Causality assessments

Systematic analysis. The data must be systematically analyzed to gain insight regarding the associations between various treatments and medical conditions. This knowledge can assist in causality assessments. 

Type A = for trends assessment Type B = for causality assessment. 

Reprinted from J Gin Epidemiol, Vol 46, Danan C, Benichou C. Causality assessment of adverse reactions to drugs-4. A novel method based on the conclusions of international consensus meetings- Application to drug-induced liver injuries pages 1323-1330, Copyright 1993, with permission from Elsevier. 

When causality assessment is undertaken by a regulatory authority or a scientist or physician in industry, it is unlikely that the full details known to the clinic treating the patient will be reported, even after further inquiry is made. The only way to obtain all available data is usually by visiting the physician and, with permission, reading the notes and discussing the case with him or her. 

Hutchinson, T.A. (1992). Causality assessments of suspected adverse drug reactions. In Detection of New Adverse Drug Reactions (Stephens, M.B.D., Ed.). Macmillan, Press, London. 

Most are weak in causality assessment (whether the drug actually caused the ADR). 

O Dormell, J., Adverse dmg reactions extent of the problem and causality assessment, in O Donnell, J.T., Ed., Drug Injury Liability, Analysis, and Prevention, L J Publishers, Tucson, AZ,... 

At the present time, several countries have well-organised and experienced spontaneous reporting systems which contribute the bulk of ADE reports. In particular the United States, the United Kingdom, France and the Scandinavian countries have records going back several decades, and can claim to have in their possession data of reasonable quality. The section on p. 438 considers the various methods of causality assessment that are available and the data that are required for their application. 

Assuming that the quality of the input is maximal then improving the output will be dependent upon the analysis and evaluation of the data. Because the spontaneous report alone will seldom, if ever, contain sufficient information to determine causality satisfactorily, it is usually necessary to seek additional data which may be available from hospital records, laboratory investigations or post-mortem reports. It is highly desirable that comparable methods and formats of reporting should be used as widely as possible, particularly if international comparisons are to be made. A major benefit of formalised systems of causality assessment, which will be considered in greater detail later in this chapter, is the element of standardisation that is brought to the process of interpretation. 

The aims of causality assessment are manifold. Adverse events need to be classified, a decision needs to be made whether a drug has caused this event, regulatory requirements need to be satisfied, signal recognition can be aided, and finally, at the end of this process, a label change may be necessary. 

In the time that has elapsed since the previous edition of this book, it has been the authors impression that enthusiasm for formal methods of causality assessment has decreased to the extent that few, if any, pharmaceutical companies still use them. Nevertheless, brief comments on methods that have been developed over the years are needed to complete the picture. 

In recent years, a method of causality assessment based on Bayes theorem has been developed by a number of workers in the United States. " Its application to the evaluation... 

CIOMS. Standardisation of definitions and criteria of causality assessment of adverse drug reactions -drug-induced cytopenia. Int J Clin Pharmacol Tker Toxicol 1991 29 75-81. 

Lane DA, Hutchinson TA, Jones JK, et al. A Bayesian Approach to Causality Assessment. University of Minnesota School of Statistics Tech Reps No 472 (no date available). 

Lane DA, Kramer MS, Hutchinson TA, et al. The causality assessment of adverse drug reactions using a Bayesian approach. Pharm Med 1987 2 265-83. 

Lane DA. 1989. Subjective probability and causality assessment. Appl Stochastic Model Data Anal 5 53-76. 

Meyboom RHB, Yechiel A, Hekster YA, Egberts ACG, Gribnau FWJ, Edwards IR. Causal or casual The role of causality assessment in pharmacovigilance. Drug Saf 1997 17(6) 374-89. 

In accordance with these general points, all adverse effects must be reported to the nearest Pharmacovigilance Center. This Center makes the causality assessment and may inidate any necessary national surveys (e.g. concentric narrowing of the visual field with vigabatrin in 30% of cases)... 

A number of variables influence the likelihood of an adverse event being reported. These include the length of time that a product has been marketed, the market share, experience and sophistication of the population using the product, and publicity about adverse events. Currently there is little incentive for health professional reporting of adverse events, which partially imderlies the problem with underreporting. Lack of exposure data and the issue of underreporting preclude estimation of incidence rates. Causality assessment is difficult or impossible because of the quality of the data received and the lack of a comparator (control) group. Finally, comparisons of product safety cannot be directly obtained from adverse event data. 

World Health Organization Definitions—Causality Assessment of Suspected Adverse Drug Reactions... 

Miremont G, Haramburu F, Begaud B, Pere JC, Dangoumau. Adverse drug reactions Physicians opinions versus a causality assessment method. Eur J Clin Pharmacol 1994 46 285-9. 

Hutchinson TA, Lane DA. Assessing methods for causality assessment of suspected adverse drug reactions. J Clin Epidemiol 1989 42 5-16. 

After detection of a possible ADE, causality assessment needs to be performed. It is important to be able to rank the likelihood of an ADR as unlikely, possible, probable, or definite. A major problem with determining causality is that confounding variables can contribute to the complexity of causality assessment. In order to determine causality, several important points of data are required. These include the nature of the adverse event, name of the putative drug, other potential causes, and the temporal relationship between the drug and adverse event. Potential causes are obtained by examining the medical history, physical examination findings, and directed diagnostic tests. 

Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001 33(l) 123-30. 

Causality assessment of adverse events following immunization (AEFI)... 

Table 1 WHO causality assessment criteria for adverse reactions to vaccines...

Collet JP, MacDonald N, Cashman N, Pless R, Halperin S, Landry M, Palkonyay L, Duclos P, Mootrey G, Ward B, LeSaux N, Caserta V. Monitoring signals for vaccine safety the assessment of individnal adverse event reports by an expert advisory committee. Advisory Committee on Causality Assessment. Bnll World Health Organ 2000 78(2) 178-85. 

Rochon J, Protiva P, Seeff LB, et al. Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury. Hepatology. 2008 48(4) 1175-1183. 

---