What is Pharmacoepidemiology? Defn: Pharmacoepidemiology is the study of the use of and the effects of drugs in large numbers of people.
New applied field bridging between clinical pharmacology and epidemiology.
The history of pharmacoepidemiology is a h/o increasingly frequent accusations about adverse drug reactions, often arising out of spontaneous reporting system, followed by formal studies proving or disproving those associations.
Potential contributions of pharmacoepidemiology (A)Information which supplements the information available from premarketing studies—better quantitation of the incidence of known adverse and beneficial effects (a) Higher precision (eg. Prazosin) (b) In patients not studied prior to marketing, e.g. the elderly, children, pregnant women (c) As modified by other drugs and other illnesses (eg. Timolol) (d) Relative to other drugs used for the same indication
(B) New types of information not available from premarketing studies (1) Discovery of previously undetected adverse and beneficial effects (a) Uncommon effects (b) Delayed effects (2) Patterns of drug utilization (3) The effects of drug overdoses (4) The economic implications of drug use
(C) General contributions of pharmacoepidemiology (1) Reassurances about drug safety (2) Fulfillment of ethical and legal obligations
Study designs available for PE studies In hierarchical order of progressively harder to perform but more convincing Randomized clinical trials Prospective cohort studies Retrospective cohort studies Case-control studies Analysis of secular trends Case series Case reports
‘Criteria for causal nature of an association’ is how one can decide, how likely an association demonstrated in a particular study is, in fact, a causal association
First put forth by Sir Austin Bradford Hill in 1965
Coherence with existing information (biological plausibility) Consistency of association Time sequence Specificity of association Strength of association Quantitative strength Dose-response relationship Study design
Case reports and case series- useful to suggest an association
Analysis of secular trends and case-control studies- useful to explore these associations
If study question warrants investment and can tolerate the delay until results become available, then cohort studies and RCTs - can be used to assess these associations more definitively.
Reasons to perform PE studies: (A) Regulatory (1) Required (2) To obtain earlier approval for marketing (3) As a response to question by regulatory agency (4) 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 quantitate 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.
Spontaneous reporting systems are the most common method used in pharmacovigilance to generate signals on new or rare adverse events not discovered during clinical trials
Very useful in HYPOTHESIS GENERATION, with need to explore possible explanations for the adverse event in question
A spontaneous report is a clinical observation that originates outside of a formal study.
In order to ensure that safe and effective pharmaceuticals are available, FDA relies on:
Voluntary reporting by health care professionals or consumers
Mandatory reportingof AEs by manufacturers as required by law and regulation.
Individual spontaneous reports of ADRs, medication errors, & product quality problems, sent to FDA directly or indirectly, combined with data from formal clinical studies and from medical and scientific literature, comprise the primary data source upon which postmarketing surveillance depends.
FDA also employs data mining techniques to identify ‘signals’ (previously unrecognized or unidentified serious AE)
After confirmation of a ‘signal’, FDA can initiate various regulatory actions like:
Withdrawal of a medical product from the market
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.
Is the use of PPA-containing products associated with hemorrhagic stroke?
To confirm this signal, an ad-hoc case-control study was conducted
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
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.
Thus, a formal epidemiological study is usually needed to confirm a signal identified through spontaneous reports.
In spite of its limitations (underreporting , incomplete reports, etc) spontaneous reports of AEs provide an important cornerstone for pharmacovigilance in the US. Yellow Card Scheme:- The UK national spontaneous ADR reporting scheme
National centres should report at a min monthly frequency.
Recently, there has been an international effort to :
harmonize the terms used to describe the adverse events and
to set criteria and definitions for at least the major serious types of reactions
to harmonize the way data are stored and communicated internationally
Main agencies involved in this are WHO, CIOMS, ICH and the EU.
The Medical Dictionary for Regulatory Activities (MedDRA) is being used more and more worldwide.
Also, ICH E2B format, which is a guideline for the transmission format for information to be included on an ADR case report is being used
Like prescription drugs, non-prescription drugs can also have serious adverse effects and unintended benefits.
Drugs previously available on prescription being approved for OTC sales
In CCS, multiple case-control studies are conducted simultaneously in order to monitor the effects of prescription and OTC medications and dietary supplements (e.g. herbals) on risk of various illnesses.
CCS relies on self-reports of medication and dietary supplement use
Asks about 43 indications or medication categories
2. Can have high statistical power because of large number of cases accrued 3. As CCS obtains data on many exposures and many outcomes, it has capacity to discover unsuspected associations.
Example : Inverse association between aspirin and risk of colorectal cancer was documented in CCS
Publication provoked many subsequent studies which confirmed the association.
4. Assessment of effects after long intervals or duration of use Eg: Adverse effect of estrogen supplements on risk of endometrial cancer persisted for 15-19 yrs after cessation of use. 5. Allows for assessment of whether genetic polymorphisms modify the effect of a medication or supplement on the risk of the illness.(buccal cell samples)
PEM is a pharmacoepidemiological study in which a cohort of users of a medicine is defined from prescriptions and followed-up for a defined period (often 6-12months) so as to identify all adverse events occurring in the early post-treatment period.
The limited contribution of spontaneous ADR reporting system in detecting hazards such as oculomucocutaneous syndrome with practolol, led Inmanto establish the system of PEM at the Drug Safety Research Unit (DSRU) at Southampton in 1981
It is one form of pharmacovigilance and is complementary to spontaneous reporting of suspected ADRs
Method of both hypothesis generation and testing
DSRU notifies PPD 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 strict confidence DSRU sends questionnaire (Green Form) to GP GP returns questionnaire to DSRU; scanned; reviewed Data from questionnaire entered on DSRU database Follow-up Pregnancies Questionnaire sent to GP for outcome Selected Events Questionnaire sent to GP Deaths Cause of death
There is a growing use of computerized databases containing medical care data, called “automated databases” which are potential data sources for pharmacoepidemiology studies.
Provide a very large sample size , so uncommon outcomes can be detected Provides denominator needed to calculate incidence rate Relatively inexpensive to use because studies using these databases do not need to incur the cost of data collection No opportunity for recall or interviewer bias When time is limited When budget is limited
Why do individuals or groups of individuals respond differently to a specific drug therapy, both in terms of beneficial and adverse effects? MOLECULAR PHARMACOEPIDEMIOLOGY Defn: It is the study of the manner in which molecular biomarkers alter the clinical effects of medications in populations
Genes can affect a drug response via:
-alteration of drug pharmacokinetics
Pharmacodynamiceffects on drug targets
Gene-drug interactions in the causal pathway of disease
Pharmacogenetics- study of how genetic variability is responsible for differences in patients’ responses to drug exposure. (candidate gene approach)
Pharmacogenomics- Studies of genetic variability on drug exposure + encompasses approaches simultaneously considering data about thousands of genotypes in drug discovery and development, as well as responses in gene expression to existing medication (genome-wide approach)
Molecular PE- focuses on effects of genetics on clinical outcomes from medication use
Pgenetic & Pgenomic studies are designed to examine intermediate endpoints between drugs and outcomes (like drug levels, PD properties or surrogate markers of drug effects)
Molecular PE answers questions related to:
Population prevalence of SNPs and other genetic variants
Evaluating how these SNPs alter disease outcomes
Assessing impact of gene-drug and gene-gene interactions on disease risk
Evaluating usefulness and impact of genetic tests in populations exposed, or to be exposed, to drugs
The ability of genes and other biomarkers to improve patient care and outcomes needs to be tested in properly controlled studies, including RCTs
Cost-effectiveness of such approaches must be justifiable given the additional costs of genetic testing in clinical care
Ethical, legal and social implications of genetic testing must be considered and addressed
Another concern, that medicines will be developed only for the most common, commercially attractive genotypes, leading to ORPHAN GENOTYPES.
Idiosyncratic side effects in susceptible patients based on genotyping---- eg. Carriers of HLA B5701 in use of abacavir…..(orphan drugs)
Violation of privacy and confidentiality is the chief risk in pharmacoepidemiology studies
Research ethics guidelines have stressed the procedural requirement of a subject’s “informed consent”
Pharmacoeconomics: Economic evaluation of Pharmaceuticals
Ongoing concern about cost of medical care
Cost of drugs is not limited to their purchase price
Includes the cost of preparation, administration, monitoring for and treating side effects,etc…
In addition to differences in efficacy and safety, differences in efficiency (or effectiveness of the agent in actual clinical practice compared to its cost) distinguish drugs from one another.
Several national governments now require presentation of pharmacoeconomic data at the time of product registration for pharmaceuticals to qualify for reimbursement through the national health insurance systems
Economic data from Phase III studies are used to support initial pricing of new therapies and are used in professional educational activities by pharmaceutical firms
Post marketing economic studies are used to compare new therapies with existing ones and also to confirm the initial Phase III economic assessments of the product.
In addition to objective measures of judging the impact of interventions like, ↓mortality, ↓rate of hospitalization, or alteration in physiological and biochemical outcomes, “Patient-reported outcomes” are also important tools of measurements
HRQOL has become an established outcome measure in clinical research
In the form of questionnaires administered to the patients to evaluate changes in health status over time with the treatment in consideration
Most common primary objective of QOL assessment in trials is ‘ to see the effects of therapy indicated by changes in score of the instrument over time’
Pharmionics Defn: The topic of ‘what patients actually do with prescribed drugs’ has become a field of research known as pharmionics. Importance: Prescription drugs are cornerstone of medical care It is a basic axiom of pharmacology that ‘all therapeutic drug actions are dose and time dependent’ Pharmionicsintegrates clinical epidemiology and clinical pharmacology for better understanding of the effects of what pts do with prescriptions , thus improving the outcomes of t/t with medications .
Methodologic problems in monitoring patient adherence to therapy:
Early methods included clinical judgement, counting of untaken pills or capsules, questionnaires, interviews, diaries and measurement of drug concentration in plasma.
White-coat compliance- major bias in interpretation of plasma drug concentrations as an indicator of quality of patient’s execution of prescribed dosing regimen.
Currently available solutions
ELECTRONIC MEDICATION EVENT MONITORING (eMEM)
Essence of eMEM is to imbed into the drug package microcircuitry that is connected to one or more micro-switches which detect when the maneuvers occur that are needed to remove a dose of drug from the package
These maneuvers which vary from one type of package to another, are referred to as “medication events”.
Microcircuitry enters the time of occurrence of each medication event and stores the information in its memory for later transfer to the computer which analyses the data.
Common dosing errors made by ambulatory patients:
Most common error- delayed dose (still taken within the scheduled interval between doses)
Miss two sequential doses, miss 3 sequential doses, so on…
A prominent feature with patients’ dosing histories is –
-the higher occurrence of dose omissions with evening doses than with morning doses -higher omissions on weekends than on weekdays -gradual ↑ in frequency of dose omissions as duration of t/t increases. -white coat compliance
There is a simple pragmatic reason for wanting to know what impact these deviations from the recommended dosing regimen have on the effectiveness and safety of the drug in question Case example: “How much adherence is enough?” Background- Doxycyclinehyclate 100mg , orally BD for 7 days, is generally accepted std of care for chlamydial infections of male urethra or lower genital tract of females. Question- How much does adherence alter responsiveness to doxycycline Approach- Study carried out by Public Health Dept of State of Alabama(USA) to examine the impact of poor compliance with prescribed dosing regimen of doxycycline on outcome of chlamydial treatment.
Prescribed doxycycline was supplied to trial participants in electronically monitored drug packages Results-
Pts who took as few as 25% of prescribed doses appeared to have had successful outcomes of t/t in no significantly lesser percentage than those who took all of the prescribed doses
Outcomes of t/t appeared to be independent of adherence!
This is prima facie evidence that prescribed dose could be substantially reduced
Pts performed the “natural experiment” of underdosing and demonstrated that as little as 25% of prescribed dose appeared to be effective in treating chlamydial infection in both males and females.
Being a natural experiment, it should be viewed as a ‘red flag’ rather than as definitive proof about how the dosing regimen could be revised
“Natural experiment” can indicate the possibility of reducing recommended doses
It is preferable from the consumers’ perspective, to make such a discovery early rather than late in a pharmaceutical product’s commercial lifetime
Pharmaceutical product developers can use such natural experiment early in drug development, before recommended dosing regimen and pricing has been set. This can avoid the adverse economic consequences of postmarketing , post pricing reduction in actually used doses.
Cessation and resumption of drug actions, as patients go into and emerge from drug holidays, are potential sources of adverse events
PE can contribute to information about drug safety and effectiveness that is not available from pre-marketing studies
The discipline of PE has been growing and will continue to grow within academia, industry and government
Methodologic advances in risk management and molecular PE
Content areas like drug utilization review, hospital PE, pharmacoeconomics, medication adherence, patient safety and surrogate markers will grow as interest and need for these foci increase
Both computerized databases and de novo studies will serve as important complements to each other
Challenges faced by PE include :- limited funding opportunities
- regulatory restrictions - privacy concerns surrounding human research - limited training opportunities - inadequate personnel resources
All sectors like academia, industry and government must address the challenges facing PE and support its continued development so as to maximize benefit and minimize risks inherent in all medications and medical devices.
References Strom BL & Kimmel SE. Textbook of Pharmacoepidemiology.