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Pharmacoepidemiology and risk management
The document discusses the concept and importance of risk management (RM) in prescription drug safety, emphasizing the need for ongoing evaluation of drug-related risks post-marketing. It outlines strategies and interventions aimed at optimizing the balance between drug benefits and risks, as well as the role of pharmacoepidemiologic research in addressing clinical problems related to drug safety. Additionally, it highlights the limitations of current methodologies and the varying effectiveness of RM programs, exemplified by the case of troglitazone and its associated risks.
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Pharmacoepidemiology and risk management
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- 2. Introduction • the term“risk management” (RM) in the setting of prescription drug safety is a relatively recent development and a consensus definition for it has not yet emerged. • Risk management represents a growing awareness of the need for continuing evaluation of risks related to drug products and the implementation of plans to minimize those risks after marketing. • The concept of RM has emerged and gradually developed, especially in response to the challenges created by accelerated review and approval times for marketed drugs, as well as drug product withdrawals for safety reasons in the US
- 3. Cont… • RM representsthose interventions that must be in place and must be effective in order to – shift the balance of benefit to risk – from an unfavorable and unacceptable position – to one that is favorable and acceptable.
- 4. Goal of RM •To enhance the safe use of medicines by optimizing the balance of benefit and risk. acco mplis hed by
- 5. Numerous interventions for balanceof benefit to risk • Physician Prescribing and on Drug Utilization Review. • specific drug products include professional labeling and package inserts • special letters sent to health care professionals • specific educational and training programs. • patient-package inserts and medication guides
- 6. Strategies for balance ofbenefit to risk • signing of informed consent forms by patients prior to drug therapy. • registration of health care practitioners before they are “certified”. • to prescribe or dispense a given drug. • requiring the performance of certain laboratory tests prior to prescribing. • establishing registries of physicians, pharmacists, or patients who, respectively, prescribe, dispense, or use a given drug product.
- 7. CLINICAL PROBLEMS TOBE ADDRESSED BY PHARMACOEPIDEMIOLOGIC RESEARCH 1. Risk Identification and Characterization 2. Postmarketing 3. Product Usage 4. Case Reports 5. Phase IV and ad hoc Postmarketing Epidemiologic Studies
- 8. Risk Identification and Characterization •Randomized controlled trials (RCTs) have a number of limitations, including – relatively small size, – short duration, and – recruitment of highly selected and hence unrepresentative patients. • Consequently, well-designed epidemiologic studies frequently offer the only way to characterize the safety risks associated with a given drug.
- 9. Postmarketing • In theearly stages of marketing of a new drug, observational studies using computerized databases are often not practicable because there has not been sufficient patient exposure to the drug of interest. • From an RM perspective, this means that during the early postmarketing phase most information about risk will be obtained from spontaneous or published case reports.
- 10. Product Usage • Fromthe start of marketing, drug use can be monitored. • Drug use in – inappropriate age groups, – at higher doses, – for longer lengths of time than labeled, or – for off-label use might signal the emergence of a potential safety problem requiring RM.
- 11. Case Reports • Reviewof well-documented case reports can provide – useful insight into the spectrum, – severity, and – natural history of an adverse drug effect, as well as – its reversibility, – predictability, – preventability • Understanding these factors should be a critical component of any decision to design or implement an RM program.
- 12. Phase IV andad hoc Postmarketing Epidemiologic Studies • Pharmacoepidemiologic studies are sometimes relied upon – to characterize further the nature and magnitude of safety signals arising during pre- approval clinical trials or from postmarketing spontaneous case reports. • Limitations in the methods and design of these studies can – Undermine their power and – utility frequently leading to negative findings.
- 13. METHODOLOGIC PROBLEMS TOBE ADDRESSED BY PHARMACOEPIDEMIOLOGIC RESEARCH 1. Properly Utilized, Pharmacoepidemiology Risk Management Goal Setting 2. Risk Management Design and Evaluation
- 14. Properly Utilized, Pharmacoepidemiology Risk ManagementGoal Setting • High quality case reports may suggest junctures along the causal path where intervention might be useful and effective. • Careful review of drug usage data can also be useful and effective. • The primary goals of a RM program must be – explicit, – relevant, – Process and – measurable.
- 15. • explicit goalis unambiguous and can be subjected to evaluation regarding success or failure of goal attainment. • relevant goal directs health outcome immediately reflective of the event that the RM program is seeking to eliminate or minimize. • Process goals assess incremental aspects or components of a RM program would not be relevant • Measurable goal is a health outcome that can be measured, permitting conclusions to be made regarding goal achievement
- 16. • Risk managementprograms are especially warranted for – the severe or serious end of the adverse effect spectrum, those that are • potentially life threatening, or • Result in hospitalization, • disability, • or death. • In these settings, the requirement that an RM program be implemented is an admission that, without effective RM, the balance of benefit to risk would be unacceptable
- 17. Risk Management Designand Evaluation • Risk management programs often represent – interventions of uncertain and unknown effectiveness that will be applied to large numbers of patients within the “laboratory” of the postmarketing health care setting. • If the design of an RM program does not foster the collection of accurate and reliable data on the health outcome of interest, there is no way to determine if the risk has been adequately managed and the balance of benefit to risk optimized.
- 18. Examples of CurrentlyAvailable Solutions • As per the addressed clinical as well as methodological problems. • implementation of an effective RM program is necessary to establish an acceptable balance. • Helps to assess the effect of intervention.
- 19. Drug Safety coronerRM Intervention Effect of interventions Acetaminophen Overdose, acute liver failure, death National law in UK mandating blister packs and sublethal package size ↓ hospitalizations, mortality, liver transplants All drugs Pediatric overdose, death National law mandating child- resistant packaging ↓ mortality from accidental poisoning Aspirin Reye’s syndrome Prolonged multifaceted national campaign at Federal government level ↓ in incidence, mortality
- 20. Effectiveness of RiskManagement Efforts • Changes to product labeling • posting of letters to health care providers about product risk, while absolutely necessary, • Help to change physician or patient behaviors. Risk management programs supported by national legislation or a nationally coordinated comprehensive campaign
- 21. CASE EXAMPLE EFFECTIVENESS OFRISK MANAGEMENT WITH TROGLITAZONE Background • Within 6 months of approval, troglitazone, an oral hypoglycemic agent, was found to increase the risk of acute liver failure. As a risk management strategy, the FDA implemented a series of labeling changes recommending that physicians perform baseline and monthly serum liver enzyme testing. Question • Did the FDA’s risk management program prevent the occurrence of acute liver failure?
- 22. Approach • Systematic reviewof adverse event case reports. • Population-based cohort study of hospitalization for acute liver injury. • Population-based cohort study of serum liver enzyme monitoring in patients treated with troglitazone. Results • Troglitazone substantially increased the risk of acute liver failure and hospitalization for acute liver injury. • The FDA risk management efforts did not result in sustained or meaningful improvement in performance of liver enzyme monitoring by physicians. • Even if monthly liver enzyme monitoring had been performed, it is unlikely that it would have prevented many, or perhaps any, cases of acute liver failure.
- 23. Strength • Comprehensive evaluationof liver failure risk and the effect of repeated waves of risk management interventions with troglitazone. Limitations • Incomplete information from adverse event case reports. • Reliance on claims data could have resulted in slight underestimation of liver enzyme monitoring performance.