Detecting Rare Adverse Events in Postmarketing Studies: Sample Size Considerations
- PDF / 10,293,831 Bytes
- 10 Pages / 648 x 864 pts Page_size
- 89 Downloads / 210 Views
INTRODUCTION Sufficient information must be available to demonstrate the efficacy and safety of a new drug in ordcr to have a Marketing Authorization allowing that drug to be sold. However, uncertainties regarding the drug's safety may persist after the drug is licensed because limited information is available in the preapproval studies. The information is limited in terms of (1) dosage recommendations: (2) assessment of side effects, especially those that are rare: ( 3 ) detection of unexpected/previously unseen adverse effects and their interactions with other compounds: (4) quantitative measurement of longterm safety/toxicity; (5) identification of risk factors and potential risk groups: and (6) use in patient populations either not studied or studied to a limited extent (1). In addition, recent studies on the incidence of adverse drug reactions (ADRs) in hospitalized patients showed a substantial incidence, and that 20%-70% of these ADRs may be preventable (2). Since 1994, 2.3% of marketed drugs have been withdrawn for safety reasons (3), including the recent case of Vioxx for cardiovascular risk. Consequently, risk management has become a n important issue in regulatory affairs. In 2002, the latest version of the PDUFA (Prescription Drug User Fee Amendments) I l l incorporated risk manage-
tecting associations between the drug and rare adverse events and have a moderate sample size requirement to reach safety decisionsmore quick!y A new sample size formula based on the Poisson distribution is developed for a design in which the incidenceof adverse eventsfor subjects treated with the compound is compared to an external control cohort not receiving the compound under study. The results provide direct evidence for a reduction in sample size with the incorporation of external controls.
ment as one of its goals. and subsequently the Food and Drug Administration (FDA) released three concept papers in 2003 addressing this goal. Thus, there is increasing emphasis placed on postmarketing safety studies.
LIMITATIONS OF PREAPPROVAL STUDIES Preapproval studies include phase 1-3 clinical trials. Phase 3 trials are the largest studies and provide much of the evidence of efficacy and safety required for approval. However, there are limitations of the preapproval study package that preclude their capacity to firmly establish the safety profile for a new drug. This is not to imply that phase 1-3 studies do not play an important and necessary role in safety assessment-they do. Rather, results from these studies are often used when considered in the broader context of postmarketing studies (PMSs) that are required in certain situations. For example, ADRs that are rare, such as those with incidence rates less than 1 in 1,000 patients, may not be seen in phase 3 trials because of limitations of sample size. The incidence of ADRs increases with the presence of risk factors, including extremes of age, multiple medications, disease state, past history of ADR or allergy. genetic factors, and large doses (4). Therefore, there is the
Data Loading...
