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European Pharmaceutical Contractor

Facing Adversity

An adverse drug reaction (ADR) is defined as: “A response which is noxious and unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease or for modification of a physiological function” (1). Prompt recognition of ADRs and their effective clinical management for preventing significant outcomes is mandatory in promoting patients’ safety.

Equally important is the correct assessment of an ADR’s causal relationship with the trial product. This is the responsibility of the clinical investigator; it relies on subjective judgement, and therefore leaves potential for under- or overestimation. Both of these outcomes are unfavourable, either increasing the risk level for other patients taking the drug, or resulting in unnecessary regulatory actions and possible capture of excessive (and incorrect) information into the summary of product characteristics – which, in turn, can narrow indications. Since neither a study sponsor nor any regulatory body can overrule the investigator’s opinion, making the correct initial assessment is key to successful drug development.

This article evaluates the causality in two example ADRs, where initial assessment by the investigators differed from that of the sponsors.

Case Study One

A 58 year old man with non-small cell lung cancer (NSCLC) was randomised in a clinical trial to receive the investigational study drug – dual inhibitor of topoisomerase-1 and hypoxia-inducible factor-1 alfa. Past medical history included: ischemic heart disease, atherosclerosis, congestive heart failure, rheumatoid arthritis and haemorrhagic gastritis. No previous cardiac arrhythmias had been reported. Concomitant medications taken at the time of the event included: famotidine, Aspirin (acetylsalicylic acid), Almagel (aluminium oxide, magnesium oxide) and diclofenac.

After 27 days from the last administration of the study drug, electrocardiography revealed a tachysystolic atrial flutter, with a regular ventricular rhythm and heart rate of 188 beats per minute, and no other clinical signs or symptoms. Laboratory findings (haematology, biochemistry and coagulation) were unremarkable, and the patient was admitted to hospital on the same day. Treatment included: Cordarone (amiodarone), Panangin (potassium magnesium asparaginate), digoxine, heparin, Mildronate (trimethylhydrazinum propionate), furosemide, Rhythmocor (propafenonum), aminocaproic acid and ethamsylate sodium.

Despite the treatment, the patient died four days later. An autopsy showed that his death was due to an acute cardiovascular insufficiency, against the background of pulmonary haemorrhage and the progression of NSCLC in the left lung, with multiple metastases and tumour breakdown leading to erosion of the lung branch tissue. The investigator considered the event of atrial flutter possibly related to the study drug.

Since no previous ADRs of cardiac arrhythmias had been reported with this medication, and this report represented the first treatment-related ADR of atrial flutter with the study drug, the sponsor disagreed with the investigator.

Case Study Two

A 72 year old man with prostate cancer was randomised in a clinical trial to receive an investigational product (an antisense nucleotide). Past medical history included: aortic aneurysm and depression. Concomitant medications taken at the time of the event included: omeprazole, lactulose, dexamethasone, Zofran (ondansetron), Coaxil (tianeptin), Pamifos (pamidronic acid), metoclopramide and furosemide.

After 14 days from the last administration of the investigational product, biochemistry testing showed hypoalbuminemia of 25g/L (normal reference range is 35-55g/L) without any clinical signs. Routine practice was to hospitalise patients with hypoalbuminemia, which was done on the same day. The patient received an albumin transfusion and a followup chemistry carried out 10 days later showed a normal albumin of 36g/L.

The investigator considered the ADR of hypoalbuminemia unlikely related to the product. However, the study sponsor disagreed and upgraded the event to ‘possibly related’, as it was considered to be a known pharmacological effect of the drug.

Detecting Reactions

Safety surveillance has always been one of the objectives of clinical trials. Rare ADRs and those with a long period before onset are difficult to detect. For example, monitoring of liver enzymes is routine in studies, and substantial increases of these are an alerting signal. But, sometimes, severe drug-induced liver disorders are identified only after the product enters the market (2).

In the last few years, the FDA has removed two drugs – bromfenac and troglitazone – from the market due to their significant hepatotoxicity. In April 2010, the agency added a black box warning to the prescribing information of propylthiouracil – an antithyroid medication – emphasising the risk of severe and, in certain cases, fatal lung injury (3). Thus, it is obvious that if an adverse event is registered during a clinical trial, but mistakenly considered unrelated to the investigational product, this may put study subjects and further patients at risk, leading to unfavourable consequences. This is preventable if the safety signals are assessed correctly, proving accurate assessment of the causal relationship is one of the cornerstones of drug development.

Causality Judgement

For any individual ADR, it is rarely possible to make judgements with absolute certainty about the causality relationship. The ‘golden rule’ of challenge, dechallenge, and then rechallenge is frequently not applicable.

Assessments of the relationship between the study drug and ADR are made by clinical investigators; their opinion reigns supreme as they are aware of the trial subjects’ clinical condition, so can distinguish between events that may be related to the study medication and those that are due to concomitant disease or therapy. At the same time, sponsors have more knowledge about the trial drug’s mechanism of action and pharmacodynamics, possible drug-to-drug interactions and the overall safety profile.

There are three main approaches to assess the causality between a drug and the occurrence of an adverse event: expert judgement, probabilistic scores and algorithms. In expert judgement, a healthcare professional – or, for trials, an investigator – expresses his or her opinion about possible causation, based on their clinical experience and scientific knowledge. Every study protocol provides a scale of causality categories, which are usually based on the WHO’s Uppsala Monitoring Center (UMC) system (see Table 1). The WHO-UMC classification categorises causal relationship to: certain, probable/likely, possible, unlikely, conditional/unclassified and unassessable/unclassifiable (4). Criteria for establishing causality include: assessment of temporal relationship, possibility of association with disease or other drugs, and response to withdrawal. However, the clinical-pharmacological aspects and previous knowledge of the ADR are not taken into account.

Reaching Consensus

Such an approach has significant subjectivism and consensus between experts may be difficult to obtain, especially when their judgements are made intuitively or based on unspecified criteria (5,6). In an attempt to minimise the subjective component, several methods for the evaluation of ADR causality have been proposed: the Naranjo, Kramer, Jones’ and Yale algorithms, among others (7). Perhaps the most popular criteria for causality assessment is the former, as it is simple, structured and consistent. A comparison of the Kramer algorithm, Naranjo criteria and Jones’ algorithm for the evaluation of ADRs in showed that all three instruments demonstrated similar results in retrospect evaluation, but greater variability was observed when they were used as an active monitoring system (8). Comparison of the WHO-UMC criteria and the Naranjo algorithm showed a wide range of disagreement, from 4.9% to 45% and 51% (9-11).

Case Study Evaluation

In both of the presented case studies, initial causality assessment was performed by the clinical investigatorsintensive care units (ICUs) with the use of the WHO-UMC system. In the first case, a positive conclusion regarding the relationship to the study medication was made by the investigator on the basis of the temporal relationship, which, in fact, was inappropriate. The investigational medication has a half-life time (T1/2) of approximately 100 hours, or four days; so 27 days after the last administration equals 6.5 x T1/2.

It takes between five and six half-lives for a medication to be eliminated from the body; consequently, it is generally accepted that it is possible to consider a temporal relationship with a medication, if the time since the last administration is <5 x T1/2. In the first case study, the patient had a medical history of cardiovascular pathology and, importantly, was receiving famotidine and diclofenac – both known for their arrhythmogenic effect. The retrospectively calculated Naranjo score was -1, or doubtful, suggesting the investigator over-estimated causality.

In the second example, the investigator considered the event unlikely related to the study medication as, in his opinion, there was no reasonable temporal relationship, and the adverse effects were more likely linked to the underlying cancer. This opinion was overruled by the study sponsor, whose decision was based on the investigational product having a T1/2 of up to 250 hours (slightly more than 10 days), and the fact that 14 days had passed since the last administration – prior to the adverse event of hypoalbuminemia – which was approximately 1.4 x T1/2.

Before this event, 50% of the patients enrolled in the clinical trial developed grade 1-2 hypoalbuminemia, and it was thought that a decrease of plasma albumin level was a pharmacological effect of the investigational product. Retrospectively, the calculated Naranjo score was +4, which is equivalent to a possible relationship, suggesting that the investigator under-estimated causality.

Factors to Consider

When evaluating an ADR, several factors that can predispose patients to adverse reactions should be considered – namely, the temporal relationship, existing information about the ADR, pharmacological plausibility, exclusion of other causes, drug interactions, dechallenge or dose reduction, and rechallenge or dose increase (12).

In the two cases outlined here, the discordance between investigators’ assessments and those made retrospectively were based primarily on three major criteria: the timing of the event, probability of an alternative explanation and known safety profile of the drug. All these measures are included in both the WHO-UMC system and the Naranjo algorithm – but in a slightly different way, making questions from the Naranjo algorithm more precise and clear. Previous knowledge of the ADR plays a less prominent role in the WHO-UMC system, while the Naranjo algorithm is structured, transparent, consistent and easy to apply, and can help in the assessment of serious ADRs – especially if experts have not yet reached a unanimous decision.

Final Thoughts

Causality assessment may significantly impact current treatment and disease outcome. Both deciding to stop an effective treatment because an ADR was mistakenly attributed to the drug, and continuing a medication because an ADR was considered unrelated, can be equally harmful. No universal and widely-accepted algorithm exists, and their use may not be feasible in day-to-day clinical practice, as implementing such systems can be complex and time-consuming. However, in clinical research, the use of specific ADR causality assessment tools – especially for the evaluation of serious events by medical monitors from a sponsoring company or CRO – may be important for the analysis of the investigational product’s safety profile.


1. Glossary of terms used in pharmacovigilance. Visit:
2. Kumar A, Kosov M, Yantorno M and Belotserkovskiy M, Mindful monitoring, Eur Biopharm Rev, pp62-66, 2012
3. Aschenbrenner D et al, Black box warning for propylthiouracil, Am J Nurs, 110(8): p29, 2010
4. The use of the WHO-UMC system for standardized case causality assessment. Visit:
5. Arimone Y et al, Inter-expert agreement of seven criteria causality assessment of adverse drug reactions, Br J Clin Pharmacol 62(4): pp482-488, 2007
6. Karch F, Smith C and Kerzner B, Adverse drug reactions – A matter of opinion, Clin Pharmacol Ther 19: pp489-492, 1976
7. Srinivasan R and Ramya G, Adverse drug reaction – Causality assessment, Int J Res Pharm Chem 1: pp606-612, 2011
8. Kane-Gill S, Forsberg E, Verrico M and Handler SM, Comparison of three pharmacovigilance algorithms in the ICU setting: A retrospective and prospective evaluation of ADRs, Drug Saf 35(8): pp645-653, 2012
9. Belhekar M, Taur S and Munshi R, A study of agreement between the Naranjo algorithm and WHO-UMC criteria for causality assessment of adverse drug reactions, Indian J Pharmacol 46(1): pp117-120, 2014
10. Son M et al, Comparison of the Naranjo and WHO-Uppsala Monitoring Center criteria for causality assessment of adverse drug reactions, Korean J Med 74: pp181-187, 2008
11. Macedo A, Marques F, Ribeiro C and Teixeria F, Causality assessment of adverse drug reactions: Comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel, Pharmacoepidemiol Drug Saf 14: pp885-890, 2005
12. Farcas A and Bojita M, Adverse drug reactions in clinical practice: A causality assessment of a case of druginduced pancreatitis, J Gastrointestin Liver Dis 18(3): pp353-358, 2009

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Maxim Kosov is Director, Medical Monitoring and Consulting at PSI CRO US. He is a boardcertified doctor in Paediatrics, and Anaesthesiology and Intensive Care, as well as being a member of the American Society of Clinical Oncology. Maxim has more than 10 years of experience in clinical research, and his expertise spans a broad range of indications. He is the author/ co-author of more than 30 publications.

John Riefler
is Director, Medical Monitoring and Consulting at PSI CRO US. He holds an MS in Microbiology and has had clinical training in Internal Medicine and Infectious Diseases. John is a Fellow of both the Infectious Disease Society of America and the American Heart Association. He has 27 years of experience in clinical development in Big Pharma and CROs, and is the author/co-author of 22 publications.

Maxim Belotserkovskiy is Head of Medical Affairs at PSI CRO AG. He holds board certifications in Internal Medicine, Rheumatology, Anaesthesiology and Intensive Care, and Haemodialysis, and is a Certified Associate Professor of Pathological Physiology. Maxim has more than 25 years of experience in clinical research as an investigator and clinical research professional. He is also the author/co-author of more than 140 publications.
Maxim Kosov
John Riefler
Maxim Belotserkovskiy
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