Adverse events predictability

Fontein DB, Seynaeve C, Hadji P, HiUe ET, van de Water W, Putter H, et al. Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors an international tamoxifen exemestane adjuvant multinational trial analysis. J CHn Oncol... 

Aleatory uncertainty —the roll of the die—describes risks that cannot practicably be predicted within the research process, for example, new failure modes, or modes that can only be detected in late stages of work, for example, humans. An example of aleatory uncertainty is the withdrawal in the UK of Bextra on the basis of two serious adverse events out of 40,000 patients this could only be discovered after launch [2]. This, without hindsight, was an uncontrollable risk. ... 

Regrettably, all chemotherapeutic agents have the potential to produce adverse reactions with varying degrees of frequency and severity, and these include hypersensitivity reactions and toxic effects. These may be dose-related and predictable in a patient with a history of hypersensitivity or a previous toxic reaction to a drug or its chemical analogues. However, many adverse events are idiosyncratic and therefore unpredictable. 

The analysis of safety data may require larger data sets, so care in ensuring that a consistent phenotype is collected will be important. Furthermore, the benefit to the drug development program could be that additional data to predict adverse events could be available at the time a drug is marketed. 

IVIVC studies are normally conducted in the fasted state. Where a product is not tolerated in the fasted state, studies may be conducted in the fed state (1). Some drugs are labeled to be administered with food, either to take advantage of greater bioavailability or lessen the incidence of adverse events. For such formulations, it could be argued that the IVIVC model should be developed using in vivo data obtained under fed conditions, so that the model predicts the in vivo performance under the intended condition of administration. We have had recent experience in successfully correlating... 

Pharmacologically Predictable Adverse Events or Nonresponse Obtained in Early-Phase Development Affect the Risk/Benefit Assessment and Product Labeling . 213... 

Are there any clinical or investigational factors that could predict who may develop the adverse event ... 

Another direction of development of the data set is to strengthen the in vitro-in vivo correlations and develop multivariate models to predict in vivo endpoints, such as therapeutic effects and adverse events. In this respect, it will be interesting to examine which data (among in silico descriptors, in vitro primary and secondary data, in vitro functional data, etc.) are most appropriate to derive robust and predictive models. 

The first requirement of an in vitro safety profiling assay is to be as predictive as possible of an adverse event, given all the limitations of in vitro assays and the other important parameters to consider in combination, such as physicochemical... 

The Value of Safety Pharmacology Data the Value and Relevance of Complete, Standardized Data Matrices for In Silica Prediction of Adverse Events... 

Today, extensive regulatory guidelines shape the way new medicines or chemicals are developed but we remain heavily reliant on the ability of the rodent, dog, rabbit, and monkey to predict the outcome of human exposure. Many potentially useful drugs are rejected due to the adverse effects (often at high doses) outweighing the potential benefit but adverse events continue to be detected in marketed drugs. 

Failure to respond to an initial medication trial does not predict failure to respond to another drug. If no or little clinical response is noted after 8-10 weeks using maximal therapy or adverse events are unacceptable, a... 

Vascular tortuosity predicting adverse events following carotid stenting. (See text for definition.)... 

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