PHARMACOEPIDEMIOLOGY

Topics
Introduction: The Contribution of Epidemiology to the Study of Drugs The Drug Approval Process Premarketing Clinical Research Post marketing Surveillance Methodologies (Randomized Clinical trial, Observational epidemiologic surveys, Casecontrol study, Cross-sectional study, Cohort study) Meta analysis in Pharmacoepidemiology Pharmacoeconomy Analysis The Role of Epidemiology in Pharmaceutical Research, Development, and Marketing

What is Pharmacoepidemiology?

Pharmacoepidemiology can be defined as the application of epidemiologic knowledge, methods, and reasoning to the study of the effects (beneficial and adverse) and uses of drugs in human populations.

What is the aim?

To describe, explain, control, and predict the effects and uses of pharmacologic treatments in a defined time, space, and population.

Efficacy, Safety, Economy

Pharmacoepidemiology as a tool to know:

Efficacy
Clinical evaluation of a drug in the premarketing phase has limitations, mostly due to ethical, practical, and economic reasons.

Safety
Adverse Drug Event

Economy
Evaluate the cost and effects of a pharmaceutical product

What is Adverse Drug Experience?

Adverse Drug Experience

Adverse Drug Experience is defined in US federal regulation 21 CFR (Code of Federal Regulations) 314.80 as:
Any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: an adverse event occuring in the course of the use of a drug product in proffesional practice; an adverse event from drug overdose whether accidental or intentional; an adverse event occuring from drug abuse; an adverse event occuring from drug withdrawal; and any significant failure of expected pharmacological action

Drugs Withdrawal
Gone, but not forgotten
Year 1961 Name Thalidomide Trade Name Distavel Valgis Valgraine Comment A sedative drug, also marketed for morning sickness that produced fetal malformation. At the time, promotional material in some markets emphasized its safety in pregnancy Recently reeintroduced to the market as an immunosuppresant and is used to treat leprosy. 1971 Diethylstilbe strol Stilboestrol Stilboestrol was prescribed for pregnant women up to 1970s. It induced cervical and vaginal cancer in the female children of treated mothers as well as genital malformation in its previous indication to prevent miscarriage. Recently reeintroduced to the market rarely to treat prostate cancer and breast cancer in postmenopausal woman

Year 2005

Name Co-proxamol

Trade Name Distalgesic Cosalgesic

Comment An analgesic combination of dextropropoxyphene and paracetamol which has been withdrawn because of its toxicity in overdose. Some patients found it beneficial to them, despite little evidence for acute analgesia benefit compared to paracetamol alone. Withdrawn in EU Jan 2010 due to the required post marketing surveillance SCOUT study showing excess cardiovascular mortality Withdrawn in France June 2011 due to increased risk of bladder cancer

2010

Sibutramine

Reductil

2011

Pioglitazone

Actos

Molecular Drug Withdrawal

2005 natalizumab Tysabri An anti-4,1 integrin monoclonal antibody which was withdrawn before European approval but after FDA approval when 3 cases of progressive multifocal leukoencephalopathy had occurred amongst 3000 treated in RCT and 5000 treated in all. At the time, EMEA rules were tighter than FDA rules Withdrawn if EU Feb 2009 due to 3 cases of progressive multifocal leukoencephalopathy

2009

Efalizumab

Raptiva

Basic molecular and cell biology research have now come of age Recombinant DNA, production of monoclonal antibody etc Although different from traditional pharmacologic agents, products based on biotechnology should be evaluated in the pharmaceutical context rather than the production techniques that are employed. Because of their unique production techniques used and their different mode of action, it is likely that news pharmacoepidemiology methodologies will need to developed.

List of approved and withdrawn drug (FDA, 2006)

Name Rofecoxib Fenfluramine Temafloxacin Troglitazon Alosteron Supofen Cisapride Grepafloxacin Rapacuronium Duration 1999-2004 1979-1980 1992-1992 1999-2000 2000-2000 1985-1987 1993-2000 1997-1999 1999-2001

The need for Post Marketing Surveillance (PMS) arises from the limitations of Phase I, II, and III clinical trial

Comparison between Premarketing and Postmarketing Study

Parameter Alat/tools Orientasi Informasi yang didapat Pre marketing Study Uji Klinik Fase 1-3 Explanatory/knowledgeoriented question Efikasi Obat Post marketing Study Uji Farmakoepidemiologi Pragmatic/Decisionoriented question Efektivitas Obat (focusing on the effectiveness of the drug under usual clinical circumstances) Tidak terlalu ketat Ada, namun bisa diseleksi saat analisa statistik

Subjek penelitian Kemungkinan lain

Hasil seleksi ketat Dapat dihilangkan, mis. Obat lain atau yang dikonsumsi, pola makan, usia

Main Areas of Inquiry Addressed in Postmarketing Studies

Area of Inquiry Long-term effects manifest after long periods of use manifest after long latency periods Low-frequency effects can only be detected in large populations Effectiveness in customary practice patients therapeutic situations Children, pregnant or elderly women with concurrent pathologies and several simultaneous treatments, flexible dosages, tolerance, noncompliance, non-response emergencies, ambulatory care Aplastic anemia: phenylbutazone; Colitis: clindamycin; Jaundice; halothane Use of exogenous estrogen during menopause and endometrial cancer Adenocarcinoma of the vagina due to diethylstilbestrol Example

Area of Inquiry healthcare settings healthcare professionals Efficacy in new indications discovered after marketing

Example emergency, ambulatory care according to training, specialty information sources Propanolol as an antihypertensive, captopril in rheumatoid arthritis, amantadine in Parkinsons disease, antihistamines in motion sickness Antihypertensives to prevent cardiovascular disease, hypoglycemic agents to prevent complications of diabetes A decrease in sodium intake can improve the efficacy of some diuretics in hypertension Severe asthmatics do not respond to metaproterenol without supplementary therapy Risk of myocardial infarction in women who use oral contraceptives may be increased by cigarette smoking

including secondary effects

Modifiers of efficacy concurrent drugs disease severity lifestyle