Council For International Organizations Of Medical Sciences Research Articles

Ethics of research

Ethics of research

Governance of research involving people with psychosocial disabilities

Health-related research with human participants is governed by research ethics regulations in most jurisdictions. Globally, the 2016 International Ethical Guidelines for Health-related Research Involving Humans, published by the Council for International Organizations of Medical Sciences (CIOMS), are especially influential and widely held as an international standard. The CIOMS guidelines support the inclusion of people with psychosocial disabilities in research and offer clear guidance to promote their recruitment, including by outlining provisions for substitute decision-making. The CIOMS guidelines sit alongside the United Nations’ Convention on the Rights of Persons with Disabilities (CRPD). Adopted in 2006 and ratified in 2008, the CRPD offers a robust framework for recognizing the rights of persons with disabilities, including individuals with psychosocial disabilities. Though the CRPD does not explicitly reference research inclusion, its core principles—especially pertaining to the right to universal legal capacity—have clear implications for research ethics governance, specifically with respect to the use of substitute decision-making for research participation. In this paper, we review the extent to which existing research ethics regulations across selected jurisdictions concord with each of these two frameworks, offering first a broad analysis of regulations across 26 African countries, and then exploring two country-specific case studies from Malaysia and Peru. We find that, while many countries’ research ethics regulations align with key aspects of the CIOMS guidelines, core principles of the CRPD are absent. Given the shortcomings of existing regulations, we analyse a key point of tension between CIOMS and the CRPD—the right to participate in research—and offer a proposal for revised regulations that aims to bridge this tension and meet the standards of both frameworks.

Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

The CIOMS consensus report on clinical research in resource-limited settings

Background. Responsible clinical research drives the advancement of healthcare. Despite tremendous improvements in the globalresearch and development environment since the 1950s, low- and middle-income countries (LMICs) are often left behind. There are several reasons for this. Firstly, operational, social, ethical and regulatory challenges in LMICs make it difficult for researchers to conduct clinical studies in those settings in line with international requirements. Secondly, many people living in low-resource settings distrust research because some past studies have not benefited the participants or the communities involved.Objectives. To present the consensus recommendations by a Council for International Organizations of Medical Sciences (CIOMS) Working Group on how to advance good-quality, ethical clinical research in resource-limited settings.Methods. CIOMS convened a Working Group of senior scientists from drug regulatory authorities, the pharmaceutical industry, publicprivate partnerships for product development, and academia.Results. This article summarises the Working Group’s report.Conclusion. The report recommendations can foster the creation of a more enabling ecosystem for clinical research and promotecollaboration between policymakers, regulators, researchers and funders.

First results from the lessons learnt from the deployment of the Med Safety App for reporting adverse drug reactions in Ghana.

The use of mobile phone technology for reporting adverse drug reactions (ADRs) in pharmacovigilance is relatively new.The objective of the study was to explore challenges and facilitators for the use of the Med Safety App for reporting ADRs in Ghana. A comparative evaluation of ADR reports received through the app and the standard paper-based form was also conducted. This was a cross-sectional study with a purposive sampling technique. The study population was persons who had downloaded the Med Safety App launched in Ghana 18 months before the study. Of the 350 participants, 121 provided answers to the questionnaire sent as a Google form, representing a response rate of 34.6%.Ninety-five (78.5%) of the participants were healthcare professionals, and the remaining were patients. Seventy-five (64.7%) of the participants were using the app after initial installation because they thought it had helpful features. However, only 33 (27.3%) participants used the app to report ADRs, and of these, seven (21.2%) participants indicated that they would continue to use the app because it was easier than the other means of reporting ADRs. Most of the respondents, 109 (94%), indicated that they would recommend the app to someone else. There were some differences between the reports received through the app and between the paper-based Council for International Organizations of Medical Sciences (CIOMS) 1 form and the app, which warrant further exploration. Most participants indicated that the app is a useful tool and easy to use, and they were satisfied with the features of the app. Given that only just under one-third of participants had used the app to report ADRs, more time and training may be required to fully evaluate the feasibility of the use of the app going forward. The findings will help improve introduction of the app in other countries.

Development of a checklist for the assessment of pharmacovigilance guidelines in Southern Africa: a document review.

National regulatory systems in Southern Africa reflect various stages of maturity, and pharmacovigilance (PV) practices are not aligned. In the absence of guidance for formulating PV guidelines in Southern African Development Community (SADC) countries, this study aimed to create a checklist that may be used to assess the rigour of PV guidelines in this region and provide guidance for the National Medicines Regulatory Agency (NMRA) authors. A document analysis was performed based on harmonised international guidelines (n = 22) that prescribed methods of PV regulation to identify themes and items to incorporate into a checklist. The contextualisation of the checklist to the African pharmaceutical environment was accomplished by referencing peer-reviewed journal articles (n = 7). The checklist was subjected to face and content validation by non-experts and PV experts. The document review yielded 5 themes, 18 sub-themes, and 73 items structured into the checklist. Themes encompassed PV systems, definitions, individual case safety reporting, aggregate reporting, and risk management. Under PV systems, aspects of the quality management system were outlined, that is, the legal basis for PV, a description of the marketing authorisation holder's (MAH's) PV system, archiving of data, contracting of PV tasks, and the duties of the person responsible for the MAH's PV obligations. Definitions of the key terms and major stakeholders were identified. Reporting of individual case safety reports (ICSRs) was explicated by considering the criteria for reporting, categories of reportable information, expedited reporting requirements, reporting timelines, and ICSR reporting format. Aggregate report submission during the development and post-marketing phases was addressed. Risk management encompassed signal detection, re-evaluation of the benefit-risk ratio, the safety decision-making process, risk management planning, risk minimisation and safety communication. The developed checklist can contribute towards assisting SADC NMRAs to formulate national PV guidelines that reflect current international practice, with local context incorporated. Developing a checklist for the evaluation of medicine safety guidelines in Southern Africa Introduction: In Southern African Development Community (SADC) countries, the guidelines for medicine safety [pharmacovigilance (PV)] that marketing authorisation holders (MAHs) and healthcare professionals need to adhere to, are not aligned. We saw the need to develop a checklist that can be used to evaluate these guidelines.Methods: We studied international documents issued by the World Health Organization (WHO), the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the Council for International Organizations of Medical Sciences (CIOMS) and the European Medicines Agency (EMA). On the organisational websites, we obtained 22 documents and identified 73 checklist items. All the items were arranged under 5 themes and 18 sub-themes to create the checklist. We adapted the checklist to the local context by using seven journal articles addressing PV concerns in Africa. Experts checked the content and usability of the checklist.Results: The themes were PV systems, definitions, individual case safety reporting (ICSR), combined reporting and risk management. PV systems had six sub-themes: legal structure, description of the MAH's PV system, contractual agreements, information storage, the qualified person responsible for PV (QPPV) and where the QPPV is located. We included the definitions of keywords and role-players. The ICSR theme had five sub-themes, i.e. criteria for reporting, categories of reportable information, expedited reporting, reporting timelines, and reporting format. Submission of summary reports comprised an overview of the safety profile of a medicine once it is approved by regulators, as well as during clinical trials. Risk management included signal detection, re-evaluation of the benefit-risk ratio, safety decision-making process, risk management planning, risk minimisation, and safety communication. The checklist is applied by allocating yes/no scoring per item.Conclusion: The checklist may be used by regulators within SADC to assess their PV guidelines for alignment with international standards and suitability to the local environment.

Analysis of risk factors associated with common terminology criteria for adverse event in cancer chemotherapy patients

Background: Chemotherapeutic drugs are commonly associated with various harmful consequences which can remarkably reduce quality life of patient and lengthen hospital admission. The objective of this study was to evaluate the frequency and its associated factors affecting cancer chemotherapy-related side effects in cancer patients. Methods: Patient case report form was used to gather information on the patient's demographics and adverse drug reactions (ADRSs) to chemotherapy medications. ADRs were analyzed for toxicity grade using National Cancer Institute Common Terminology NCI-CTCAE version 4.0. Causality Assessment and Predictability of ADRs were analyzed using World Health Organization' (WHO) Causality assessment scale and Council for International Organization of Medical Sciences (CIOMS) method respectively. Utilizing the chi square test and descriptive statistics, the relationship between the grade of ADRs and the patient's characteristics was investigated. Results: A total of 120 patients were included in the study. Mean age of participant was 46.87 (SD-10.1). Majority (60%) participants were female. 81.7% of total patient received poly-chemotherapy in their treatment modality. Total 412 numbers of ADRs were noted. The most frequent adverse drug reactions were observed to be nausea and vomiting (17.7%), neutropenia and alopecia. On NCI-CTCAE grading maximum number of ADR was assessed as “Grade 2” ADR (33%).

MedDRA Labeling Groupings to Improve Safety Communication in Product Labels

The granularity and structure of the International Council for Harmonisation’s (ICH) Medical Dictionary for Regulatory Activities (MedDRA) are useful for precise coding of adverse events (AEs) for data analysis. In product labeling for healthcare practitioners, however, the granularity of MedDRA Preferred Terms (PTs) can obscure the communication of adverse reactions (ARs). Driven by a focus on patient safety, business needs, and regulatory guidance, many sponsors and regulators have begun to develop institution-specific approaches to clustering similar AR terms in medical product prescribing information on a product-by-product basis. However, there are no agreed upon conventions that describe which AR terms may be appropriate to group together. In order to improve safety communication to patients and healthcare providers, there is an urgent need for a harmonized international approach to the creation and use of groups of MedDRA PTs which we refer to as “MedDRA Labeling Groupings (MLGs)” in medical product prescribing information. Given its long-standing contributions towards the design of Standardised MedDRA Queries (SMQs), the Council for International Organizations of Medical Sciences (CIOMS) convened an Expert Working Group (EWG) with involvement of multiple major stakeholders to produce a consensus document on principles and points to consider in the development of MLGs. The CIOMS MLG EWG identified variations in grouping of MedDRA PTs in product labels, and in the current document, proposes a strategy for improving the communication of drug safety labeling. It is envisaged that the use of these consensus recommendations would be voluntary and applied to product labels in a manner that is consistent with existing regulatory frameworks.

Silymarin for Treating Toxic Liver Disease: International Consensus Recommendations

Silymarin for Treating Toxic Liver Disease: International Consensus Recommendations

ES13.05 The Ethics of International Research

ES13.05 The Ethics of International Research

Pharmacovigilance in India and five ASEAN countries (Malaysia, Singapore, Thailand, Indonesia, Philippines): A comparison study

The World Health Organization (WHO) defines PV as the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other possible drug-related problems (WHO 2004). In 1968, during the 16th World Assembly the 16.36 resolution called for “a systematic collection of information on serious adverse drug reactions during the development and particularly after medicines have been made available for public use”. This led to the formation of the WHO Programme for International Drug Monitoring (PIDM) in 1968. PV systems should include all entities and resources that protect the public from medicines-related harm (adverse reactions, poor product quality, medication errors, and therapeutic ineffectiveness), whether in personal healthcare or public health services. The PV system safeguards the public through efficient and timely identification, collection, and assessment of medicine-related adverse events and by communicating risks and benefits. The WHO has provided technical and normative leadership on PV since the development of the first voluntary notification scheme in 1961. As of January 2016, 123 countries have joined the WHO PIDM, and in addition 28 associate members are awaiting full membership. WHO has defined norms and guidelines for PV and has allowed information sharing among the participant countries. Another WHO PV-related activity is the work of the Council for International Organizations of Medical Sciences (CIOMS) which was established jointly by WHO and UNESCO in 1949. Starting with the publication of the Suspect Adverse Reaction Report Form (CIOMS Form I) by the CIOMS working group II, other CIOMS publications have greatly shaped the direction of PV. CIOMS publications have also greatly influenced the development of International Conference on Harmonization of Technical requirements for Registration of Pharmaceuticals for Human Use (ICH) E2A-E2F guidelines in drug safety. The standard

Acute liver failure secondary to Ayurvedic Herbal medication in a child: a case report

Ayurvedic and Herbal medicine induced liver injury is rarely reported in children. The injury can range from mild asymptomatic elevation of liver enzymes to severe presentation with acute liver failure leading to death. The diagnosis is by exclusion and relies on accurate history and clinical examination supported by laboratory investigations. Various causality assessments such as council for international organizations of medical sciences (CIOMS) and Roussel Uclaf Causality Assessment Method (RUCAM) have been reported to be useful in reaching the diagnosis of Herbal Induced Liver Injury (HILI). However, these scales have not been validated specifically for pediatric age group. In this report, we present a case of a child who was presented to our department with acute liver failure after taking unlabeled ayurvedic medicine for jaundice and loss of appetite. The child was examined for age specific causes of hepatic injury and acute liver failure and he was managed conservatively. Despite extensive search, we did not find any etiology and suspected herbal medicine induced hepatic injury. She recovered completely after stopping the offending medicines. This case highlights the paradoxical hepatotoxic effect of such medications, widely considered safe and natural by the masses. Pediatric hepatologists and general practitioners should be well aware about such adverse effects of herbal medications when encountered with patients with abnormal liver functions. The health authorities need to establish strict quality check and regulations both in the production and sale of ayurvedic medications.

Risk Management for the 21st Century: Current Status and Future Needs.

Global adoption of risk management principles outlined in the International Conference on Harmonisation (ICH) E2E guideline and the Council for International Organizations of Medical Sciences (CIOMS) Working Group VI guidance introduced greater proactivity and consistency into the practice of pharmacovigilance and benefit–risk management throughout the lifecycle of a drug. However, following the release of these guidelines there have been important advances in the science and practice of risk minimisation itself, especially in terms of how risk minimisation measures (RMMs) are designed, implemented, disseminated and evaluated for effectiveness in real-world healthcare settings. In this article, we describe how the field of design, implementation, dissemination and evaluation of RMMs has advanced in recent years while highlighting current areas of challenge and possible solutions. Where possible we cite global examples to demonstrate how evidence-based approaches have informed the development of RMMs. In this context, while taking into consideration local healthcare system policies and national legislations, we conclude with a call for a global effort to harmonise certain areas that focus on, but are not limited to, standardising certain terms and definitions, consistent application of robust methodologies, and outline of best practices for risk minimisation design, implementation, and dissemination.

Comparison of laboratory threshold criteria in drug-induced liver injury detection algorithms for use in pharmacovigilance.

For the purpose of pharmacovigilance, we sought to determine the best performing laboratory threshold criteria to detect drug-induced liver injury (DILI) in the electronic medical records (EMR). We compared three commonly used liver chemistry criteria from the DILI expert working group (DEWG), DILI network (DILIN), and Council for International Organizations of Medical Sciences (CIOMS), based on hospital EMR for years 2010 and 2011 (42 176 admissions), using independent medical record review. The performance characteristics were compared in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value, accuracy, F-measure, and area under the receiver operating characteristic curve (AUROC). DEWG had the highest PPV (5.5%, 95% CI: 4.1%-7.2%), specificity (97.0%, 95% CI: 96.8%-97.2%), accuracy (96.8%, 95% CI: 96.6%-97.0%) and F-measure (0.099). CIOMS had the highest sensitivity (74.0%, 95% CI: 64.3%-82.3%) and AUROC (85.2%, 95% CI: 80.8%-89.7%). Besides the laboratory criteria, including additional keywords in the classification algorithm improved the PPV and F-measure to a maximum of 29.0% (95% CI: 22.3%-36.5%) and 0.379, respectively. More stringent criteria (DEWG and DILIN) performed better in terms of PPV, specificity, accuracy and F-measure. CIOMS performed better in terms of sensitivity. An algorithm with high sensitivity is useful in pharmacovigilance for detecting rare events and to avoid missing cases. Requiring at least two abnormal liver chemistries during hospitalization and text-word searching in the discharge summaries decreased false positives without loss in sensitivity.

Challenges and Opportunities for Clinical Pharmacogenetic Research Studies in Resource-limited Settings: Conclusions From the Council for International Organizations of Medical Sciences–Ibero-American Network of Pharmacogenetics and Pharmacogenomics Meeting

PurposeThe symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics. MethodsA total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted. FindingsThe main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common. ImplicationsThe main discussion points were gathered in the Declaration of Mérida/T'Hó and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Náhualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.

Drug induced liver damage in a universitary hospital

<strong>Background:</strong> Drug Induced Liver Injury (DILI) is responsible for wide spectrum of liver injury. Clinically, these events are presented in various forms and for reaching a different diagnosis other injury causes must be excluded. <strong>Aim:</strong> Identify and characterize cases of hepatotoxicity induced by drugs, herbal and dietary supplements in University Hospital in Brazil. <strong>Material and Methods: </strong>Observational and retrospective study. Was collected in records of University Hospital, between August 2009 at August 2014. The causality of the drug reactions suspected were evaluated Council for International Organizations of Medical Sciences (CIOMS). <strong>Results:</strong> We selected 30 suspected cases, 50% was female and average was 39 years. The therapeutic classes most common was: anti-infectives; antineoplastic agents; central nervous system drugs, anabolic steroid and herbal and dietary supplements (HDS). Cholestatic or mixed injury was observed in 73% these cases; 60% were highly probable, according to CIOMS. <strong>Conclusion:</strong> DILI is caused by a wide variety of drugs, dietary supplements and dietary supplements. Anti-infectives and chemotherapy were responsible for much of the response

Post-trial Access in Maternal Vaccine Trials.

Provisions for post-trial access (PTA) of the experimental intervention are required before the start of a clinical trial. Although there has been ample attention for PTA in the context of preventive vaccine research, discussions on PTA barely include maternal vaccine trials in which mother-infant pairs are exposed to the intervention. In maternal vaccination trials, specific PTA arrangements are required because pregnancy is transient and PTA may apply to the next pregnancy or the child. In this article, we examine the application and adherence to PTA in the context of maternal vaccine trials. We focused on differences between publications before and after 2000 when international ethical guidance documents formalized PTA requirements. Randomized maternal vaccine trials were included after a systematic search for clinical trials in phases II and III with a maternal vaccine as intervention. We used PTA as defined at the time of publication in the World Medical Association's Declaration of Helsinki (DoH) or in the ethical guidelines of the Council for International Organizations of Medical Sciences (CIOMS). In addition, we investigated whether PTA was included in the trial design. Therefore, we contacted principal investigators (PI's) of the publications found in the review to fill out a questionnaire regarding provisions for PTA. Before and after 2000, no trial articles examined in the systematic review described PTA in their trial publication (0/7, 0% and 0/17, 0%, respectively). In addition, more than half of the PI's of the trials found were not familiar with PTA recommendations in international ethical guidelines. Most cases of PTA included making knowledge available by publishing the results of the trial. The revision of the DoH in 2002 and the CIOMS ethical guidelines in 2002 has not resulted in increased PTA provisions for maternal vaccination trials. PTA is a shared responsibility of various stakeholders including sponsors, Institutional Review Boards, regulators, political entities, and researchers. Inclusion of PTA provisions in trial protocols and publications on maternal vaccination trials is essential to increase transparency on the form and content of these provisions.

A limited number of medicines pragmatic trials had potential for waived informed consent following the 2016 CIOMS ethical guidelines

ObjectivesEuropean regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe. Study Design and SettingThis is a survey of all phase 4 “ongoing” RCTs on the EU clinical trial register between July 1, 2016 and June 30, 2018, to identify those with potentially high levels of pragmatism. Trials that were excluded were as follows: those conducted on rare diseases; conducted on healthy volunteers (except those assessing vaccines); masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients, and REC members assessed the fulfillment of the CIOMS provisions as “yes,” “not sure” or “no.” ResultsOf the 638 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials. ConclusionsWe found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials.

The complex ethical landscape of biobanking

The complex ethical landscape of biobanking

Assessment of cholestasis in drug-induced liver injury by different methods.

Cholestasis in drug-induced liver injury (DILI) can be assessed by biochemical and pathologic methods, but the agreement between the 2 methods remains unclear.The aim of this study was to identify the accurate method for assessment of cholestasis in DILI.The DILI standard established and revised by the Council for International Organizations of Medical Sciences (CIOMS) (R values were calculated by liver function at different time points), cholestatic liver disease guideline (European Association for the Study of the Liver, EASL), and liver pathology were used to assess, compare, and analyze the cholestasis in 133 patients with DILI.The R values at different time points in CIOMS standard had no statistical difference for the assessment of cholestatic DILI (a = 0.05, χ2 = 1.51, P = .679). There were statistical differences among the results of CIOMS, EASL, and pathology (a = 0.05, χ2 = 99.97, P < .001). EASL standard had no statistical difference with pathology (a = 0.003, χ2 = 8.00, P = .005).CIOMS and EASL standards based on biochemical parameters underestimated cholestatic DILI, as compared to liver pathology.