Adverse events cohort studies

In this context, a decision on whether postmarketing surveillance studies should be built into the development programme must be taken. Such an observational study may signal the occurrence of adverse events or alternatively it may signal and quantify the frequency of adverse events. At this point in the life cycle of a new medicine, post-marketing surveillance is likely to involve cohort observational studies of 10-20 000 patients. The value of these studies is likely to be three-fold ... 

Following construction, characterization, and scale-up of trastuzumab, phase I testing of the humanized mAh was carried out in patients with HER2-overexpressing metastatic breast cancer. The initial phase I study evaluated the safety and pharmacokinetics of a single, escalating (10-500 mg) intravenous dose of trastuzumab. A subsequent phase I study evaluated the safety and pharmacokinetics of multiple-dose administration, with weekly intravenous doses and similar dose escalation by cohort (10-500 mg). Both studies of 32 patients overall demonstrated that trastuzumab monotherapy was very well tolerated, with no serious adverse events attributable to mAh treatment. A third phase I study included trastuzumab, again via weekly intravenous administration of 10-500 mg, in combination with cisplatin chemotherapy at 50 or 100 mg/m2 per 4-week cycle. Toxicities in this trial were those commonly seen with cisplatin. 

A British study conducted on the basis of prescription-even monitoring (PEM) involved cohorts exceeding 10,000 patients for paroxetine, fluvoxamine, sertraline, and fluoxetine (Mackay et ah, 1997). The study confirmed the general similarity of reported adverse events, with two possible exceptions Fluvoxamine (Luvox) had an increased number of reported adverse events, and paroxetine (Paxil) had an increased number of reported withdrawal reactions. 

Fellay, J. Bouhaker, K. Ledergerher, B. Bemasconi, E. Furrer, H. Battegay, M. Hirschel, B. Vemazza, R FrancioH, P. Greuh, G. Flepp, M. Telenti, A. Prevalence of adverse events associated with potent antiretroviral treatment Swiss HIV Cohort Study. Lancet, 2001, 358 1322 1327. 

Cannon GW, Holden WL, Juhaeri J, Dai W, Scarazzini L, Stang P. Adverse events with disease modifying antirheumatic drugs (DMARD) a cohort study of leflunomide compared with other DMARD. J Rheumatol 2004 31(10) 1906-11. 

Precipitates can develop in parenteral nutrition admixtures because of a number of factors such as the concentration, pH, and phosphate content of the amino acid solutions, the calcium and phosphorus additives, the order of mixing, or the mixing process. The consequences can be serious. In one cohort study of hospitalized patients who received peripheral parenteral nutrition, a subgroup developed unexplained chest pain, dyspnea, cardiopulmonary arrest, or new interstitial infiltrates on chest radiograph. A change in the amino acid source of a parenteral nutrition mixture was associated with respiratory adverse events that ranged from interstitial infiltrates to sudden death. The events apparently resulted from infusion of calcium phosphate precipitate in an opaque admixture, and the deposition of the crystals in the pulmonary microvasculature (147). 

Martin RM, Dunn NR, Freemantle S, Shakir S. The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England cohort studies. Br J Clin Pharmacol 2000 50(4) 366-72. 

Cohort studies of rare adverse events would be useful, but are generally not feasible, particularly for economic reasons. One promising alternative approach is the use of large linked databases. The databases appropriate for such studies are derived from defined populations, such... 

A variety of biomarkers have been shown to be valuable individually for one or several toxicant or disease situations. Few of these biomarkers have been systematically evaluated for the plethora of situations that might provoke false positive responses. Acceleration of the current pace of biomarker evaluation and qualification demands (a) the availability of panels of biomarker-assays that can be comparatively evaluated on well-defined common sample sets, (b) fit-for-purpose performance evaluation in controlled animal studies with carefully benchmarked histological endpoints and samples from well-defined focused clinical trial cohorts, and (c) ready availability of banked blood and urine sample archives from clinical trial populations with carefully documented morbidities such as the Framingham Heart Study,45 or the Drug-Induced Liver Injury Network (DILIN) prospective study,46 to name a few. Availability of such panels of validated biomarker assays and well-documented preclinical and clinical samples, as well as increased cooperation between animal model researchers and clinical researchers will enable individual biomarkers to be qualified for sensitivity of specifically defined adverse events, qualified for appropriate specificity using samples of defined benign events, and collected into panels that yield complementary information about the health and safety of animals and patients. 

On the other hand, certain drugs have gone through the fast-track process and, at the time of authorisation, information on the safety of these medications has been limited, especially for children. In such cases non-interventional observations such as cohort or case-control studies could be a valuable tool to evaluate adverse events. 

A patient might be exposed to a drug at one time point but not at another. This is particularly important for metabolic diseases, where the progression of the disease should be monitored over a long period and patients should be monitored pre- and post-treatment. Incidence rates can be calculated from the population exposure. Cohort studies are useful when there is a need to know the incidence rates of adverse events in addition to the relative risks of adverse events. 

A case-control study is a retrospective analysis it is generally easier to administer than a cohort study. Cases of diseases or events are identified. Controls and patients exposed to the treatment are selected from the source population. The exposure status of the two groups is compared using the odds ratio, an estimate of relative risk of exposure and non-exposure. Case-control studies are less expensive than cohort studies, but provide weaker empirical evidence than well-executed cohort studies. These studies are useful for identifying the relationship between drug treatments with one specific rare adverse event, or for identifying risk factors for adverse events. Risk factors can include renal and hepatic insufficiency that might modify the risk profile. 

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