to detect.

Narrowly defined

population

Premarketing studies generally do not include special

populations such as children, women of childbearing

age, or the elderly.

Narrow set of

indications

Manufacturers pursue specific indications for use during

premarketing studies.

Limited

comparison

groups

The comparison group is often limited to placebo.

Limitations of Premarketing Clinical Trials

• About 20% of drugs get new “black box”

warnings after marketing

• About 4% of drugs are ultimately

withdrawn for safety reasons

Consequences of Limitations of Pre-marketing

Trials

•Suicidal tendency increased tendency associated to the use of fluoxetine and other

SSRI antidepressants

•Tardive dyskinesia associated with long-term use of metoclopramide and many

antipsychotic

•Stroke or heart attack associated with sildenafil (Viagra) when used with

nitroglycerine

•Cerivastatin. Treatment of hypelipdeimeia

•Introduced in 1990s, withdrawn in 2001

•Why ? , 52 deaths were reported from rhabdomyolysis and its resultant renal

failure

•The story of thalidomide is well known

•Chloramphenicol and Grey Baby Syndrome

•Gynaecological cancer in offspring of women receiving Diethyl Stilboestrol

•Oculomucocutaneous syndrome with practolol

•Liver disease from benoxaprofen

•Valvular heart disease from Dexfenfluramine

•Cardiac arrhythmias with terfenadine

Despite the rigorous process for drug approval and regulation, several

important medications have been removed from the market because of serious

ADEs over the past 30 years as a result of Pharmacoepidemiological studies

Pharmacoepidemiological consulting services on numerous projects

also provided supportive evidences. Some examples include:

Cardiovascular risk among women using dietary supplements

Liver failure risks among users of anticonvulsants

Clinical and economic impacts on asthma and COPD of a new

respiratory bronchodilator

Costs associated with complications after cataract surgery

Effectiveness of adding omega-3 supplements to diet

Projection of future needs, clinical trends, and economic impact for

knee and hip replacement surgery

Assessment of potential patient population size for proposed orphan

drug application and filing of Pediatric Investigation Plan

Epidemiologic evaluation of factors influencing patterns of care in

chemotherapy treatment for common female cancers,

Beneficial findings of Pharmacoepidemiological studies

Aim of Pharmacoepidemiology

• Signal Generation: Most commonly associated with ADR but also use to detect new applications

– E.g Minoxidil 1st indicated for hypertension but case report (signal generation) soon identified it causes hirsutism in a number of patients, side effect was investigated and now it is marketed for purpose mainly stimulation of hair growth

• Risk Quantification: of ADR often require large sample size

Hypothesis testing

Require the use of comparison group to determine

whether there are difference in variable of interest (risk

factor, trait, characteristic, drug exposed, or clinical

conditions)

Statistical methods are used to assess whether the

observed difference could have occur by chance alone

Conclusions about relation b/w exposure to a drug and

clinical event thus based on the ability to reject the null

hypothesis, postulating that the 2 group are no difference

with regard to either the drug exposure or the clinical

event

Example: Signal identified via spontaneous reporting

confirmed by a formal Pharmacoepidemiology study.

Background-

•Phenylpropanolamine (PPA)- ingredient used in OTC and

prescription cough and cold medications as a decongestant, and

in OTC weight loss products.

•In 1984, FDA received reports of Hemorrhagic stroke (bleeding

into brain or into tissue surrounding brain) in association with

PPA.

•In addition, there were published reports in literature.

•Question-

•Is the use of PPA-containing products associated with

hemorrhagic stroke?

Approach-

To confirm this signal, an ad-hoc case-control study was

conducted

Results

The study demonstrated a statistically significant increased risk of

hemorrhagic stroke among both appetite suppressant users and

first-time users of PPA as cough/cold remedy

Outcome-

FDA Advisory Committee meeting discussed the case-control

study and recommended that PPA be considered not safe for

OTC use

FDA then took steps to remove PPA from all drug products and

requested all drug companies to discontinue or reformulate PPA-

containing products.

Reasons to perform PE studies:

(A) Regulatory

(1) Required to obtain earlier approval for marketing

(2) As a response to question by regulatory agency

(3) To assist application for approval for marketing elsewhere

(B) Marketing

(1) To assist market penetration by documenting the safety of the

drug

(2) To increase name recognition

(3) To assist in repositioning the drug

(a) Different outcomes, e.g., quality-of-life and economic

(b) Different types of patients, e.g., the elderly

(c) New indications

(d) Less restrictive labeling

(4) To protect the drug from accusations about adverse effects

(C) Legal

(1) In anticipation of future product liability litigation

(D) Clinical

(1) Hypothesis testing

(a) Problem hypothesized on the basis of drug structure

(b) Problem suspected on the basis of preclinical or premarketing

human data

(c) Problem suspected on the basis of spontaneous reports

(d) Need to better identify the frequency of adverse reactions

(2) Hypothesis generating—need depends on:

(a) whether it is a new chemical entity

(b) the safety profile of the class

(c) the relative safety of the drug within its class

(d) the formulation

(e) the disease to be treated, including

(i) its duration

(ii) its prevalence

(iii) its severity

(iv) whether alternative therapies are available

Thus, the decision to conduct a PE study can be viewed as similar

to the regulatory decision about whether to approve a drug for

marketing or the clinical decision about whether to prescribe a

drug.

In both cases, decision making involves weighing the costs and

risks of a therapy against its benefits.

Application of Pharmacoepidemiology

• Estimation of risk of drug use

• Use in patient counseling

• Formulation of public health policy decision

• Formulation of therapeutic guidelines and discovery

of new indications

• Facilitate thepharmaco-economic evaluation

Pharmacoepidemiology in Practice

• The basic idea of pharmacoepidemiology is to

measure the source, use, and effects of drugs in a

population and to determine the frequency and

distribution of drug use outcomes in that population

The focus of this type of research includes

(1) what is being used (an assessment of specific

drugs being used in certain situations)

(2) How it is being used (an assessment of the

patterns of use, including how much, where and

when, and by whom); and

(3) Why it is being used (an assessment of the reasons

for drug-taking behaviors and the functions that

drugs serve in society).

World Health Organization

WHO focuses its pharmacoepidemiological efforts on ensuring the

quality, safety, and efficacy of drugs and their use in specific

populations and studies are performed to :

1) Describe current patterns of drug use in specific patient

populations

2) Determine changes in drug use over time

3) Measure the effects of information, education, promotional

activities, media accounts, and price on drug use

4) Detect inappropriate drug use and associated problems

5) Estimate drug needs in terms of disease patterns and outbreaks

6) Plan the selection, supply, and distribution of drugs.

Research methods used most often by

pharmacoepidemiologists • Cross-sectional study: a prevalence survey of health

and illness in the population at one point in time

• Case-control study, a retrospective analysis comparingsubjects with the condition (cases) to those without it(controls) with respect to possible risk or causativefactors

• Cohort study, an incidence study that follows apopulation free of health problems over time,examining subsequent development of problems andfactors associated with them.

• Clinical trials, an experimental approach that tests thevalue of a new treatment or intervention comparedwith a standard treatment or a placebo, are alsoconsidered to be an epidemiological method

Thus, Pharmacoepidemiology relies on the same study designs

(cohort, case control, case-crossover, case-cohort studies), as other

branches of epidemiology.

The field also offers unique challenges in:

Controlling For Confounding Factors

Addressing The Limitations Of Health Care Databases

Obtaining Accurate Assessment Of Drug Exposure And Use

Accounting For Potential Selection Bias Concerns.

Common research methods used by Pharmacoepidemiologists –

Cont’d

Moreover, Pharmacoepidemiological studies provide "real

world" assessments of potential short-term and long-term

adverse drug events in the general population with a wide range

of health status and demographic characteristics and with a

much longer follow-up period than clinical trials, which

evaluate initial drug efficacy and safety.

Sources of Data on Drug Use

• Institutional record systems and databases

– Drug utilization studies

– Hospital-based medical audits (inpatient)

• System wide databases

– Institutionally based reviews (outpatient)

– Health insurance groups and third-party payers

– Pharmaceutical organizations

– Commercial vendors of marketing studies and

sales data

• National databases

– government-sponsored studies

– essential drug lists and inventory data

– pharmacoepidemiological surveillance systems

• Field data

– records of drug dispensers, sellers, and distributors

– drug-taking behaviors of individuals and small groups

• Experimental data

– clinical trial results

Sources of Data on Drug Use- Cont’d

Problem Solving with Pharmacoepidemiology

Medical drug use

Beneficial effects of drug therapy

Risks (e.g., adverse reactions, side effects) of drug therapy

Inappropriate prescribing behaviours

Patient noncompliance

Irrational self-medication practices

Poor drug use outcomes

Cost-effectiveness of drug therapy

Problem Solving with Pharmacoepidemiology- Cont’d

Nonmedical drug use

Social-recreational drug use and associated

problems

Acute incidents of drug toxicities (e.g., overdoses)

Chemical dependencies

Outbreaks and sources of drug epidemics

Conclusion

All drugs have adverse effects and Pharmacoepidemiology will

never succeed in preventing them.

It can only detect them, hopefully early, and thereby educate health -

care providers and the public, which will lead to better medication

use.

The net results of increased activity in pharmacoepidemiology will

be better for industry and academic world but, most importantly, for

the public’s health.

The next drug disaster cannot be prevented by

pharmacoepidemiology. However, pharmacoepidemiology can

minimize its adverse impact by detecting it early.

The past few decades have demonstrated the utility of this new

field.

With good fortune, the next few years will see the utility is

accentuated and the problems will be improved.