[Exception drugs status: specific characteristics and the role in the proper use of drugs]. / Les médicaments d'exception: spécificité et rôle dans le cadre du bon usage des médicaments.

BACKGROUND: In 1994, the French health care system established a special status for certain costly drugs reimbursed for ambulatory use: exception drugs. Drugs with this status are reimbursed only when prescribed for specified indications. The purpose of this study was to identify the specific characteristics of drugs with the exception status, and to understand the role of this status in proper use of drugs. METHODS: Drugs included in the study were analyzed using three types of data: administrative, clinical and economic. RESULTS: For most of the drugs, prescription was restrictive. For five of them, the sickness fund accepted reimbursements for fewer indications than mentioned in the marketing authorisation. For the majority, reimbursement was 100%. The exception drugs were indicated for the treatment of 15 diseases. Eighty percent of expenditures for exception drugs concerned ten drugs. CONCLUSION: The characteristics considered in the study did not enable a specific description of the inherent features of exception drugs. This special status was established for the purpose of economic efficiency. Currently, its role in ensuring proper use of drugs is questionable.

Antipsychotic prescribing trends: a review of pharmaco-epidemiological studies.

OBJECTIVE: To review findings from pharmaco-epidemiological studies exploring antipsychotic (AP) drugs prescribing trends. METHOD: We retrieved original studies that explored AP prescribing trends in general population samples since 2000. For each study, we extracted information on sampling method, period, assessment of AP use and corresponding estimates (incidence rates, prevalence rates, pharmacy sales, prescription data) and diagnostic assessment. RESULTS: Nearly all studies meeting the inclusion criteria (n = 17) showed an increase in AP prescriptions, mainly because of a dramatic rise in second-generation antipsychotics (SGAP) prescriptions. APs are often prescribed for non-psychotic disorders in adults as well as in children and adolescents. CONCLUSION: Considering the growing number of persons from the general population exposed to APs, population studies assessing the risk/benefit ratio of SGAP use in disorders other than psychosis are necessary, particularly in children and adolescents.

Antipsychotic use patterns in persons initially treated with mood stabilizers: a naturalistic study.

INTRODUCTION: Little information is available on the pattern of use of antipsychotics in naturalistic conditions in persons initially treated with "conventional" mood stabilizers (lithium and anticonvulsants). METHODS: Data on community prescriptions were extracted from the 2004-2006 claims database of a French health care insurance fund for self-employed workers. Patients included were those continuously exposed to mood stabilizers without concomitant dispensing of antipsychotics over at least a 3-month period. RESULTS: Of the 3 958 persons included, 17.8% had at least one addition/switch to antipsychotics over the follow-up period. The most frequent pattern was addition of second-generation antipsychotics (SGAPs) (41%) or first-generation antipsychotics (FGAPs) (23%) to the mood stabilizer for a relatively short period of time. A switch from mood stabilizer to SGAPs (20%) or FGAPs (15%) was less frequent. Mood stabilizers alone were prescribed again in most patients with the addition of FGAPs (72%) or SGAPs (61%) to mood stabilizers. Conversely, the majority of patients with a switch from mood stabilizers to FGAPs (55%) or SGAPs (58%) went on with these latter treatments over the follow-up. CONCLUSIONS: SGAPs are preferentially prescribed in combination with mood stabilizers and their pattern of use is similar to that of FGAPs.

Impact of antidepressants on the risk of suicide in patients with depression in real-life conditions: a decision analysis model.

BACKGROUND: The impact of antidepressant drug treatment (ADT) on the risk of suicide is uncertain. The aim of this study was to determine in a real-life setting whether ADT is associated with an increased or a reduced risk of suicide compared to absence of ADT (no-ADT) in patients with depression. METHOD: A decision analysis method was used to estimate the number of suicides prevented or induced by ADT in children and adolescents (10-19 years old), adults (20-64 years old) and the elderly (65 years) diagnosed with major depression. The impact of gender and parasuicide history on the findings was explored within each age group. Sensitivity analyses were used to assess the robustness of the models. RESULTS: Prescribing ADT to all patients diagnosed with depression would prevent more than one out of three suicide deaths compared to the no-ADT strategy, irrespective of age, gender or parasuicide history. Sensitivity analyses showed that persistence in taking ADT would be the main characteristic influencing the effectiveness of ADT on suicide risk. CONCLUSIONS: Public health decisions that contribute directly or indirectly to reducing the number of patients with depression who are effectively administered ADT may paradoxically induce a rise in the number of suicides.

Congruence between diagnosis of recurrent major depressive disorder and psychotropic treatment in the general population.

OBJECTIVE: We explored in a sample representative of the French general population the congruence between lifetime use of psychotropic drugs and diagnosis of recurrent major depressive disorder (rMDD). METHOD: A total of 2111 (5.6%) subjects with rMDD were identified in the sample of 36 785 subjects assessed in the Mental Health survey in the General Population. A treatment congruent with a diagnosis of rMDD was defined as lifetime use of antidepressants or mood stabilizers. RESULTS: Only one-third of subjects with rMDD reported having ever used a congruent treatment. Female gender, higher income and presence of anxiety disorder were associated with a higher probability of having used a congruent treatment. CONCLUSION: Although these findings indicate that a large proportion of subjects with rMMD do not benefit from adequate treatment, community surveys not primarily designed to assess utilization and adequacy of psychotropic treatment in the community may overestimate the frequency of unmet need for care.

[Psychotropic drug use and correspondence with psychiatric diagnoses in the mental health in the general population survey]. / Usage et congruence diagnostique des traitements à visée psychotrope: résultats de l'enquête santé mentale en population générale en France métropolitaine.

OBJECTIVES: The aims of this study were to assess the lifetime prevalence rate of psychotropic drugs use in the French general population and the correspondence between psychotropic drug use and psychiatric diagnoses. METHODS: Data were derived from the multicentric survey mental health in the general population, carried out in 47 French public sites between 1999 and 2003. A face-to-face questionnaire was used to interview a representative sample of French metropolitan subjects, aged 18 and over, noninstitutionalized or homeless. These subjects were recruited using quota sampling for age, sex, socioprofessional and education levels, according to data from the 1999 national French population census. Lifetime use of psychotropic drugs was explored by an open question. Psychiatric diagnoses were identified using the mini international neuropsychiatric interview (MINI). A national database was then constituted by pooling data from all sites, weighted for age, sex, level of education, socioprofessional level and work status, to be representative of the French general population. RESULTS: Of the 36785 individuals included in this study, more than one out of three subjects reported having used at least one psychotropic drug during their life. Anxiolytics were the most commonly used drugs, reported by 19.4% of the sample. The other frequently used psychotropic drugs were antidepressants (11.6%) and hypnotics (9.2%). Nearly half of the subjects with a MINI diagnosis reported no lifetime psychotropic drug use. Among the subjects meeting criteria for a diagnosis of mood disorder, 66.3% used psychotropic drugs. However, less than one out of three subjects with a diagnosis of major depressive disorder used antidepressants while 37.2% reported having used anxiolytics. Less than one out of four subjects with a diagnosis of anxiety disorder used antidepressants while 34.3% used anxiolytics. Among subjects with a diagnosis of anxiety disorder, antidepressants and anxiolytics were the most commonly used drugs for subjects with a diagnosis of panic disorder with agoraphobia (46.4 and 58.1%, respectively). Conversely, these were the treatments used the least by subjects with a diagnosis of generalized anxiety disorder (21.9 and 31.5%, respectively). Only 14.9% of subjects with a psychotic syndrome reported having used neuroleptics. Lastly, the highest proportion of subjects with at least one psychiatric diagnosis was found in mood stabilizer and neuroleptic users. However, one third of mood stabilizer users, a quarter of neuroleptic users and less than half of antidepressant and anxiolytic users presented no psychiatric disorder identified by the MINI. CONCLUSION: This study highlights the high frequency of exposure to psychotropic drugs in the general French population, and the marked inadequacy between the presence or absence of a psychiatric diagnosis and the lifetime presence or absence of a psychotropic drug treatment.

[One-year follow-up in real clinical practice conditions of type 2 diabetic patients treated with rosiglitazone: the Avantage study]. / Suivi sur un an dans les conditions de pratique courante d'une cohorte de patients diabétiques de type 2 traités par rosiglitazone: l'étude Avantage.

The Avandia, tolérance à grande échelle (Avantage) study was an observational study conducted in a large cohort of type 2 diabetic patients (T2D) followed for 12 months. Its aim was to assess in real clinical practice conditions, the tolerability of rosiglitazone, an oral antidiabetic agent of the new thiazolidinedione ("glitazone") class, available in France since May 2002. Study was carried out from December 2002 to January 2005. To be included, T2D seen during the inclusion period should start the rosiglitazone treatment (within eight days prior to 15 days after) in agreement with therapeutic indications and drug datasheet information in force at that time. Patient characteristics, clinical and biological data and adverse events (AE) during the 12-month follow-up were recorded. Among the 3845 T2D enrolled from January to November 2003, 3580 constituted the analyzed population (at least one documented rosiglitazone intake). At inclusion, mean age (+/-S.D.) was 62+/-11 years, 52% were male, mean BMI was 29.9+/-5.3kg/m2 and mean HbA1c was 8.5+/-1.4%. Ongoing antidiabetic treatments were mainly a monotherapy (46% of patients, metformin or a sulfonylurea) or a bitherapy (in 47%). Main reasons to prescribe rosiglitazone were insufficient control of diabetes (91% of patients), associated or not with a poor tolerance to the ongoing oral antidiabetic treatment at inclusion (in 29%) and/or with a contraindication to metformin (in 4%). Two thousand four hundred and twenty-four patients (71%) completed the 12-month follow-up. Along the study, 514 T2D (14%) experienced at least one AE, judged related to the treatment in the physician's opinion for 377 patients (11%). Two hundred and fifteen patients dropped out from the study due to AE. AE notified in more than 1% of patients were: weight gain (n=100 patients; 3% of the cohort), nausea (n=57; 2%), edema (n=55; 2%) and anemia (n=40; 1%). A seriousness criteria was reported for 105 patients (3% of the cohort), including 18 (<1%) heart failure. Mean HbA1c level decreased from 8.5+/-1.4% at inclusion to 7.8+/-1.6% at study end. Mean value of the main lipid parameters remained stable. Mean systolic blood pressure (BP) decreased from 137+/-13 to 135+/-12mmHg and diastolic BP from 79+/-8 to 78+/-8mmHg. Mean weight was 82+/-15kg at inclusion and 83+/-17kg at study end (NS), mean waist circumference was not significantly modified. In conclusion, the observational Avantage study, conducted in a large cohort of type 2 diabetic patients treated with rosiglitazone in clinical practice conditions and followed-up for 12 months, confirmed the results of controlled double blind clincal studies, with a clinical and biological tolerability in accordance with the known AE profile and a beneficial effect on metabolic control and arterial blood pressure.

[Use and misuse of benzodiazepines out of France]. / Usages et mésusages de benzodiazépines hors France.

Among 8 countries included in the report of ANSM, France is second behind Spain, when defined daily doses (DDD) are considered. Few studies, recent and based on representative samples of population, investigated the use of benzodiazepines in other countries and data are limited to compare France and other countries. In most countries, the use of benzodiazepines increases with age and is more frequent in women than in men. Variations of benzodiazepines use that were observed in other countries are similar to those observed in France, with a slight decrease but persistent high levels of use. In most countries, the long-term use of benzodiazepines is stable over time even though simple use decreases.

[Cardiac tolerance of moxifloxacin: Clinical experience from a large observational French study in usual medical practice (IMMEDIAT study)]. / Tolérance cardiaque de la moxifloxacine: expérience clinique issue d'une large étude observationnelle française en pratique médicale usuelle (étude IMMEDIAT).

BACKGROUND: Moxifloxacin (Izilox) is prescribed for bacterial respiratory tract infections. ECG analysis done in clinical trials showed a mean QT prolongation at 6 ms that could lead to Torsades de Pointe. However, Izilox was well tolerated during clinical trials. To confirm the correct safety profile of Izilox in a large sample of patients, a French PMS study - MMEDIAT - was carried out in usual medical practice. METHODS: This prospective observational uncontrolled and monitored study was conducted in 13,578 patients with respiratory tract infection and treated with moxifloxacin 400 mg daily (duration: 5 to 10 days in accordance to the Market Authorization). Any clinical event being potentially a surrogate of a ventricular rhythm disorder ("critical event") were collected and analyzed by a Scientific Committee in charge to determine the potential cardiac origin of the reported event and to establish a causal relationship with the treatment. RESULTS: Among 13,578 patients, 1046 adverse events (678 patients [5%]) were reported, including 854 drug related events (564 patients [4.15%]). Of these 1046 adverse events, 95 (62 patients [0.46%]) were serious. A total of 189 critical adverse events (159 patients [1.2%]) were reviewed by the Scientific Committee. After analysis, 34 adverse events (28 patients [0.21%]) were assessed from potential cardiac origin. Of these 34 adverse events, 25 (19 patients [0.14%]) were assessed as drug-related: palpitations [13 patients], tachycardia [4 patients], malaise [4 patients], vertigo [3 patients] and pallor [1 patient]. All adverse events were transient and had favourable outcome. CONCLUSION: This PMS study confirmed that Izilox is well-tolerated in usual medical practice, in adequation with the safety data obtained in clinical trials.

Effectiveness and safety profile of leflunomide in rheumatoid arthritis: actual practice compared with clinical trials.

OBJECTIVE: Leflunomide, an immunosuppressant agent for treating rheumatoid arthritis, was first marketed in France in 2000. Three years after its launch, we sought to assess its prescription patterns in the real world of prescription and use, and to see if its efficacy and safety profiles observed during clinical trials were confirmed. METHODS: All patients treated with leflunomide from May 2000 to April 2003 in the Department of Rheumatology of the Bordeaux University Hospital were identified, and their treatment patterns and outcome ascertained. This was compared to data from clinical trials. RESULTS: 116 were included (mean age = 55 years, 70% women). Almost 21.7% stopped treatment for lack of efficacy (after a mean delay of 3.6 months), 16% for secondary loss of efficacy (median = 7 months), and 32% for the occurrence of an adverse event (half within 4 months). Over a similar time frame in clinical trials, in patients of about the same age and sex but with less severe disease, the corresponding figures were 7-17% for lack or loss of efficacy, and 14-22% for adverse effects. At one year of follow-up, the discontinuation rate was 70% in the cohort compared to 28-47% in clinical trials. DISCUSSION: The differences between the two populations confirm the need to conduct post-marketing studies in order to obtain better knowledge on the effectiveness and safety of a new drug. In many cases, a simple drug utilization study can provide relevant information on the degree of shift between populations included in clinical trials and those treated in real life.

[A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder]. / Troubles cognitifs, syndrome extrapyramidal et hyperammoniémie sous traitement thymorégulateur par divalproate de sodium: a propos d'un cas.

Several cases of Parkinsonian syndrome, cognitive impairment or hyperammonemia induced by sodium valproate have been described in the literature. We report the first case presenting an association of the three adverse effects occurring with divalproate sodium prescribed for bipolar disorder: a 58-year-old man with a history of bipolar type I disorder presented with Parkinsonian syndrome and cognitive impairment of insidious onset. This patient had been treated for several years with lithium carbonate, with a successful effect on mood swings, but with distressing adverse effects such as hand tremor and diarrhoea. Lithium therapy was progressively withdrawn while sodium divalproate was initiated. Associated medications, unchanged for several years, were amisulpride (daily dose: 100 mg), liothyronine, ciprofibrate and benfluorex. The patient was treated with sodium divalproate for seven months (daily dose: 1,000 mg), and with trihexyphenidyle for one month for extrapyramidal symptoms. At hospital admission, he presented with temporal disorientation, slowed thinking, severe anterograde memory deficits, and Parkinsonian syndrome. The minimal mental state (MMS) score was 16 (maximum: 30). The patient was anxious but did no present with mood symptoms. He also developed hyperammonemia (124 micromol/liter, normal range: 15 to 60 micromol/liter) without signs or biochemical evidence of hepatic failure. Valproate concentrations were within the therapeutic ranges (79 mg/l, normal range: 50 to 100 mg/l). The CT-scan showed cerebral and cerebellar atrophy with enlarged ventricles. The electroencephalogram showed generalized slowing waves. All the symptoms resolved within one month after the withdrawal of divalproate: the extrapyramidal hypertonia resolved, the MMS score was 29. The CT-scan and the electroencephalogram returned to normal. The divalproate was replaced by lithium. After a one-year follow-up, the cognitive and neurological symptomatology did not reappear at the exception of the pre-existing hand tremor. The pathophysiology of valproate induced hyperammonemic encephalopathy remains unclear. A possible mechanism is neuronal toxicity induced by increased intracellular concentrations of glutamate and ammonium in astrocytes. Indeed, these abnormal intracellular concentrations increase the intracellular osmolarity and thus induce rise in intracranial pressure and cerebral oedema. Reversible dementia could be due to a direct toxic effect of valproate on the central nervous system or to an indirect effect mediated through valproate-induced hyperammonemia. It has been suggested that the occurrence of extrapyramidal syndrome could be explained by a disturbance in the GABAergic pathways inducing reversible dopamine inhibition. A drug adverse reaction should always be considered when a patient treated with valproate presents with extrapyramidal symptoms and cognitive disorders even when valproate concentrations are within standard therapeutic ranges.

Computerized comparison of six adverse drug reaction assessment procedures.

Several standardized assessment procedures are currently used in the evaluation of adverse drug reactions (ADRs). Disagreement in rating ADRs can result from between-raters variability and between-methods differences in weighting the evidence. We eliminated between-raters variability by computer simulation of 1134 ADRs (including all the possible combinations of criteria currently used) and by automatic rating using different algorithms adapted from six published methods. Percentage agreement (Po) and weighted kappa test (kappa w) between pairs of methods are always better than with randomized scores, but the strength of agreement is only moderate (0.26 less than Po less than 0.59; 0.14 less than kappa w less than 0.51). The weightings of criteria are evaluated in terms of sensitivity, specificity, and predictive values. Criteria are neither sensitive (0.41 less than Se less than 0.70) nor specific (0.18 less than Sp less than 0.63) and have poor predictive values. Disagreements on weightings are considerable for three major criteria: timing of event, dechallenge, and alternative etiologic candidates. We discuss some ways of improving reliability of ADR diagnosis.

Comparison of patient questionnaires, medical records, and plasma assays in assessing exposure to benzodiazepines in elderly subjects.

OBJECTIVE: Exposure in pharmacoepidemiologic studies can rely on various sources such as medical records, patient questionnaires, or plasma samples, which do not always concur. This study endeavored to compare sources of information on current exposure to benzodiazepines in elderly subjects. METHODS: In a study in a hospital admissions department, 1136 elderly subjects included in a case-control study each completed a structured questionnaire. In addition, an inspection of the medical records of each subject was performed, as well as screening of a plasma sample (high-pressure liquid chromatography--diode array detector) for current exposure to benzodiazepines. RESULTS: Benzodiazepines were found in the plasma of 33% of 1013 patients, in the records of 31% of patients, and in the questionnaires of 36% of 797 respondents. With use of the plasma results as a standard, questionnaires had 11% false positives and 28% false negatives; medical records had 14% false positives and 23% false negatives. The kappa for concordance between questionnaires and records was 0.63. Most of the errors were related to the unexpected presence in plasma of clorazepate, commonly used as a hypnotic agent. CONCLUSIONS: Patient recall and medical records are not reliable measures of current exposure to benzodiazepines in elderly persons, although this unreliability may be more marked with certain drugs used as hypnotic agents.

Incidence of serious adverse drug reactions in general practice: a prospective study.

BACKGROUND: Many studies have been conducted to estimate the incidence and economic impact of adverse drug reactions. Most of these studies used historical data or were based on single hospital units. Little is known, however, about the frequency of serious adverse drug reactions in general practice. OBJECTIVE: To estimate the incidence of serious adverse drug reactions in the community. METHODS: A prospective study during 5 consecutive working days between March 1 and April 30, 1998, was conducted among a random representative sample of 254 general practitioners in Aquitaine, France. The main outcome measure was the number of serious adverse drug reactions (ie, resulting in death, life-threatening condition, hospitalization, incapacity, or sequel) observed by each general practitioner during the study period and validated by an expert panel. RESULTS: Thirteen validated serious adverse drug reactions, 2 of which were fatal (1 subarachnoidal hemorrhage with oral anticoagulant and 1 aplastic anemia with antineoplastics), were observed, resulting in an incidence density of 10.2 (95% confidence interval [CI], 5.4 to 17.5) per 1000 days of practice. Eleven case subjects (84.6%) were hospitalized. This represents an average of 2.6 cases per general practitioner per year, and 123,000 adverse drug reaction cases (95% CI, 65,400 to 210,000) for the 60,000 general practitioners in France. Antineoplastics and anticoagulants were the drugs most frequently involved, and blood dyscrasia and bleeding were the most frequent adverse drug reactions. CONCLUSION: This study, which is one of the few available that has prospectively measured the incidence of serious adverse drug reactions in general practice settings, confirms that serious adverse drug reactions are a major public health concern.

Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis.

The pharmacokinetics of cefpiramide, a new cephalosporin, were investigated after a single 1 gm intravenous injection in 11 patients with alcoholic cirrhosis and compared with those of 11 healthy subjects. In patients with cirrhosis the plasma elimination half-life was three times longer than that in normal subjects. The total plasma clearance was decreased significantly (p less than 0.001): 12.3 +/- 6.5 ml/min in patients and 25.6 +/- 4.6 ml/min in healthy volunteers, respectively. The urinary excretion of unchanged drug (percent of intravenous dose) for patients (69.8% +/- 29.9%) was statistically higher (p less than 0.01) than that for subjects (16.2% +/- 3.9%). The renal elimination became increasingly important with hepatic impairment. Protein binding of cefpiramide was reduced significantly in the group with cirrhosis. The average unbound fraction was 10.4% +/- 9.5% in patients with cirrhosis and 1.9% +/- 0.3% in normal subjects (p less than 0.01). Because the rate of elimination from plasma in patients is slower, the dosage regimen of cefpiramide would probably be modified in cirrhosis.

Sample size calculations for risk equivalence testing in pharmacoepidemiology.

Equivalence testing has been widely discussed and is commonly used in pharmacokinetics (bioequivalence) and clinical trials (therapeutic equivalence). It can also be applied to pharmacoepidemiology, where the aim may be to test with a known risk (one-group design) or with another drug (two-group design). Whether the approach is two-sided or one-sided, predefined equivalence limits are required. The definition of the equivalence region can be based on either risk difference or risk ratio. Risk equivalence testing is complicated by the binary nature of the outcome, its low frequency, and by the absence of commonly defined equivalence limits for differences or ratios. In this context, we consider usable formulae for sample sizes. In most cases, at least when the risk studied is large enough (above 1/1,000), it appears that these formulae result in sample sizes that may be acceptable for practical purposes. For example, demonstrating equivalence with a known risk of 0.01, a 20% maximal risk difference, and a one-sided test (alpha = 0.05 and beta = 0.2) requires: under the one-group design (known risk), 15,309 patients; and under the two-group design, 30,617 patients per group. This approach is the appropriate way to conclude equivalence, rather than the commonly used approach of difference testing and concluding equivalence when the null hypothesis of equality is not rejected.

Power and weakness of spontaneous reporting: a probabilistic approach.

It has been clearly demonstrated that spontaneous reporting remains one of the best ways for picking up new adverse drug reactions (ADRs) once a drug is on the market. The probability of revealing a new ADR by spontaneous reporting was studied as a function of reporting rate, strength of drug-event association (relative risk), background incidence of the event and number of patients treated. The model included determination of (i) the probability of reporting at least one drug-event association case and (ii) the overall probability of concluding that the drug-event association is not coincidental. Both probabilities were generally low. The results suggest that the identification of a new risk by spontaneous reporting implies a strong association between the drug treatment and the occurrence of the event.

Nonsteroidal antiinflammatory drug use and cognitive function in the elderly: inconclusive results from a population-based cohort study.

As part of the cohort Paquid, we studied the relationship between the use of NSAID, incidence of dementia, and evolution of cognitive functions. Dementia was diagnosed by DSM-III criteria and cognitive functions was assessed through the Mini-Mental Status Examination (MMSE). During 2 years of follow-up, the incidence rate of dementia was 3.84% among 53 NSAID users as compared with 3.77% in 1199 nonusers (OR, 0.98; 95% CI, 0.23-4.16). Using a cutoff of -3 points for the MMSE score and taking into account age and educational status in a logistic regression model, NSAID use was related to an unfavourable variation of the MMSE score (OR, 2.84; 95% CI, 0.99-8.1).

Sample size calculations for single group post-marketing cohort studies.

In pharmacoepidemiology, single group cohort is the most frequently proposed design to determine if the incidence rate of an adverse drug reaction among the exposed differs from a reference value. In many situations, the number of events expected in the cohort is too small to conduct sample size calculations based on the normal distribution. This paper proposes, for a single group cohort study, calculations and tables derived from the Poisson distribution. The results are based on a one-sided test with a 0.05 significance level and a power of 0.9 and 0.8. Two parameters have to be specified a priori: the expected incidence of the event under the null hypothesis and the minimum risk ratio to be detected. The required sample size and the critical number of events to reject the null hypothesis are directly derived from the tables. Results show that the normal approximation may lead to an underestimation of the required sample size.

Comparing the toxicity of two drugs in the framework of spontaneous reporting: a confidence interval approach.

Spontaneous reporting remains the most frequently used technique in post-marketing surveillance. Decision-making usually depends on comparisons between the number of adverse drug reactions (ADRs) reported for two drugs on the basis of an equivalent number of prescriptions. The validity of such comparisons is expected to be jeopardized by probable underreporting ADR cases. This problem is accentuated when it cannot be assumed that the magnitude of underreporting is the same for the both drugs. Differences in reporting ratios can overemphasize, cancel, or reverse the conclusions of a statistical comparison based on the number of reports. We propose a single method for (1) calculating confidence intervals for relative risks estimated in the context of spontaneous reporting and (2) deriving the range of reporting ratios for which the conclusion of the statistical comparison remains statistically valid.